Neurobiology of Consummatory Behavior:
Mechanisms Underlying Overeating and Drug Use
Jessica R. Barson, Irene Morganstern, and Sarah F. Leibowitz
Abstract
Introduction
Consummatory behavior is driven by both caloric and emotional need, and a wide variety of animal models have been
useful in research on the systems that drive consumption of
food and drugs. Models have included selective breeding for
a specific trait, manipulation of gene expression, forced or
voluntary exposure to a substance, and identification of
biomarkers that predict which animals are prone to overconsuming specific substances. This research has elucidated
numerous brain areas and neurochemicals that drive consummatory behavior. Although energy homeostasis is primarily mediated by the hypothalamus, reinforcement is
more strongly mediated by nuclei outside the hypothalamus, in mesocorticolimbic regions. Orexigenic neurochemicals that control food intake can provide a general signal
for promoting caloric intake or a more specific signal for
stimulating consumption of a particular macronutrient,
fat, carbohydrate, or protein. The neurochemicals involved
in controlling fat ingestion—galanin, enkephalin, orexin,
melanin-concentrating hormone, and the endocannabinoids—
show positive feedback with this macronutrient, as these
peptides both increase fat intake and are further stimulated
by its intake. This positive association offers some explanation for why foods high in fat are so often overconsumed.
Consumption of ethanol, a drug of abuse that also contains
calories, is similarly driven by the neurochemical systems
involved in fat intake, according to evidence that closely relates fat and ethanol consumption. Further understanding of
the systems involved in consummatory behavior will enable
the development of effective therapies for the treatment of
both overeating and drug abuse.
ince the 1980s, the prevalence of obesity in the United
States has more than doubled—from 14% to 31%
(Carroll et al. 2008; Flegal et al. 2002). Scientists and
medical providers have attributed this staggering change to
the combination of sedentary behavior and unhealthy diet,
including, specifically, an increase in both fat and carbohydrate intake (Wright et al. 2004).
Food intake is driven not only by caloric need but also by
emotional need, particularly the desire for reward. This drive
made sense evolutionarily as the most palatable and rewarding foods tend to be the most calorically dense, allowing for
energy storage in an environment where food supply is uncertain. The reward obtained by eating these foods increases
the likelihood that they will be consumed again. Whereas
historically this reward system was effectively balanced by
limited exposure, calorically dense foods are now readily
available and hence overconsumed.
Neurochemical signaling that controls caloric intake
may be categorized as orexigenic or anorexigenic, and
overconsumption can be due to excessive orexigenic signaling or insufficient anorexigenic signaling. Notably, just
as certain neurochemicals appear to stimulate the consumption of specific foods, they may also stimulate the consumption of specific drugs in certain environments, with
their roles possibly changing as the consumer progresses
from casual use to addiction.
In this review we discuss neurobiological mechanisms that
control food intake, particularly the excessive consumption of
foods rich in fat or carbohydrates, and how these systems may
be coopted to control the consumption of drugs of abuse. The
review is not intended to be exhaustive but rather to cover what
we consider the most important facts for understanding how
chemical systems in the brain can drive overeating or drug
abuse. To this end, we focus specifically on orexigenic peptides, although many anorexigenic peptides also play an important role in these processes. We examine alcohol as our
example of a drug of abuse, keeping in mind that findings with
alcohol may not always generalize to other drugs.
We begin with a brief explanation of the animal models
used to obtain this information, and then describe a number
of brain regions involved in food and drug intake. Next we
discuss food intake regulation. Finally, we examine how a
number of neurochemicals may also regulate alcohol intake.
Key Words: ethanol; fat; hypothalamus; mesocorticolimbic;
orexigenic; peptide; rodent model
Jessica R. Barson, PhD, is a postdoctoral fellow; Irene Morganstern, PhD,
is a postdoctoral associate; and Sarah F. Leibowitz, PhD, is a research associate professor, all in the Laboratory of Behavioral Neurobiology at The
Rockefeller University in New York, New York.
Address correspondence and reprint requests to Dr. Sarah F. Leibowitz,
Laboratory of Behavioral Neurobiology, The Rockefeller University, New
York, New York 10065 or email [email protected].
Volume 53, Number 1
2012
S
35
Animal Models of Consummatory
Behavior
Animal models are useful for examining the neurobiological
mechanisms that mediate consummatory behavior. These
models most often involve the use of rats or mice that prefer
palatable, high-energy diets or ethanol solution and have been
selectively bred, genetically altered, or trained over time to
consume these substances. Each model has unique advantages as well as disadvantages, depending on the question(s)
under investigation. The main difference between models
used to study palatable diet and ethanol consumption is that
outbred animals, which are easily trained to consume a palatable diet, do not consume large amounts of ethanol. Therefore
the more popular models used in ethanol research require the
occurrence of some form of natural or genetic selection. In
this section we introduce some of the rodent models used in
studies (described in later sections) that examine the involvement of hypothalamic and mesocorticolimbic neurochemical
systems in controlling the consumption of food and ethanol.
Natural Preference/Selective Breeding
Inherent behavioral traits observed in mice and the selective
breeding of both mice and rats have yielded a number of
popular models of both palatable food and ethanol overconsumption. These models mostly stem from a serendipitous
discovery in which certain animals from a particular line or
strain show distinct behavioral patterns, such as enhanced
food or ethanol preference or consumption, and are either
directly used or bred for multiple generations until a stable
and recurring phenotype is established.
Selective breeding has yielded several important models
of palatable diet overconsumption. For example, Brattleboro
rats, originally bred from a diabetic rat line, show a high
preference for a lipid diet, consuming fat as 45% of their
daily caloric intake when given a choice of three macronutrients (Laycock 1976; Odorizzi et al. 1999). Subjects bred
from Sprague-Dawley (SD) rats show a high or low preference for a saccharin solution and are addiction-prone and
addiction-resistant, respectively (Carroll et al. 2008). Other
models, which are more often used in obesity research and
show an increased affinity for dietary fat, include dietinduced obese rats, which are derived from SD rats and consume 25% more high-energy diet compared with diet-resistant
rats (Levin et al. 1997), and Zucker obese (fa/fa) rats, which
consume 45% more standard chow than their lean counterparts (Cleary et al. 1980; Zucker and Zucker 1961).
With regard to ethanol consumption, the preferring
C57BL/6J and the avoiding DBA/2J mice are the best characterized and perhaps the most commonly used models of
high versus low ethanol consumption and preference (Belknap
et al. 1997; Short et al. 2006). The C57BL/6J mice have a
natural preference for ethanol, and investigations in these
animals have significantly advanced understanding of the
genetics of alcoholism.
36
Several well-established rat lines are also used to study
ethanol drinking behavior. Most investigations on the neurochemical and behavioral mechanisms of ethanol consumption have involved selectively bred rats such as the
alcohol-preferring (P) and nonpreferring (NP) lines originally
bred by researchers at Indiana University from Wistar rats
(Li et al. 1993). Other rat lines that have been successfully
used to study ethanol drinking behavior are the ALKO alcohol (AA) and nonalcohol (ANA) rats derived from various
rat lines (Sommer et al. 2006), the high and low alcoholdrinking (HAD and LAD, respectively) rats (Li et al. 1993),
and the Sardinian preferring (sP) and nonpreferring (sNP)
rats (Colombo 1997). Generally, after ethanol training, the
preferring rats consume between 4 and 8 g/kg of ethanol per
day, resulting in blood ethanol content (BEC1) ranging from
20 to 200 mg% (Bell et al. 2006; Li et al. 1993; Middaugh
et al. 2003), which is associated with legal intoxication in
humans. Upon withdrawal, preferring rats trained in an ethanol choice paradigm and C57/BJ6 mice trained on an ethanol-containing liquid diet show slight signs of dependence
(Rabin et al. 1980; Waller et al. 1982).
Collectively, these rodent models are important for investigating the brain neurochemical systems involved in the
overconsumption of various nutrients and ethanol, as well as
the accompanying behaviors that may contribute to such abnormal patterns of consumption, as we discuss below.
Transgenes
Aside from selectively breeding animals, investigators can
genetically manipulate mice to lack or overexpress a particular gene and can even site-specifically induce the mutation in
particular tissues or brain regions. Such models enhance understanding of the function of a known gene or corresponding protein of interest in various behaviors, including those
related to food and ethanol consumption.
Transgenic animals used in the study of consummatory
behavior often show similar patterns of consumption when
given access to a palatable diet or ethanol solution. In studies
of fat consumption, these models focus on manipulating
peptide systems that control energy balance via the hypothalamus, as discussed in detail in subsequent sections.
For ethanol studies, one popular transgenic model is the
dopamine D2 receptor knockout mouse, which shows reduced ethanol reward as well as ethanol self-administration
(Cunningham et al. 2000; Phillips et al. 1998). Models used
to investigate both fat and ethanol consumption include mice
that lack or overexpress the galanin (GAL1) gene, which is
that appear ≥3x throughout this article: AgRP, agouti-related
protein; AMY, amygdala; ARC, arcuate nucleus; BEC, blood ethanol content;
CeA, central nucleus of the amygdala; DA, dopamine; ENK, enkephalin;
GABA, ␥-aminobutyric acid; GAL, galanin; GHRF, growth hormone–
releasing factor; GLUT, glutamate; LH, lateral hypothalamus; MCH, melaninconcentrating hormone; mPFC, medial prefrontal cortex; mRNA, messenger
RNA; NAc, nucleus accumbens; NPY, neuropeptide Y; OX, orexin; PFLH,
perifornical lateral hypothalamus; PVN, paraventricular nucleus of the
hypothalamus; VTA, ventral tegmental area; WT, wild-type
1Abbreviations
ILAR Journal
closely related to fat ingestion and energy balance in addition to ethanol consumption as described below. Mice lacking the mu opioid receptor (MOR), which is known to
mediate the hedonic aspects of food and drug consumption
(Pecina and Berridge 2005; Zhang and Kelley 2002), show
reduced reinforcement from sucrose and chow (Papaleo
et al. 2007) and consume less ethanol solution compared
with their wild-type (WT1) counterparts (Becker et al. 2002).
These models have gained increasing recognition in the
field of consummatory behavior, as it is now understood that
the genes involved in the consumption of one substance
(e.g., fat) may also function in controlling the consumption
of other substances (e.g., ethanol).
Forced Exposure
Most studies investigating the effects of fat on various behavioral or neurochemical parameters supply a palatable diet
as the only source of calories (Chang et al. 2007b, 2010b),
because animals strongly prefer a diet rich in fat and/or sucrose over a standard chow diet. This approach facilitates the
exact monitoring of how many calories an animal consumes
and how many of them come from fat. The experimenter can
also manipulate the source of fat (Dziedzic et al. 2007; Wang
et al. 2002) and examine the neurobiological consequences
of various fatty acids. Other studies have exposed rats to fat
via a lipid emulsion injected into the peritoneal cavity or via
intubation with a feeding needle (Carrillo et al. 2004; Liu
et al. 2004a). Such a procedure is most often used to study
the acute effects of dietary fat and under conditions that require tight control over the number of calories provided.
In studies with ethanol, investigators use several methods that involve forced consumption to reach steady and
pharmacologically relevant BEC values. The simplest such
paradigms are intubation of ethanol with a feeding needle or
injection of ethanol into the peritoneal cavity. These methods, usually performed in rats, enable experimenters to
control the amount of ethanol and length of exposure, as described in studies examining ethanol’s acute or chronic regulation of certain neurochemical systems (Morganstern et al.
2010a,b). Rats can also be compelled to consume ethanol as
part of a liquid diet that usually contains 36% of total calories from ethanol. Over several weeks, animals consume
about 13 g/kg of ethanol each day, with BEC values ranging
from 20 to 240 mg% depending on the time of measurement
(Lumeng and Li 1986). In a similar manner but with chow
also available, ethanol intake in rats can be forced by supplying it as the only source of liquid in varying concentrations
that range from 3% to 30% (Lograno et al. 1993; Lucchi
et al. 1988; Pietzak et al. 1988; Schramm-Sapyta et al. 2008).
This method is often used to examine the long-term consequences of ethanol drinking on various behavioral or neurochemical measures.
Forced consumption can also serve as a useful technique
to elicit later free-choice ethanol intake. In an early study,
rats forced to consume a 20% ethanol solution intermittently
Volume 53, Number 1
2012
(every other day) for 30 days continued to consume more
ethanol and showed a slight preference for ethanol when
switched to a free-choice paradigm with water also available (Wise 1973). This model, which has been used repeatedly and improved upon in alcohol research, has led to a
new model of ethanol dependence. The new model, which
uses chronic intermittent alcohol vapor exposure for 10 weeks
(95% ethanol evaporated and delivered at 22–27 mg/mL
for 14 hours), results in BECs of 150–200 mg% and leads
to increased ethanol self-administration after withdrawal
from the vapor chambers (Gilpin et al. 2008b; O’Dell et al.
2004). Although technically challenging, the model elicits
clear signs of physical and psychological dependence
(Gilpin et al. 2008b), suggesting that it may be a very useful
tool with which to examine the neurochemical mechanisms
of ethanol dependence.
Restricted Access
An additional paradigm used to induce binge-type behavior
with palatable diets is the restricted or intermittent access
model. Because rodents exhibit a natural preference for
sugar, presentation of a sucrose solution for 12 hours per day
can lead to binge-type behavior as well as sugar dependence
in experimental rats (Avena et al. 2005; Colantuoni et al.
2002). In a similar paradigm but with vegetable shortening
available for 2 hours per day, rats show very distinct binge
eating and consume in 2 hours as many calories as they
would normally eat over 24 hours with ad libitum access
(Corwin 2004; Corwin and Wojnicki 2006). Others, who
have reported similar binge eating with 2-hour access to a
sweet fat–rich diet (Berner et al. 2008) or 3-hour access to
the chocolate-flavored nutrition drink Ensure (Kelley et al.
2003), have noted significant changes in various neurochemical systems as a result of such excess consumption. These
studies underscore the utility of such a model in identifying
the pathways that may be disturbed and contribute to binge
eating of palatable diets rich in sugar and/or fat.
The restricted access paradigm can also be applied to
ethanol, where it leads to a binge-type consumption pattern
that resembles the clinical condition of binge drinking. One
specific example of this model involves intermittent access
to an escalating concentration of ethanol (2%, 4%, 7%, 9%)
during the animals’ 12-hour dark period, which leads to
greater intake values (2.5 g/kg/day) and BEC levels (39 mg/
dL) compared to rats with 24-hour access to a similar concentration of ethanol (Avena et al. 2004; Carrillo et al. 2004;
Chang et al. 2007a). Shorter periods of access are needed,
however, to increase intake to levels that cause binge-type
behavior. With a 30-minute access paradigm, C57BL/6J
mice have been shown to consume approximately 2 to 2.5
g/kg of ethanol, which significantly elevates BEC levels and
produces motor impairments (Cronise et al. 2005). Even
greater ethanol consumption is obtained in this mouse strain
with limited access to ethanol (20%) for 4 hours each day,
starting 3 hours into the dark cycle. This model, known as
37
“drinking in the dark” (DID), can drive mice to consume as
much as 7 g/kg of ethanol in the 4-hour access period
(Hendrickson et al. 2009; Rhodes et al. 2005).
Overall, these studies suggest that animals will overconsume ethanol when it is presented during scheduled sessions,
and this model can be helpful for examining mechanisms of
binge-drinking behavior, which is characterized by intermittent excessive consumption.
Voluntary Access
Perhaps the most natural model used to examine consummatory behavior in rodents involves their voluntary access to
nutrients or drugs such as ethanol. Although the intake levels
using this method are considerably lower than those obtained with forced or restricted access, voluntary consumption presents a useful model for investigating natural patterns
of consumption and their underlying neurochemical or behavioral mechanisms. This method has been used to understand the consumption of diets with varying levels of either
fats or proteins (Kim et al. 1991), various sources of fats
(Nakashima 2008; Orosco et al. 2002), and different fatty
acid composition (Rice et al. 2000).
Voluntary access presents a particular challenge with
ethanol, however, as rodents often avoid it because of its bitter taste. One popular technique used to elicit voluntary
drinking, “sucrose fading,” involves initially mixing ethanol
with sucrose for training purposes and then slowly reducing
the sucrose concentration until animals show stable drinking
(Samson 1986). Another technique is to start animals on a
very low ethanol concentration and then slowly increase it
every few days until the desired concentration is reached
(Karatayev et al. 2010a; Morganstern et al. 2010a; Sandbak
and Murison 1996). Both of these methods give the animal a
choice between an ethanol solution and water. Similar paradigms are used in feeding studies, with animals given a daily
choice among several diets composed of varying macronutrients, such as fat, carbohydrate, or protein (Jean et al. 2002;
Shor-Posner et al. 1994).
These voluntary access paradigms have enabled scientists
to examine common behaviors and neurochemical systems
regulating the natural choice of one substance over another.
Prediction Models
“Prediction” models are used to assess the innate characteristics of outbred animals that will go on to consume higher
amounts of food or ethanol. These models have provided information about various behavioral or biological markers, making
it possible to predict a phenotype before significant substance
exposure and also to identify neurochemical changes that may
be causally related to an overconsumption phenotype rather
than a consequence of the substance exposure.
For palatable foods, initial intake of or natural preference
for fat when first introduced to rats is positively related to
changes in caloric intake, weight gain, and body fat accrual
38
that occur weeks or months later (Chang et al. 2010b;
Morganstern et al. 2010c; Shor-Posner et al. 1994). Furthermore, single measures of locomotor activity and of circulating triglyceride levels after a fat-rich meal are closely related
to and even predict caloric intake of chronically available
high-fat diet in SD rats (Karatayev et al. 2009b; Morganstern
et al. 2010c). Most interesting is the finding that these measures of activity and triglycerides predict long-term patterns
of ethanol drinking and lever pressing for ethanol (Karatayev
et al. 2010a; Nadal et al. 2002), and the consumption of a
sweet saccharin solution or a low 2% ethanol solution for
just a few days can similarly predict long-term patterns of
ethanol self-administration (Karatayev et al. 2010a; Koros
et al. 1998). Conversely, alcohol-preferring P rats and several other rat lines and mouse strains (e.g., C57/BL) also
show a strong preference for sweet taste (Overstreet et al. 1993;
Sinclair et al. 1992), suggesting that sweet preference not only
predicts ethanol intake but may also share common neurobiological mechanisms with the drive to consume this substance.
By identifying predictive factors, researchers can better
understand what brain or behavioral abnormalities exist before substance exposure and may be involved in driving an
animal to consume excess fat or ethanol.
Neural Circuitry Involved in
Consummatory Behavior
Food and ethanol consumption not only provide energy and
nutrition but also are rewarding. Energy homeostasis, the process of maintaining energy balance, is primarily mediated by
nuclei in the hypothalamus, whereas emotion and reinforcement are more strongly mediated by nuclei outside the hypothalamus, in mesocorticolimbic regions. Figure 1 provides
an overview of the principal nuclei involved in consummatory behavior and the connections between them, along with
some of the neurochemicals produced in each of these nuclei. We provide details in this and subsequent sections.
Hypothalamic Areas
Arcuate Nucleus
The arcuate nucleus (ARC1) contains “first-order” neurons involved in feeding: those that transcribe neuropeptide Y (NPY1)
and agouti-related protein (AgRP1), two orexigenic peptides
that are largely coexpressed, and growth hormone–releasing
factor (GHRF1) and ghrelin. All of these peptide-expressing
neurons, which lie adjacent to the median eminence and lack
protection by the blood brain barrier, detect changes in peripheral signals, such as glucose and lipids. Thus, cells of the ARC
recognize alterations in homeostatic parameters and transmit
their information to “second-order” neurons in more dorsal regions of the hypothalamus, such as the paraventricular nucleus
(PVN1) (Legradi and Lechan 1998) and perifornical lateral
hypothalamus (PFLH1) (Beaulieu et al. 1996). The ARC
neurons also send projections outside the hypothalamus to
ILAR Journal
Figure 1 Schematic representation of neural connections and neurochemical content of some principal nuclei that promote consummatory
behavior. AgRP, agouti-related protein; AMY, amygdala; ARC, arcuate nucleus; DA, dopamine; ENK, enkephalin; GABA, ␥-aminobutyric
acid; GAL, galanin; GHRF, growth hormone–releasing factor; GLUT, glutamate; MCH, melanin-concentrating hormone; ME, median
eminence; NAc, nucleus accumbens; NPY, neuropeptide Y; OX, orexin; PFC, prefrontal cortex; PFLH, perifornical lateral hypothalamus;
PVN, paraventricular nucleus of the hypothalamus; VTA, ventral tegmental area
emotion-regulating areas such as the amygdala (AMY1) and
arousal-regulating areas such as the midline thalamic nuclei
(Kampe et al. 2009), and these two areas in turn send feedback
to the ARC (Magoul et al. 1993) to modulate the central appetite signaling.
Paraventricular Nucleus
Second-order neurons in the PVN include those that transcribe
the orexigenic peptides, GAL and enkephalin (ENK1). Like the
ARC, this region is involved in maintaining energy balance,
but it also plays a role in reward functions. In addition to major
input from the ARC, the PVN receives projections from the
PFLH and extrahypothalamic areas such as the AMY and thalamus (Csaki et al. 2000). The efferent projections of the PVN
remain predominantly in the hypothalamus, including the ARC
(Magoul et al. 1993) and PFLH (Barone et al. 1981), although
some PVN neurons send output to the ventral tegmental area
(VTA1) (Rodaros et al. 2007), a mesocorticolimbic structure.
Perifornical Lateral Hypothalamus
Another hypothalamic nucleus with second-order neurons is
the PFLH, which contains the peptides orexin (OX1), also
Volume 53, Number 1
2012
known as hypocretin, and melanin-concentrating hormone
(MCH1), which are transcribed almost exclusively within
this nucleus. The PFLH has large reciprocal connections
with mesocorticolimbic nuclei that provide an interface between the homeostatic and reward systems of the brain. In
addition to afferents from the ARC and PVN, the PFLH
receives input from and sends efferent projections to the
VTA, AMY, nucleus accumbens (NAc1), and medial prefrontal cortex (mPFC1) (Barone et al. 1981; Cheng et al.
2003; Kita and Oomura 1981; Phillipson and Griffiths 1985;
Silverman et al. 1981).
Extrahypothalamic Areas
Ventral Tegmental Area
Outside the hypothalamus, the VTA is a major source of the
reinforcement-regulating neurotransmitter dopamine (DA1)
(Dahlstrom and Fuxe 1964) and also contains ␥-aminobutyric
acid (GABA1) interneurons and projection neurons (Van
Bockstaele and Pickel 1995). This nucleus receives a number of inputs from hypothalamic and extrahypothalamic regions, including the PVN (Rodaros et al. 2007), PFLH
39
(Fadel and Deutch 2002), NAc (Kalivas et al. 1993), AMY
(Wallace et al. 1992), and mPFC (Sesack and Pickel 1992).
In turn, it predominantly sends DA-containing projections
back to the majority of these regions (Barone et al. 1981;
Oades and Halliday 1987; Swanson 1982) to provide signals
related to motivated behavior.
signals, which initiate or prolong eating. Whereas some of
these neurochemicals may provide a general signal for promoting caloric intake, there are others, particularly in the hypothalamus, that provide a more specific signal for stimulating
consumption of a particular macronutrient: fat, carbohydrate,
or protein. Figure 1 provides an overview of the different
areas where these neurochemicals are transcribed.
Nucleus Accumbens
The NAc processes reward signals from ingested food and
drugs and programs action and motivation to obtain food and
drugs. It receives major OX and MCH projections from the
PFLH (Fadel and Deutch 2002; Georgescu et al. 2005), DA
from the VTA (Swanson 1982), and glutamate (GLUT1)
from the AMY and mPFC (Christie et al. 1985; Kelley et al.
1982), and sends output projections back to these regions
(Barone et al. 1981; Kalivas et al. 1993; Kim et al. 2004).
While the medium spiny output neurons of the NAc all contain GABA, specific efferents also colocalize with orexigenic peptides such as ENK (Meredith 1999).
Amygdala
The AMY plays a major role in processing emotion, particularly anxiety, as well as associative conditioning for pairing
food and drug reward with action required to obtain the substance. Like the NAc, the AMY receives OX from the PFLH
(Baldo et al. 2003), DA from the VTA (Oades and Halliday
1987), and GLUT from the mPFC (McDonald et al. 1996).
It then sends GABA or GLUT outputs to the PVN (Csaki
et al. 2000), PFLH (Barone et al. 1981), VTA (Wallace et al.
1992), NAc (Phillipson and Griffiths 1985), and mPFC
(Bacon et al. 1996).
Prefrontal Cortex
The prefrontal cortex (PFC), particularly the mPFC, is responsible for processes of executive function, including attention and decision making needed to obtain food or drugs.
In addition to major inputs from the VTA, which largely contain DA (Swanson 1982), the mPFC receives afferents from
the hypothalamus and AMY (Hoover and Vertes 2007). It
then sends GLUT efferents back to the VTA (Sesack and
Pickel 1992), NAc (Phillipson and Griffiths 1985), PFLH
(Kita and Oomura 1981), and AMY (Brinley-Reed et al.
1995) to inhibit behaviors inappropriate for goal-directed action such as obtaining food or drugs.
Neurochemicals Involved in Food and
Macronutrient Intake
The regulation of food intake is coordinated by a large
array of neurochemicals throughout the brain. Although anorexigenic signals that inhibit feeding behavior can be disturbed and lead to overeating, our focus here is on orexigenic
40
Stimulation of Food Intake
The neurotransmitters DA, GABA, and GLUT, which are
produced and released in multiple nuclei of the brain, appear
to provide general signals to modulate food intake. A brief
description of each signaling process appears below.
Dopamine
The role of the catecholamine neurotransmitter DA in overeating depends on the area of the brain examined. Injection
of low doses of DA or dopaminergic agonists in the NAc can
increase food intake (Evans and Vaccarino 1986), whereas in
the hypothalamus DA decreases feeding (Yang et al. 1997).
The orexigenic effects of DA injections have been shown for
both fat (Rao et al. 2008a) and carbohydrates, particularly
sucrose (Hodge et al. 1994). Levels of endogenous DA are
also higher in the NAc after consumption of fat or sugar
(Hajnal et al. 2004; Rada et al. 2010). These two pieces of
evidence together suggest that an increase in DA may drive
excessive intake of foods high in fat and carbohydrates.
Other evidence indicates that low basal levels of DA in
mesocorticolimbic regions may drive intake of these rewarding foods. Rats prone to overeating and becoming obese on
a fat-rich diet exhibit reduced levels and evoked release of
DA in both the NAc and mPFC (Geiger et al. 2008; Rada
et al. 2010), and mice lacking the DA receptors D2 or D3, and
hence having reduced DA function, consume more calories
than WT mice with intact DA systems (Garcia-Tornadu et al.
2009, 2010; McQuade et al. 2004).
Clinical studies also support the role of low DA in driving food intake, as antipsychotic medications that block dopaminergic activity cause patients to overeat and become
obese (Blouin et al. 2008; Kluge et al. 2007). Although this
pharmacological effect could also occur through the blockade of serotonin or histamine receptors (Theisen et al. 2007;
Ujike et al. 2008), the involvement of D2 receptors is supported by evidence that humans with specific variant alleles
for these receptors exhibit greater weight gain on antipsychotic medication (Hong et al. 2010; Muller et al. 2010).
Furthermore, other studies of humans with alleles for the D2
receptor and the DA transporter show a positive correlation
with overeating and binge eating of foods high in fat and
sucrose (Eny et al. 2009; Shinohara et al. 2004). Thus it is
possible that subjects with low endogenous DA in the NAc
compensate by overconsuming fat or carbohydrates to raise
their DA levels to sufficiently high levels to be rewarding.
ILAR Journal
GABA
The inhibitory amino acid neurotransmitter GABA may
drive eating behavior through actions in the PVN and NAc,
although it does not show a close association with any particular macronutrient.
Injection of GABA agonists into the PVN or NAc causes
rats to increase their intake of standard laboratory chow
(Stratford and Kelley 1997; Tsujii and Bray 1991), whereas
injection into the AMY or lateral hypothalamus (LH1) decreases intake (Minano et al. 1992; Turenius et al. 2009).
When the diets are chronically available, peripheral injection
of GABA increases consumption of fat but not sucrose
(Berner et al. 2009), and injection directly into the NAc can
stimulate intake of sucrose (Stratford and Wirtshafter 2010).
However, when a fat-rich diet is available for only a brief
period of 1 to 2 hours a day, binge eating of this diet is suppressed by peripheral GABA administration (Berner et al.
2009; Wojnicki et al. 2006), suggesting that GABA functions
differently in binge eating than it does in general eating.
Studies also show that GABA levels increase in the hypothalamus in response to food intake and that this effect occurs with fat and carbohydrate as well as protein (Fisler et al.
1989; White et al. 2003; Zhu et al. 2010), indicating that this
neurotransmitter may not be associated with any specific
macronutrient. Studies in humans also support a role for
GABA in overeating, with specific variant alleles of GAD2,
a gene responsible for GABA production, linked with disinhibited eating and increased concentration of lipids or carbohydrates in the diet (Boutin et al. 2003; Choquette et al. 2009).
Glutamate
The excitatory amino acid neurotransmitter GLUT plays an
opposite role to GABA in many cases, acting through the LH
(rather than the PVN) to nonspecifically drive food intake.
Although agonists of GLUT stimulate food intake when
injected into the LH (Stanley et al. 1993), they reduce it
when injected in the NAc (Stratford et al. 1998). Also in the
NAc, GLUT agonists decrease sucrose intake (Stratford et al.
1998) but increase fat intake (Will et al. 2006), confirming that
these effects, as with GABA, are not macronutrient specific.
In the LH, where GLUT injection stimulates feeding,
this amino acid may show a positive feedback association
with food consumption, as GLUT release in this region is
stimulated by the ingestion of fat, carbohydrate, and protein
(Thongkhao-on et al. 2008; White et al. 2003). Similarly, although GLUT in the NAc suppresses food intake, consumption of a sweet/fat diet reduces endogenous GLUT release in
this region (Saulskaya and Mikhailova 2002), which would
disinhibit further intake of rewarding foods. Mice with low
GLUT function, due to deletion of the metabotropic GLUT
receptor 5 subtype, consume less chow than their WT littermates (Bradbury et al. 2005), supporting the idea that high
GLUT function in certain brain areas can drive food intake.
As with GABA, GLUT can clearly promote overconsumption, through region- but not macronutrient-specific effects.
Volume 53, Number 1
2012
Stimulation of Fat Intake
Unlike carbohydrate or protein intake, which is more tightly
regulated through negative feedback systems, the intake of
fat shows additional elements of positive feedback, with the
ingestion of a fat-rich food source often stimulating the desire for more fat. In both human and rodent studies, preloads
containing fat result in larger subsequent meals and shorter
latencies to those meals compared to preloads with carbohydrate or protein (Marmonier et al. 2000; Warwick et al.
2003). Fat intake also results in greater orexigenic and less
anorexigenic signaling in both the circulation and the brain
(Beck et al. 1990; Sanchez et al. 2010).
From an evolutionary point of view, this attenuated satiety from fat makes sense, as fatty foods are energy dense and
have traditionally been difficult to procure. But in today’s
developed societies, with abundant high-fat food sources,
this quality can lead to overeating and a host of attendant
health complications.
The neuropeptides GAL, ENK, OX, and MCH and the
bioactive lipids endocannabinoids, all of which are produced
in the hypothalamus, appear to have a special role in the positive feedback regulation of fat intake.
Galanin
The peptide GAL, which is widely expressed in the brain,
including in the hypothalamus, appears to show a special association with fat.
Injections of GAL in the PVN or AMY are orexigenic
and stimulate chow intake in rats maintained on a chow diet
(Kyrkouli et al. 1990). Although GAL injections do not consistently alter the preference for pure fat over carbohydrate
or protein (Smith et al. 1997; Tempel et al. 1988), the feeding response is nonetheless stronger and more prolonged in
subjects maintained on a high-fat compared with a low-fat
diet (Nagase et al. 2002). Studies with genetically modified
mice also support this association: animals that overexpress
the GAL gene consume more fat than WT mice, despite similar intake of standard chow (Hohmann et al. 2003; Karatayev
et al. 2009a); conversely, GAL knockout mice show decreased
fat intake and preference (Adams et al. 2008; Karatayev et al.
2010b).
Gene expression and peptide production of GAL in the
PVN are stimulated by consumption of dietary fat but not by
carbohydrate or protein (Akabayashi et al. 1994), demonstrating a positive association between GAL and fat intake.
Furthermore, GAL expression and levels are elevated in situations where fat intake is preferred, such as in female rats at
puberty onset and during proestrus (Leibowitz et al. 1998,
2009) and in Brattleboro rats, which have a high preference
for fat (Beck and Max 2007). Circulating levels of GAL may
reflect recent consumption of dietary fat, as obese menopausal women have higher serum levels of GAL (Milewicz
et al. 2000) and recovered anorexic women have reduced
levels in their cerebrospinal fluid (Frank et al. 2001).
41
Despite its association with fat intake, GAL may not be
responsible for the development of obesity. The only study
in humans to examine GAL alleles with regard to body weight
found no difference between obese and healthy young adults
(Schauble et al. 2005), and a study in rats found that chronic
ventricular injection of GAL does not increase body weight
(Smith et al. 1994). Thus, although it may not be responsible
for body weight per se, GAL appears to drive consumption
of diets high in fat content.
Enkephalin
The opioid peptide ENK is expressed in multiple mesocorticolimbic nuclei and, acting in the hypothalamus, is positively related to fat consumption.
Chow intake is stimulated by injection of ENK analogues in the PVN or PFLH (Stanley et al. 1988), VTA or
NAc (Mucha and Iversen 1986), central nucleus of the
amygdala (CeA1) (Gosnell 1988), and even the mPFC (Mena
and Baldo 2009). These injections have also been shown to
stimulate the intake of high-fat over high-carbohydrate diets
(Naleid et al. 2007; Zhang et al. 1998), although ENK analogues in the NAc also increase the consumption of a variety
of rewarding foods, including sucrose and even salt (Zhang
and Kelley 2002).
The expression of ENK in the hypothalamus is positively
related to fat intake (Chang et al. 2007b), but restricted access
to a sweet/fat diet reduces or has little effect on ENK expression in the NAc (Kelley et al. 2003). Like GAL, ENK expression and levels are elevated in the PVN of female rats at
puberty onset, when preference for fat increases (Leibowitz
et al. 2009), and in the PVN, NAc, and CeA of outbred rats
prone to overconsuming a high-fat diet (Chang et al. 2010b).
The possibility that ENK is responsible for driving fat intake
is supported by studies in mice that lack the ENK gene, as
these mice are less willing to work to obtain a fat pellet reward as compared with WT mice (Hayward et al. 2002).
Unfortunately, no studies in humans exist to corroborate
these rodent findings on ENK and fat.
Orexin
In addition to its well-known role in regulating sleep/wake
states (Sakurai et al. 2010), OX plays a major role in the intake of rewarding food, particularly fat.
Injection of OX into the PVN, PFLH, or NAc (but not the
CeA) stimulates chow intake (Dube et al. 1999; Thorpe and
Kotz 2005). Similarly, injection of OX adjacent to the hypothalamus, in the third ventricle, stimulates rats to consume a
high-fat diet in preference to a carbohydrate diet (Clegg et al.
2002), although it can also increase sucrose intake when that
is the only food available (Baird et al. 2009). Furthermore,
peripheral injection of OX antagonists suppresses fat but not
sucrose intake (Richards et al. 2008; White et al. 2005). These
latter effects have been observed using specific OX-1 receptor antagonists, although the recent commercial availability
42
of OX-2 antagonists will likely soon result in information
about this receptor and fat intake.
One unique property of OX is that cells expressing this
neuronally excitatory peptide are confined almost entirely to
the PFLH (de Lecea et al. 1998; Sakurai et al. 1998). Consumption of a high-fat diet compared with a moderate or
low-fat diet for up to 2 weeks stimulates expression and
levels of OX in the PFLH (Gaysinskaya et al. 2007; Wortley
et al. 2003) and rats prone to overeating fat show elevated
OX expression (Morganstern et al. 2010c), confirming the
positive association between OX and dietary fat. This effect
is site specific, occurring in the perifornical rather than the
lateral area of the PFLH (Wortley et al. 2003). In certain
circumstances, OX may also be positively related to sucrose,
as binge access to this nutrient compared with standard chow
stimulates hypothalamic OX messenger RNA (mRNA1) expression (Olszewski et al. 2009).
Some studies indicate, however, that this peptide may
actually be inversely related to weight gain. In selectively
bred obesity-prone rats OX mRNA is lower or no different
from that in obesity-resistant rats (Levin et al. 2005; Teske
et al. 2006), a finding that may have more to do with the ability of OX to increase energy expenditure than an inability to
stimulate food intake (Funato et al. 2009). It is possible that
OX ultimately stimulates intake of fatty foods by coordinating arousal with energy homeostasis (Sakurai et al. 2010).
Although OX knockout mice compared with WT mice show
little change in chow intake (Kaur et al. 2008), they are less
able to acquire the behavioral output necessary to procure
food (Akiyama et al. 2004; Sharf et al. 2010).
Together, this evidence supports a role for OX in promoting caloric intake and having a close association specifically
with a high-energy, fat-rich diet.
Melanin-Concentrating Hormone
Cells that express MCH are largely concentrated in the
PFLH (Skofitsch et al. 1985) and are thought to play a reciprocal role with OX in the sleep/wake cycle (Adamantidis and
de Lecea 2008).
Injection of MCH or an MCH agonist into the PVN or
NAc increases food intake (Georgescu et al. 2005; Rossi
et al. 1999), and injection into the cerebral ventricles stimulates intake of a high-fat diet more strongly than it does intake of standard chow (Gomori et al. 2003). This effect may
be due to a desire for rewarding foods in general, because
ventricular injection of MCH also stimulates sucrose intake
(Duncan et al. 2005).
The expression of MCH appears to be more responsive to
fat content than to general reward. Hypothalamic MCH expression and peptide levels are stimulated by the consumption of a high-fat diet but not by saccharin (Elliott et al. 2004;
Furudono et al. 2006), and are similarly elevated in the PFLH
of rats, maintained on laboratory chow, that are prone to overconsuming a high-fat diet (Morganstern et al. 2010c). Studies
using transgenic mouse strains also support the existence of a
ILAR Journal
special association between MCH and fat: although mice
lacking the MCH gene consume less chow (Shimada et al.
1998), those that overexpress MCH consume greater quantities of a high-fat diet than WT mice (Ludwig et al. 2001).
Limited studies also suggest a role for MCH in human
obesity. They report that certain populations with early-onset
obesity are more likely to carry variations of the MCH 1 receptor than normal weight controls (Gibson et al. 2004; Wermter
et al. 2005).
Collectively, these studies demonstrate a positive feedback association between MCH and the intake of fat.
Cannabinoids
The endogenously expressed endocannabinoids include
N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol (2-AG), which are present in multiple areas of
the brain, including the hypothalamus.
Injection of endocannabinoids or the cannabinoid agonist delta-9-tetrahydrocannabinol (THC) into the PVN or
NAc stimulates food intake (Mahler et al. 2007; Verty et al.
2005). Studies with peripheral injections suggest that, although cannabinoids play a role in carbohydrate intake,
they are more tightly linked with dietary fat. For example,
THC stimulates the intake of a high-fat or sweet-fat diet,
but its effects are stronger for the pure fat diet (Koch 2001),
and an antagonist decreases drinking of a lipid emulsion
more than it does a sucrose solution (Thornton-Jones et al.
2007). Levels of 2-AG and binding to the cannabinoid CB1
receptor in the hypothalamus are also increased by a highfat compared with a low-fat diet (Higuchi et al. 2011; South
and Huang 2008), while CB1 receptor expression is upregulated by sucrose intake (Lindqvist et al. 2008), suggesting
that sucrose decreases endocannabinoid levels in this brain
region. In addition, like GAL and ENK, levels of anandamide in the hypothalamus are markedly elevated in female rats immediately before puberty onset (Wenger et al.
2002), when preference for fat is highest. Studies with
knockout mice further support a strong role for endocannabinoids in controlling fat intake as well as a role in carbohydrate intake. Mice lacking the central CB1 receptor
compared with WT mice exhibit a delayed onset of preference for high-fat compared with standard chow (Ravinet
Trillou et al. 2004) and consume less of a sucrose solution
(Poncelet et al. 2003).
Studies in humans support these animal findings: specific alleles for the CB1 receptor are more common in men
and women with higher levels of body fat (Jaeger et al. 2008;
Russo et al. 2007).
Stimulation of Carbohydrate Intake
Compared with fat intake, carbohydrate intake is more
tightly regulated by negative feedback systems. Fasting leads
to the desire for carbohydrates, but its consumption more
Volume 53, Number 1
2012
readily satiates this desire (Marmonier et al. 2000; Warwick
et al. 2003). The neuropeptides NPY and AgRP, which are
both expressed and synthesized in the ARC, appear to have a
special role in the regulation of carbohydrate intake.
Neuropeptide Y
Neuropeptide Y is a highly orexigenic peptide that is produced in many areas of the brain but exerts its effects on
feeding predominantly in the hypothalamus.
Injections of NPY in the ARC, PVN, or PFLH potently
stimulate feeding but they are ineffective in the NAc or
AMY (Bouali et al. 1995; Brown et al. 2000; Stanley et al.
1985a). These hypothalamic injections lead rats to increase
carbohydrate intake in favor of fat (Brown et al. 2000;
Stanley et al. 1985b). Expression and levels of NPY in the
hypothalamus are increased by food deprivation, particularly immediately before scheduled feeding (Kalra et al.
1991; Marks et al. 1992), confirming the important role of
NPY in driving food intake.
Carbohydrates have a stimulatory effect on NPY expression, although the effect may vary depending on the time of
examination. One week of carbohydrate diet consumption
results in elevated ARC NPY expression compared with
high-fat or standard chow diets (Giraudo et al. 1994; Wang
et al. 1998). A similar increase occurs a few hours after injection of glucose, although the reverse effect is evident immediately after the injection, supporting a negative feedback
regulation of carbohydrate intake (Chang et al. 2005).
In further support of the link between NPY and food
overconsumption, outbred rats that are prone to obesity
when fed a high-energy diet have higher NPY levels than
obesity-resistant rats even when both set of rats are maintained on a chow diet (Levin 1999). Moreover, NPY knockout mice consume less chow diet and binge less on a highly
palatable diet than WT mice (Bannon et al. 2000; Sindelar
et al. 2005), whereas NPY-overexpressing mice consume
greater quantities of a sucrose diet (Kaga et al. 2001).
The role of NPY in energy balance is also supported by
research in humans, as specific alleles for NPY and the NPY
receptor Y2 have been linked to increased body mass index
(Bray et al. 2000; Lavebratt et al. 2006).
Agouti-Related Protein
The peptide AgRP is related to both carbohydrate and fat,
and its macronutrient specificity is less well defined than that
of NPY. Largely coexpressed with NPY, it is produced exclusively in the ARC and acts by blocking receptors for the
anorexigenic melanocortin peptides.
Injection of AgRP into specific regions of the hypothalamus, the PVN or dorsomedial nucleus (DMN), or the CeA
potently stimulates food intake, whereas injection into the
ARC or PFLH is ineffective (Kim et al. 2000; Wirth and
Giraudo 2000). Injection of this peptide into the DMN
43
preferentially stimulates intake of a sucrose diet (Wirth and
Giraudo 2001), while injection into the third ventricle stimulates intake of diets higher in fat content (Hagan et al.
2001).
Much like NPY, AgRP expression is increased by both
food deprivation (Palou et al. 2009) and the injection of glucose
(Chang et al. 2005); although it is suppressed immediately
after glucose administration, its mRNA expression increases
several hours later (Chang et al. 2005), indicating that, like
NPY, it shows elements of negative feedback by carbohydrate.
A general role for AgRP in overconsumption is strongly
supported by studies in mice with altered AgRP expression.
Targeted ablation of AgRP leads animals to die from starvation within 1 week (Bewick et al. 2005; Luquet et al. 2005),
and transgenic overexpression of this peptide causes animals to overeat and develop severe obesity (Graham et al.
1997; Ollmann et al. 1997).
The role of AgRP in driving overconsumption in humans
is supported by studies showing increased plasma levels of
AgRP during fasting (Shen et al. 2002) and altered macronutrient intake and body weight in populations with specific
AgRP alleles (Kalnina et al. 2009; Loos et al. 2005).
Stimulation of Protein Intake
Protein is not the macronutrient of choice for overeating because it is more satiating than fat or carbohydrate (Marmonier
et al. 2000), but two hypothalamic peptides facilitate protein
intake: GHRF and ghrelin.
Growth Hormone–Releasing Factor
The peptide GHRF, which stimulates the release of growth
hormone into the circulation, is transcribed in cells in and
around the hypothalamus (including the ARC) and shows a
positive feedback association with protein intake.
Injection of GHRF into the suprachiasmatic nucleusmedial preoptic area or ventromedial hypothalamic nucleus,
but not the PVN or PFLH, stimulates food intake (Dickson
and Vaccarino 1990; Tanaka et al. 1991) and, specifically,
intake of protein more than carbohydrate (Dickson and
Vaccarino 1994). Lateral hypothalamic injection of an antibody against GHRF suppresses consumption of protein but
not carbohydrate or fat (Rains et al. 2001), confirming the
selective role of GHRF in protein intake.
As with the regulation of fat-related peptides by dietary fat,
hypothalamic expression of GHRF is stimulated by dietary
protein but not by fat or carbohydrate (Bruno et al. 1991). In
contrast to the carbohydrate-related peptides, hypothalamic
expression of GHRF is suppressed by food deprivation (Bruno
et al. 1990; White et al. 1990). Although foods high in protein
are not typically overconsumed, studies in mice with altered
GHRF confirm the importance of this peptide in obesity. Transgenic mice that overexpress GHRF have significantly greater
amounts of abdominal fat (Cai and Hyde 1999) and knockout
mice have less than WT mice (Fintini et al. 2005).
44
One study in humans also supports a role for GHRF in
obesity, as subjects heterozygous for a GHRF receptor allele
weigh less than those homozygous for the common form of
the allele (Pereira et al. 2007). Although high levels of protein in the diet may help prevent overeating and the development of obesity, GHRF appears to promote both protein
intake and body fat accrual.
Ghrelin
Another peptide that stimulates the release of growth hormone, ghrelin, is expressed predominantly in the stomach
but is also found in a population of cells in the ARC.
Ghrelin stimulates food intake after injection in a variety
of brain areas—the PVN, PFLH, and ARC (Currie et al.
2005; Szentirmai et al. 2007) as well as the VTA, dorsal raphe nucleus, and even the hippocampus (Abizaid et al. 2006;
Carlini et al. 2004). Although this peptide shows an association with all three macronutrients, it may have a particularly
strong association with protein. Injection of ghrelin has been
demonstrated to stimulate intake of the preferred diet,
whether high or low in fat (Liu et al. 2004b), but it has also
been shown to stimulate intake of chow over sucrose (Bomberg
et al. 2007), suggesting that factors other than palatability
are important.
Ingestion of any of the three macronutrients can reduce
ghrelin peptide levels, although the most prolonged suppression occurs with protein (Koliaki et al. 2010). Unlike GHRF,
fasting potently increases plasma ghrelin levels (Bagnasco
et al. 2002), and fat-preferring rats have higher levels of
plasma ghrelin (Beck and Max 2007), demonstrating that
ghrelin shares some similarities with the fat- and carbohydraterelated peptides.
This peptide may not be as important as others in food
consumption, despite its ability to stimulate intake, as ghrelin
knockout mice show no difference from WT mice in consumption of chow or a high-fat diet (Sun et al. 2003, 2008).
Furthermore, mice that overexpress ghrelin show no difference in chow intake (Reed et al. 2008) and actually consume
less of a high-fat diet (Gardiner et al. 2010).
Studies in humans partially support the rodent work, as
injection of the carbohydrate glucose has been found to decrease plasma ghrelin levels (Shiiya et al. 2002), and ghrelin
alleles have been linked to early-onset or severe obesity
(Hinney et al. 2002; Miraglia del Giudice et al. 2004). Thus,
although ghrelin appears to have a more complex connection
with feeding, it is similar to GHRF in showing a stronger
association with protein.
Neurochemicals Involved in Ethanol Intake
The neurochemical systems involved in ethanol consumption are very similar to those that control food ingestion, particularly those related to dietary fat. Although DA, GABA,
GLUT, and ghrelin appear to play a more general role in the
regulation of food and ethanol consumption, the peptides
ILAR Journal
GAL, ENK, OX, and MCH and the bioactive lipids endocannabinoids all have a stronger and more specific association
with fat and ethanol. Furthermore, ethanol consumption
shows a weaker link with peptides related to carbohydrate or
protein consumption, such as NPY, AgRP, and GHRF.
Drawing on the discussions in the preceding section, we
describe evidence that supports the idea that ethanol and fat
intake are mediated by common neurochemical mechanisms.
Dopamine
The mesolimbic DA system, originating in the VTA and projecting to the NAc, has long been implicated in ethanol reinforcement and consumption. Acute exposure to ethanol
potently stimulates extracellular DA levels in this system,
and this stimulation is known to directly influence the rewarding aspects of ethanol consumption (Di Chiara and
Imperato 1988; Piepponen et al. 2002; Yan et al. 2005). Dopamine levels also increase in the hypothalamus after systemic exposure to ethanol (Seilicovich et al. 1985).
Levels of DA are closely associated with ethanol preference and consumption in several animal models. Like rats
prone to overeating fat, those selectively bred to prefer ethanol, but not exposed to it, exhibit reduced baseline levels of
DA in the NAc (Bustamante et al. 2008) and mPFC (Engleman
et al. 2006). However, when allowed to consume ethanol,
they show an exaggerated release of DA in these areas as well
as an increase in DA neuronal firing in the VTA (Bustamante
et al. 2008; Katner and Weiss 2001; Morzorati et al. 2010;
Tuomainen et al. 2003).
These studies, which suggest that a disruption of DA balance in mesolimbic and possibly hypothalamic regions can
lead to enhanced ethanol consumption, are further strengthened by reports demonstrating an attenuation of ethanol
intake with systemic administration (Ingman et al. 2006;
Samson and Chappell 2003) or direct VTA injection (Eiler
and June 2007; Samson and Chappell 1999) of agents that
block DA. With the evidence described above suggesting
that mesolimbic DA can also influence fat consumption (Rao
et al. 2008a; Wong et al. 2009), it is likely that dopaminergic
signaling, possibly by increasing reinforcement, may similarly drive the consumption of both ethanol and fat.
GABA
The inhibitory amino acid GABA controls ethanol consumption, particularly in mesolimbic or hypothalamic regions
where GABA influences the release of DA or the actions of
certain peptide systems, respectively.
Initial studies in rats and mice that assessed the central
effects of ethanol exposure indicated that ethanol itself might
potentiate GABAergic neurotransmission by modulating the
activity and density of GABA-benzodiazepine (BDZ) receptor sites (Ticku et al. 1983). With significant advances in alcohol research since then, the effect of ethanol on GABA
neurotransmission has been shown to be more complex than
Volume 53, Number 1
2012
originally thought and largely dependent on the route of administration or brain region of interest. Voluntary consumption of ethanol increases extracellular levels of GABA
(Szumlinski et al. 2007), whereas forced acute oral or systemic
administration has little effect (Cowen et al. 1998; Dahchour
et al. 1994; Heidbreder and De Witte 1993; Kemppainen
et al. 2010). In vivo studies with ethanol-induced GABA release in regions outside the DA mesolimbic circuit are lacking, but in vitro application of ethanol enhances GABA
release in the hypothalamus (Seilicovich et al. 1988).
Receptor changes also occur with oral ethanol intake in
preferring rats—there is a specific reduction in GABA-A␣1
subunit mRNA in the cerebral cortex (Devaud et al. 1995)
and in GABA-BDZ receptor densities in the NAc and PFC
(Thielen et al. 1997)—possibly leading to ethanol tolerance
associated with chronic ethanol exposure. Research shows
that a disruption in GABA neurotransmission promotes
ethanol consumption. For example, studies in alcoholpreferring rats have indicated that a reduction in GABA release in the VTA (Melis et al. 2009) and in GABAA receptor
expression in the NAc (Chen et al. 1998) may drive animals
to consume more ethanol.
An important role for GABA in ethanol consumption is
further supported by studies demonstrating reduced ethanol
consumption or operant responding with administration
of specific ionotropic GABAA antagonists or metabotropic
GABAB agonists that reduce GABA activity and/or release,
either centrally—into the NAc (Hodge et al. 1995), VTA
(Moore and Boehm 2009), or CeA (Foster et al. 2004)—or
systemically (Quintanilla et al. 2008; Walker and Koob
2007). Additionally, BDZ inverse agonists such as RO194603 or high-affinity antagonists such as ZK 93426 or
CGS8216 have been shown to reduce ethanol responding
in preferring rats (June et al. 1998a,b), suggesting that the
GABA-BDZ receptor complex can mediate the rewarding
effects of ethanol.
Although active blockade of GABA neurotransmission
may reduce the rewarding effects of ethanol and thereby decrease consumption preclinically, in the clinic, agents that
potentiate the actions of GABA (e.g., gabapentin) are used to
reduce the anxiety associated with abstinence from ethanol
(Brower et al. 2008; Furieri and Nakamura-Palacios 2007).
Together with findings that suggest a role for GABA in
driving consumption of fat and other nutrients, these studies
demonstrate that this inhibitory amino acid may function,
although not exclusively, to enhance consumption of both
fatty foods and ethanol.
Glutamate
The excitatory amino acid GLUT influences ethanol operant
responding and consumption by interacting directly with DA
neurons in the mesolimbic reward system.
Similar to the findings with GABA, GLUT neurotransmission is differentially affected by ethanol depending on the
route of administration. Although no changes in GLUT release
45
have been observed in the VTA with acute ethanol injection
(Kemppainen et al. 2010), GLUT neurotransmission is enhanced when ethanol is applied to isolated VTA neurons
(Deng et al. 2009). In the NAc, a dose-dependent effect has
been observed: the release of GLUT rises at a lower dose of
systemic ethanol but is reduced or unaltered at a higher dose
(Dahchour et al. 1994; Moghaddam and Bolinao 1994). Extracellular GLUT levels in the hypothalamus are also enhanced
with ethanol perfusion (Noto et al. 1984). Together, these results indicate that GLUT may mediate the effects of ethanol on
local circuits in the VTA, NAc, and hypothalamus.
A limited number of studies have examined the status of
the GLUT system in alcohol-preferring animals, but they
seem to indicate that preferring rats exposed to ethanol exhibit
enhanced expression of metabotropic GLUT receptors in the
NAc and CeA (Obara et al. 2009) and increased GLUT terminal density in the NAc shell (Zhou et al. 2006). Studies with
specific GLUT antagonists have also suggested that systemic
or local blockade of GLUT neurotransmission in the NAc
leads to a pronounced reduction in ethanol self-administration
in rats (Besheer et al. 2010; Rassnick et al. 1992).
These results are similar to the clinical outcome of increased abstinence and reduced relapse observed in alcoholics after treatment with the GLUT antagonist acamprosate
(Tempesta et al. 2000; Whitworth et al. 1996).
The fact that GLUT neurotransmission plays a significant, albeit nonspecific, role in fat ingestion suggests that the
consumption of fat and ethanol may be similarly controlled
by the signaling cascades of this excitatory amino acid.
Galanin
The peptide GAL, which is specifically involved in fat consumption, is also closely associated with ethanol drinking.
In animals trained to voluntarily consume ethanol, central injection of GAL into the third ventricle or PVN leads to
an increase in ethanol intake, which does not occur with injections of this peptide into the LH or NAc (Lewis et al.
2004; Rada et al. 2004; Schneider et al. 2007). The opposite
effect of reduced ethanol consumption is seen with injection
of the GAL antagonist M40 into the PVN or third ventricle,
further supporting an important role for this peptide in the
hypothalamus with respect to ethanol drinking behavior
(Lewis et al. 2004; Rada et al. 2004).
At the same time, the consumption of ethanol stimulates
the expression of GAL in certain hypothalamic nuclei, such
as the PVN and DMN (Leibowitz et al. 2003), and of the
GAL receptor 1 in the whole hypothalamus (Pickering et al.
2007), suggesting that ethanol itself, by enhancing GAL
neurotransmission, can further increase ethanol drinking
behavior. Although the status of GAL has not been explored
in animals that prefer ethanol, transgenic mice that lack
the gene encoding GAL show reduced ethanol consumption (Karatayev et al. 2010b), and those overexpressing this
peptide consume more ethanol compared with WT animals
(Karatayev et al. 2009a).
46
Clinical investigations corroborate the important role of
GAL in ethanol consumption, showing that mutation of the
GAL gene or a GAL receptor gene is associated with alcoholism in certain ethnic populations (Belfer et al. 2006, 2007).
Enkephalin
The opioid ENK plays a critical role in ethanol consumption
in addition to its role in controlling fat ingestion. The injection
of ENK analogues into the PVN or NAc results in enhanced ethanol drinking (Barson et al. 2009, 2010),
whereas the injection of an opioid antagonist into the PVN,
NAc, or AMY reduces such drinking (Barson et al. 2009,
2010; Heyser et al. 1999).
Ethanol alters the expression of endogenous ENK, but its
effects appear to depend on the region and length of exposure. Acute systemic administration increases ENK expression in the PVN (Chang et al. 2007a), CeA (Criado and
Morales 2000), and PFC (Mendez and Morales-Mulia 2006)
as well as the NAc (Mendez and Morales-Mulia 2006).
Whereas chronic voluntary consumption of ethanol also
stimulates ENK expression in some of these same regions
(Chang et al. 2007a; Cowen and Lawrence 2001), the effects
in the NAc vary markedly depending on the dose and route
of administration. In rats, forced administration has no effect
on ENK expression in the NAc (Lindholm et al. 2000;
Mathieu-Kia and Besson 1998), voluntary consumption of
less than 2 g/kg/day leads to an increase in expression
(Chang et al. 2010a), and consumption of 3 to 6 g/kg/day
reduces ENK expression (Cowen and Lawrence 2001; Oliva
and Manzanares 2007). In ethanol-preferring rats or mice
compared with their nonpreferring counterparts, expression
of ENK generally appears to be reduced in the hypothalamus
(Blum et al. 1987), NAc (Cowen et al. 1998; Nylander et al.
1994), AMY, and VTA (Jamensky and Gianoulakis 1999).
Although these studies strongly suggest that ENK not
only is stimulated in most brain regions by ethanol consumption but also functions to promote further drinking, animals
that lack the ENK gene do not show disturbances in ethanol
responding or preference (Hayward et al. 2004; Koenig and
Olive 2002). However, mice that lack the MOR, through
which ENK can function, do exhibit a reduction in ethanol
reinforcement (Hall et al. 2001).
Recent clinical studies support the idea that disturbances
in MOR expression may lead to abnormal patterns of ethanol
consumption, as they show a close association between a variant allele of MOR-1 and alcoholism (Nishizawa et al. 2006;
Town et al. 1999) as well as resistance to treatment with the
general opioid antagonist naltrexone (Gelernter et al. 2007).
Orexin
In addition to its effects on arousal and the consumption of
fat, the peptide OX plays an important role in ethanol
drinking. It most likely influences ethanol consumption via
hypothalamic circuits, since injection of OX into the PVN
ILAR Journal
and LH, but not the NAc, specifically enhances ethanol intake (Schneider et al. 2007). It also appears to mediate
ethanol preference, as both OX-1 and -2 receptor antagonists, when systemically delivered to rats trained to selfadminister ethanol, can significantly attenuate ethanol
preference and responding for ethanol as well as other
drugs of abuse (Lawrence et al. 2006; LeSage et al. 2010;
Moorman and Aston-Jones 2009; Shoblock et al. 2011).
The regulation of OX expression appears to depend on the
length of administration—OX mRNA is increased by acute
oral gavage of ethanol but reduced by chronic consumption
(Morganstern et al. 2010a).
Interestingly, both expression and injection studies have
revealed a functional difference between OX neurons in the
more medial areas around the fornix and those in lateral
areas of the LH: the latter, but not the former, are involved in
the consumption of ethanol and other commonly abused substances (Aston-Jones 2005; Harris and Aston-Jones 2006;
Morganstern et al. 2010a).
Clinical support is not available to support a role for OX
in ethanol drinking behavior, but studies have shown that narcoleptic patients, who have extremely low OX levels (Nishino
et al. 2000), rarely develop addiction to the drug methamphetamine, which is used in narcolepsy treatment (Guilleminault
et al. 1974; Parkes et al. 1975).
Melanin-Concentrating Hormone
The peptide MCH regulates ethanol consumption, in addition to feeding and fat ingestion, via both hypothalamic and
mesolimbic circuits.
Central injection of MCH into the third ventricle, PVN,
or NAc selectively enhances ethanol intake in rats trained to
drink ethanol in a two-bottle choice paradigm (Duncan et al.
2005; Morganstern et al. 2010b) or to press a lever for ethanol (Duncan et al. 2006). In contrast, injection into surrounding regions such as the LH or zona incerta (ZI) has no effect
(Morganstern et al. 2010b). Furthermore, an MCH antagonist has been shown to be effective in reducing ethanol selfadministration when injected systemically (Cippitelli et al.
2010), suggesting that complex neuronal networks surrounding the ventricle may limit the therapeutic effectiveness of
such antagonists.
The consumption of ethanol also alters MCH peptide
expression, depending largely on the length of exposure
and region analyzed. Although acute ethanol exposure enhances MCH mRNA expression in the LH, it reduces it in
the adjacent ZI, which is more closely related to locomotor
activity than ethanol reward (Morganstern et al. 2010b). In
contrast, chronic consumption of ethanol leads to significantly reduced levels of MCH mRNA in the entire LH and
ZI region (Morganstern et al. 2010b), much as it does with
OX in the PFLH.
The status of MCH has not yet been evaluated in alcoholpreferring animals, but one study demonstrates that mice
lacking the gene encoding the MCH receptor 1 actually
Volume 53, Number 1
2012
consume more ethanol solution than WT mice (Duncan et al.
2007). Although this finding appears at first glance to contradict a stimulatory role for MCH in ethanol consumption, the
increase in ethanol consumption in these mutant animals
may be a nonspecific result of a hyperaroused state produced
by knockout of the MCH receptor, through which MCH is
known to inhibit OX and thus arousal (Rao et al. 2008b).
To our knowledge, no studies in humans have yet
examined the role of MCH in clinical alcoholism, which
requires the availability of well-characterized and effective
MCH antagonists.
Cannabinoids
In addition to their role in fat consumption, the cannabinoids
have received recent attention in relation to ethanol consumption, with a specific role in stimulating ethanol drinking and
self-administration behaviors.
In animal studies, peripheral injections of various CB1
agonists lead to enhanced ethanol drinking or relapse to drinking (Alen et al. 2009; Colombo et al. 2002). More specifically, the reward-related VTA may be a prime locus for these
effects as the injection of a CB1 agonist into this region potently stimulates ethanol binge drinking (Linsenbardt and
Boehm 2009). On the other hand, systemically or centrally
treating alcohol-preferring animals with a CB1 antagonist
significantly reduces ethanol intake (Serra et al. 2001).
Ethanol itself has an inhibitory effect on the endogenous
cannabinoid anandamide as well as on CB1 levels. Animals
that receive an acute injection or have access to ethanol show
a marked reduction in levels of anandamide in the hypothalamus, NAc, and AMY (Ferrer et al. 2007; Rubio et al. 2007) as
well as in CB1 levels in the AMY and PFC (Rubio et al. 2009).
Other support for an important role of cannabinoids in
ethanol consumption comes from studies in transgenic mice
with a deletion in the CB1 gene. These animals show reduced
ethanol consumption and preference compared with their
WT counterparts (Lallemand and de Witte 2005; Naassila
et al. 2004; Wang et al. 2003). Furthermore, in both rat and
mouse models with a high preference for ethanol, the density
of CB1 receptors in brain regions such as the hypothalamus,
NAc, AMY, and PFC is lower, suggesting that the animals
may have enhanced endogenous cannabinoid levels in brain
regions associated with consummatory behavior, reward,
anxiety, and cognition (Hansson et al. 2007; Hungund and
Basavarajappa 2000; Ortiz et al. 2004).
Clinical studies support the involvement of cannabinoids
in alcoholism, with the identification of a mutant CB1 allele
in alcoholics undergoing severe withdrawal or in patients
who show high brain activation from alcohol use (Hutchison
et al. 2008; Schmidt et al. 2002).
Neuropeptide Y
Neuropeptide Y, which has a specific function in stimulating
carbohydrate consumption, also plays a role in ethanol intake.
But in contrast to the neurochemicals positively related to fat
47
intake, NPY appears to be inversely related to the consumption of ethanol.
In alcohol-preferring rats, injection of NPY into the third
ventricle, PVN, or CeA significantly reduces ethanol intake
(Badia-Elder et al. 2001; Gilpin et al. 2008a; Lucas and
McMillen 2004), whereas injections into similar brain regions of nonpreferring animals have little effect on drinking
behavior (Badia-Elder et al. 2001; Katner and Weiss 2001;
Lucas and McMillen 2004). Paradoxically, central injection
of specific NPY antagonists similarly reduces ethanol intake, suggesting that this peptide’s regulation of ethanol
consumption is more complex than originally believed
(Schroeder et al. 2003; Sparta et al. 2004).
Ethanol ingestion itself can affect NPY expression, with
studies showing that both acute and chronic intake of ethanol
reduces the mRNA and peptide levels of NPY specifically in
the ARC (Kinoshita et al. 2000; Leibowitz et al. 2003; Roy
and Pandey 2002). Studies with mutant mice further support
the inhibitory role of this peptide in ethanol consumption:
mice lacking the NPY gene showed enhanced drinking behavior, and those overexpressing it reduced intake (Thiele
et al. 1998). The NPY Y1 receptor may be specifically involved in such behaviors, inasmuch as deletion of the gene
encoding this receptor yields a high ethanol–consuming
phenotype (Thiele et al. 2002). However, deletion of the
NPY Y2 gene has the opposite effect and results in reduced
drinking, suggesting opposite regulation of ethanol ingestion
by these two NPY receptor subtypes (Thiele et al. 2004).
The literature on NPY expression in alcohol-preferring
animals is mixed and largely depends on the line of rats
used as well as their access to ethanol. When ethanol is
available, NPY immunoreactivity in various hypothalamic
regions is greater in alcohol-preferring P rats compared with
control alcohol-nonpreferring (NP) rats (Hwang et al. 1999),
but reduced in these regions in high versus low alcoholdrinking rats (Hwang et al. 1999) and in mesolimbic regions
of the ethanol-preferring C57BL/6J mice (Hayes et al.
2005). In contrast, studies have reported no changes in
mRNA expression of NPY in any of these brain regions in
alcohol-preferring animals at baseline (Caberlotto et al.
2001; Kinoshita et al. 2004).
Clinical studies support a role for NPY in ethanol use,
with a variant allele of this peptide identified in heavy versus
moderate drinkers (Kauhanen et al. 2000) and in alcoholics
compared with control subjects (Lappalainen et al. 2002;
Mottagui-Tabar et al. 2005).
Agouti-Related Protein
The peptide AgRP, which enhances both fat and carbohydrate consumption, also affects ethanol intake. Although the
literature concerning AgRP regulation of ethanol consumption is limited, several studies suggest a positive association
between this peptide and ethanol intake.
Ventricular administration of AgRP stimulates ethanol
intake in C57BL/6J preferring mice (Navarro et al. 2005) but
48
not in nonpreferring strains (Navarro et al. 2003; Polidori
et al. 2006). Furthermore, acute administration of ethanol in
C57BL/6J mice, but not nonpreferring mice, results in enhanced peptide levels of AgRP in the ARC (Cubero et al.
2010), although chronic consumption of an ethanol diet has
little effect on this peptide (Navarro et al. 2008).
No clinical studies exist to support a role for this peptide in alcohol use, but mutant mice with a genetic deletion
of AgRP exhibit reduced lever pressing for ethanol as well
as ethanol binge drinking in a limited access paradigm
(Navarro et al. 2009).
These few studies suggest that AgRP may have some
function in controlling ethanol intake, although other peptide systems such as those specific for fat may have a more
prominent role.
Growth Hormone–Releasing Factor
Little is known about the function of GHRF in ethanol consumption. An early report noted a decrease in GHRF mRNA
in the hypothalamus of animals that consume an ethanol
diet, and this decrease may have been the cause of the reduced weight gain also observed in these animals (Soszynski
and Frohman 1992). In other studies, acute or chronic ethanol exposure has consistently led to reduced testosterone and
growth hormone levels, although these changes were independent of altered GHRF levels in the hypothalamus (Steiner
et al. 1997; Tentler et al. 1997). Together, these few studies
indicate that GHRF, a peptide more closely related to the
consumption of protein than fat (Dickson and Vaccarino
1994; Rains et al. 2001), has relatively little function in ethanol consumption.
Ghrelin
Ghrelin has been implicated in the consumption of foods
rich in protein, carbohydrates, and fat, with a slightly greater
role in protein ingestion. Investigators have also studied the
role of this peptide in ethanol consumption and found that
central administration of ghrelin enhances ethanol consumption in a site-specific manner.
Injection of ghrelin into the third ventricle or rewardrelated tegmental areas such as the VTA and lateral tegmental
area can enhance ethanol intake, whereas in the hypothalamus it has little effect (Jerlhag et al. 2009; Schneider et al.
2007). The ethanol intake–promoting effects of ghrelin may
be attributed in part to enhanced activity of the reward pathway, because tegmental injection of the peptide increases
DA levels in the NAc (Jerlhag et al. 2007). In contrast, peripheral administration of ghrelin has been shown not to affect ethanol drinking (Lyons et al. 2008), although in this
case the peptide may not have reached the brain to produce
its central effects. However, when a ghrelin antagonist was
administered peripherally, ethanol preference, intake, and
locomotor activity induced by ethanol were all attenuated
(Jerlhag et al. 2009; Kaur and Ryabinin 2010). Again, this
ILAR Journal
effect may be related to a reduction in the rewarding effects
of ethanol, inasmuch as the ghrelin antagonist has also been
shown to reduce NAc DA levels and ethanol-conditioned
place preference (Jerlhag et al. 2009).
The status of ghrelin has not been examined in alcoholpreferring rat or mouse models, although one study reported a
reduction in alcohol-induced locomotor activity, NAc DA, and
alcohol-conditioned place preference in mutant mice with a
deletion of the gene that encodes ghrelin (Jerlhag et al. 2009).
The involvement of ghrelin in clinical alcoholism has
also received support from the literature, suggesting that
this peptide may play a more prominent role in abstinent
than current alcoholic patients. For example, abstinent alcoholics have greater ghrelin levels than active drinkers
(Kraus et al. 2005), and levels of this peptide have a positive association both with the time the patient has been abstinent (Kim et al. 2005) and with the level of craving for
alcohol during withdrawal (Wurst et al. 2007). However,
two separate clinical reports have demonstrated reduced
ghrelin levels in current alcoholic patients (Addolorato
et al. 2006) and a mutation in proghrelin in heavy alcohol
users (Landgren et al. 2008).
These studies collectively demonstrate that ghrelin,
which has a nonspecific role in the ingestion of several macronutrients, is involved in mediating the rewarding effects of
ethanol intake.
Conclusions
Using a number of animal models of food and ethanol intake, researchers in the last few decades have discovered important factors involved in regulating the intake of these
substances. Although the hypothalamus is classically associated with food intake due to its regulation of energy balance,
more recent reports have suggested that nuclei in mesocorticolimbic regions also play a role due to their regulation of
emotion and reinforcement.
A strikingly large number of neurochemical systems
participate in driving food intake. In the hypothalamus,
many of these systems have close associations with a specific macronutrient, whereas in mesocorticolimbic areas
they appear to be more strongly related to general reward.
Systems involved in fat intake appear to function in a positive feedback loop, further potentiating the consumption of
this macronutrient, whereas systems involved in carbohydrate or protein intake are more often negatively regulated
by ingestion of these nutrients.
Unlike food, alcohol is not necessary for survival, yet
this calorie-containing drug of abuse functions through
many of the same systems that evolved for food intake. In
addition to increasing reward and reinforcement through
the mesocorticolimbic regions, alcohol intake functions
through neurochemicals in the hypothalamus and, remarkably, appears to have a special association with the same
hypothalamic neuropeptides that control fat intake. This characteristic may in part explain how alcoholism can develop,
Volume 53, Number 1
2012
acting through a system designed to maximize intake.
Although it is doubtful that all drugs of abuse act through
fat-related neurochemicals, it is likely that they act through
many of the same systems that evolved to control food intake in general.
Based on the research described in this review, it may be
possible to apply knowledge gained about the regulation of
feeding behavior to the development of medications to treat
alcohol use and drug addiction.
Acknowledgments
This research was supported by US Public Health Service
grants AA12882 and DA21518.
References
Abizaid A, Liu ZW, Andrews ZB, Shanabrough M, Borok E, Elsworth JD,
Roth RH, Sleeman MW, Picciotto MR, Tschop MH, Gao XB, Horvath
TL. 2006. Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite. J Clin
Invest 116:3229-3239.
Adamantidis A, de Lecea L. 2008. Physiological arousal: A role for hypothalamic systems. Cell Mol Life Sci 65:1475-1488.
Adams AC, Clapham JC, Wynick D, Speakman JR. 2008. Feeding behaviour in galanin knockout mice supports a role of galanin in fat intake and
preference. J Neuroendocrinol 20:199-206.
Addolorato G, Capristo E, Leggio L, Ferrulli A, Abenavoli L, Malandrino
N, Farnetti S, Domenicali M, D’Angelo C, Vonghia L, Mirijello A,
Cardone S, Gasbarrini G. 2006. Relationship between ghrelin levels,
alcohol craving, and nutritional status in current alcoholic patients. Alcohol Clin Exp Res 30:1933-1937.
Akabayashi A, Koenig JI, Watanabe Y, Alexander JT, Leibowitz SF. 1994.
Galanin-containing neurons in the paraventricular nucleus: A neurochemical marker for fat ingestion and body weight gain. Proc Natl Acad
Sci U S A 91:10375-10379.
Akiyama M, Yuasa T, Hayasaka N, Horikawa K, Sakurai T, Shibata S. 2004.
Reduced food anticipatory activity in genetically orexin (hypocretin)
neuron-ablated mice. Eur J Neurosci 20:3054-3062.
Alen F, Santos A, Moreno-Sanz G, Gonzalez-Cuevas G, Gine E, Franco-Ruiz
L, Navarro M, Lopez-Moreno JA. 2009. Cannabinoid-induced increase in
relapse-like drinking is prevented by the blockade of the glycine-binding
site of N-methyl-D-aspartate receptors. Neuroscience 158:465-473.
Aston-Jones G. 2005. Brain structures and receptors involved in alertness.
Sleep Med 6(Suppl 1):S3-S7.
Avena NM, Carrillo CA, Needham L, Leibowitz SF, Hoebel BG. 2004.
Sugar-dependent rats show enhanced intake of unsweetened ethanol.
Alcohol 34:203-209.
Avena NM, Long KA, Hoebel BG. 2005. Sugar-dependent rats show enhanced responding for sugar after abstinence: Evidence of a sugar deprivation effect. Physiol Behav 84:359-362.
Bacon SJ, Headlam AJ, Gabbott PL, Smith AD. 1996. Amygdala input to
medial prefrontal cortex (mPFC) in the rat: A light and electron microscope study. Brain Res 720:211-219.
Badia-Elder NE, Stewart RB, Powrozek TA, Roy KF, Murphy JM, Li TK.
2001. Effect of neuropeptide Y (NPY) on oral ethanol intake in Wistar,
alcohol-preferring (P), and -nonpreferring (NP) rats. Alcohol Clin Exp
Res 25:386-390.
Bagnasco M, Kalra PS, Kalra SP. 2002. Ghrelin and leptin pulse discharge
in fed and fasted rats. Endocrinology 143:726-729.
Baird JP, Choe A, Loveland JL, Beck J, Mahoney CE, Lord JS, Grigg LA.
2009. Orexin-A hyperphagia: Hindbrain participation in consummatory
feeding responses. Endocrinology 150:1202-1216.
49
Baldo BA, Daniel RA, Berridge CW, Kelley AE. 2003. Overlapping
distributions of orexin/hypocretin- and dopamine-beta-hydroxylase
immunoreactive fibers in rat brain regions mediating arousal, motivation, and stress. J Comp Neurol 464:220-237.
Bannon AW, Seda J, Carmouche M, Francis JM, Norman MH, Karbon B,
McCaleb ML. 2000. Behavioral characterization of neuropeptide Y
knockout mice. Brain Res 868:79-87.
Barone FC, Wayner MJ, Scharoun SL, Guevara-Aguilar R, Aguilar-Baturoni
HU. 1981. Afferent connections to the lateral hypothalamus: A horseradish peroxidase study in the rat. Brain Res Bull 7:75-88.
Barson JR, Carr AJ, Soun JE, Sobhani NC, Leibowitz SF, Hoebel BG. 2009.
Opioids in the nucleus accumbens stimulate ethanol intake. Physiol
Behav 98:453-459.
Barson JR, Carr AJ, Soun JE, Sobhani NC, Rada P, Leibowitz SF, Hoebel
BG. 2010. Opioids in the hypothalamic paraventricular nucleus stimulate ethanol intake. Alcohol Clin Exp Res 34:214-222.
Beaulieu J, Champagne D, Drolet G. 1996. Enkephalin innervation of the
paraventricular nucleus of the hypothalamus: Distribution of fibers and
origins of input. J Chem Neuroanat 10:79-92.
Beck B, Max JP. 2007. Hypothalamic galanin and plasma leptin and ghrelin
in the maintenance of energy intake in the Brattleboro rat. Biochem
Biophys Res Commun 364:60-65.
Beck B, Stricker-Krongrad A, Burlet A, Nicolas JP, Burlet C. 1990. Influence of diet composition on food intake and hypothalamic neuropeptide
Y (NPY) in the rat. Neuropeptides 17:197-203.
Becker A, Grecksch G, Kraus J, Loh HH, Schroeder H, Hollt V. 2002. Rewarding effects of ethanol and cocaine in mu opioid receptor-deficient
mice. Naunyn Schmiedebergs Arch Pharmacol 365:296-302.
Belfer I, Hipp H, Bollettino A, McKnight C, Evans C, Virkkunen M, Albaugh
B, Max MB, Goldman D, Enoch MA. 2007. Alcoholism is associated
with GALR3 but not two other galanin receptor genes. Genes Brain
Behav 6:473-481.
Belfer I, Hipp H, McKnight C, Evans C, Buzas B, Bollettino A, Albaugh B,
Virkkunen M, Yuan Q, Max MB, Goldman D, Enoch MA. 2006. Association of galanin haplotypes with alcoholism and anxiety in two ethnically distinct populations. Mol Psychiatry 11:301-311.
Belknap JK, Richards SP, O’Toole LA, Helms ML, Phillips TJ. 1997. Shortterm selective breeding as a tool for QTL mapping: Ethanol preference
drinking in mice. Behav Genet 27:55-66.
Bell RL, Rodd ZA, Lumeng L, Murphy JM, McBride WJ. 2006. The alcoholpreferring P rat and animal models of excessive alcohol drinking.
Addict Biol 11:270-288.
Berner LA, Avena NM, Hoebel BG. 2008. Bingeing, self-restriction, and
increased body weight in rats with limited access to a sweet-fat diet.
Obesity (Silver Spring) 16:1998-2002.
Berner LA, Bocarsly ME, Hoebel BG, Avena NM. 2009. Baclofen suppresses binge eating of pure fat but not a sugar-rich or sweet-fat diet.
Behav Pharmacol 20:631-634.
Besheer J, Grondin JJ, Cannady R, Sharko AC, Faccidomo S, Hodge CW.
2010. Metabotropic glutamate receptor 5 activity in the nucleus accumbens is required for the maintenance of ethanol self-administration in a
rat genetic model of high alcohol intake. Biol Psychiatry 67:812-822.
Bewick GA, Gardiner JV, Dhillo WS, Kent AS, White NE, Webster Z, Ghatei
MA, Bloom SR. 2005. Post-embryonic ablation of AgRP neurons
in mice leads to a lean, hypophagic phenotype. FASEB J 19:16801682.
Blouin M, Tremblay A, Jalbert ME, Venables H, Bouchard RH, Roy MA,
Almeras N. 2008. Adiposity and eating behaviors in patients under second generation antipsychotics. Obesity (Silver Spring) 16:1780-1787.
Blum K, Briggs AH, Trachtenberg MC, Delallo L, Wallace JE. 1987. Enkephalinase inhibition: Regulation of ethanol intake in genetically predisposed mice. Alcohol 4:449-456.
Bomberg EM, Grace MK, Wirth MM, Levine AS, Olszewski PK. 2007.
Central ghrelin induces feeding driven by energy needs not by reward.
Neuroreport 18:591-595.
Bouali SM, Fournier A, St-Pierre S, Jolicoeur FB. 1995. Effects of NPY and
NPY2-36 on body temperature and food intake following administration into hypothalamic nuclei. Brain Res Bull 36:131-135.
50
Boutin P, Dina C, Vasseur F, Dubois S, Corset L, Seron K, Bekris L,
Cabellon J, Neve B, Vasseur-Delannoy V, Chikri M, Charles MA, Clement
K, Lernmark A, Froguel P. 2003. GAD2 on chromosome 10p12 is a
candidate gene for human obesity. PLoS Biol 1:E68.
Bradbury MJ, Campbell U, Giracello D, Chapman D, King C, Tehrani L,
Cosford ND, Anderson J, Varney MA, Strack AM. 2005. Metabotropic
glutamate receptor mGlu5 is a mediator of appetite and energy balance
in rats and mice. J Pharmacol Exp Ther 313:395-402.
Bray MS, Boerwinkle E, Hanis CL. 2000. Sequence variation within the
neuropeptide Y gene and obesity in Mexican Americans. Obes Res 8:
219-226.
Brinley-Reed M, Mascagni F, McDonald AJ. 1995. Synaptology of prefrontal cortical projections to the basolateral amygdala: An electron microscopic study in the rat. Neurosci Lett 202:45-48.
Brower KJ, Myra Kim H, Strobbe S, Karam-Hage MA, Consens F, Zucker
RA. 2008. A randomized double-blind pilot trial of gabapentin versus
placebo to treat alcohol dependence and comorbid insomnia. Alcohol
Clin Exp Res 32:1429-1438.
Brown CM, Coscina DV, Fletcher PJ. 2000. The rewarding properties of
neuropeptide Y in perifornical hypothalamus vs. nucleus accumbens.
Peptides 21:1279-1287.
Bruno JF, Olchovsky D, White JD, Leidy JW, Song J, Berelowitz M. 1990.
Influence of food deprivation in the rat on hypothalamic expression of
growth hormone-releasing factor and somatostatin. Endocrinology 127:
2111-2116.
Bruno JF, Song JF, Berelowitz M. 1991. Regulation of rat hypothalamic
preprogrowth hormone-releasing factor messenger ribonucleic acid by
dietary protein. Endocrinology 129:1226-1232.
Bustamante D, Quintanilla ME, Tampier L, Gonzalez-Lira V, Israel Y, HerreraMarschitz M. 2008. Ethanol induces stronger dopamine release in nucleus
accumbens (shell) of alcohol-preferring (bibulous) than in alcohol-avoiding
(abstainer) rats. Eur J Pharmacol 591:153-158.
Caberlotto L, Thorsell A, Rimondini R, Sommer W, Hyytia P, Heilig M.
2001. Differential expression of NPY and its receptors in alcoholpreferring AA and alcohol-avoiding ANA rats. Alcohol Clin Exp Res
25:1564-1569.
Cai A, Hyde JF. 1999. The human growth hormone-releasing hormone
transgenic mouse as a model of modest obesity: Differential changes in
leptin receptor (OBR) gene expression in the anterior pituitary and hypothalamus after fasting and OBR localization in somatotrophs. Endocrinology 140:3609-3614.
Carlini VP, Varas MM, Cragnolini AB, Schioth HB, Scimonelli TN, de Barioglio
SR. 2004. Differential role of the hippocampus, amygdala, and dorsal
raphe nucleus in regulating feeding, memory, and anxiety-like behavioral
responses to ghrelin. Biochem Biophys Res Commun 313:635-641.
Carrillo CA, Leibowitz SF, Karatayev O, Hoebel BG. 2004. A high-fat meal
or injection of lipids stimulates ethanol intake. Alcohol 34:197-202.
Carroll ME, Morgan AD, Anker JJ, Perry JL, Dess NK. 2008. Selective
breeding for differential saccharin intake as an animal model of drug
abuse. Behav Pharmacol 19:435-460.
Chang GQ, Barson JR, Karatayev O, Chang SY, Chen YW, Leibowitz SF.
2010a. Effect of chronic ethanol on enkephalin in the hypothalamus and
extra-hypothalamic areas. Alcohol Clin Exp Res 34:761-770.
Chang GQ, Karatayev O, Ahsan R, Avena NM, Lee C, Lewis MJ, Hoebel
BG, Leibowitz SF. 2007a. Effect of ethanol on hypothalamic opioid
peptides, enkephalin, and dynorphin: Relationship with circulating triglycerides. Alcohol Clin Exp Res 31:249-259.
Chang GQ, Karatayev O, Ahsan R, Gaysinskaya V, Marwil Z, Leibowitz SF.
2007b. Dietary fat stimulates endogenous enkephalin and dynorphin in
the paraventricular nucleus: Role of circulating triglycerides. Am J
Physiol Endocrinol Metab 292:E561-E570.
Chang GQ, Karatayev O, Barson JR, Chang SY, Leibowitz SF. 2010b. Increased enkephalin in brain of rats prone to overconsuming a fat-rich
diet. Physiol Behav 101:360-369.
Chang GQ, Karatayev O, Davydova Z, Wortley K, Leibowitz SF. 2005. Glucose injection reduces neuropeptide Y and agouti-related protein expression in the arcuate nucleus: A possible physiological role in eating
behavior. Brain Res Mol Brain Res 135:69-80.
ILAR Journal
Chen F, Rezvani A, Jarrott B, Lawrence AJ. 1998. Distribution of GABAA
receptors in the limbic system of alcohol-preferring and non-preferring
rats: In situ hybridisation histochemistry and receptor autoradiography.
Neurochem Int 32:143-151.
Cheng SB, Kuchiiwa S, Gao HZ, Kuchiiwa T, Nakagawa S. 2003. Morphological study of orexin neurons in the hypothalamus of the Long-Evans
rat, with special reference to co-expression of orexin and NADPHdiaphorase or nitric oxide synthase activities. Neurosci Res 46:53-62.
Choquette AC, Lemieux S, Tremblay A, Drapeau V, Bouchard C, Vohl MC,
Perusse L. 2009. GAD2 gene sequence variations are associated with
eating behaviors and weight gain in women from the Quebec family
study. Physiol Behav 98:505-510.
Christie MJ, James LB, Beart PM. 1985. An excitant amino acid projection
from the medial prefrontal cortex to the anterior part of nucleus accumbens in the rat. J Neurochem 45:477-482.
Cippitelli A, Karlsson C, Shaw JL, Thorsell A, Gehlert DR, Heilig M. 2010.
Suppression of alcohol self-administration and reinstatement of alcohol
seeking by melanin-concentrating hormone receptor 1 (MCH1-R) antagonism in Wistar rats. Psychopharmacology (Berl) 211:367-375.
Cleary MP, Vasselli JR, Greenwood MR. 1980. Development of obesity in
Zucker obese (fafa) rat in absence of hyperphagia. Am J Physiol 238:
E284-E292.
Clegg DJ, Air EL, Woods SC, Seeley RJ. 2002. Eating elicited by orexin-a,
but not melanin-concentrating hormone, is opioid mediated. Endocrinology 143:2995-3000.
Colantuoni C, Rada P, McCarthy J, Patten C, Avena NM, Chadeayne A,
Hoebel BG. 2002. Evidence that intermittent, excessive sugar intake
causes endogenous opioid dependence. Obes Res 10:478-488.
Colombo G. 1997. ESBRA-Nordmann 1996 Award Lecture: Ethanol drinking behaviour in Sardinian alcohol-preferring rats. Alcohol Alcohol
32:443-453.
Colombo G, Serra S, Brunetti G, Gomez R, Melis S, Vacca G, Carai MM,
Gessa L. 2002. Stimulation of voluntary ethanol intake by cannabinoid
receptor agonists in ethanol-preferring sP rats. Psychopharmacology
(Berl) 159:181-187.
Corwin RL. 2004. Binge-type eating induced by limited access in rats does
not require energy restriction on the previous day. Appetite 42:139-142.
Corwin RL, Wojnicki FH. 2006. Binge eating in rats with limited access to
vegetable shortening. Curr Protoc Neurosci Chapter 9:Unit 9:23B.
Cowen M, Chen F, Jarrott B, Lawrence AJ. 1998. Effects of acute ethanol
on GABA release and GABA(A) receptor density in the rat mesolimbic
system. Pharmacol Biochem Behav 59:51-57.
Cowen MS, Lawrence AJ. 2001. Alterations in central preproenkephalin
mRNA expression after chronic free-choice ethanol consumption by
fawn-hooded rats. Alcohol Clin Exp Res 25:1126-1133.
Criado JR, Morales M. 2000. Acute ethanol induction of c-Fos immunoreactivity in pre-pro-enkephalin expressing neurons of the central nucleus
of the amygdala. Brain Res 861:173-177.
Cronise K, Finn DA, Metten P, Crabbe JC. 2005. Scheduled access to ethanol results in motor impairment and tolerance in female C57BL/6J
mice. Pharmacol Biochem Behav 81:943-953.
Csaki A, Kocsis K, Halasz B, Kiss J. 2000. Localization of glutamatergic/
aspartatergic neurons projecting to the hypothalamic paraventricular
nucleus studied by retrograde transport of [3H]D-aspartate autoradiography. Neuroscience 101:637-655.
Cubero I, Navarro M, Carvajal F, Lerma-Cabrera JM, Thiele TE. 2010.
Ethanol-induced increase of agouti-related protein (AgRP) immunoreactivity in the arcuate nucleus of the hypothalamus of C57BL/6J, but
not 129/SvJ, inbred mice. Alcohol Clin Exp Res 34:693-701.
Cunningham CL, Howard MA, Gill SJ, Rubinstein M, Low MJ, Grandy
DK. 2000. Ethanol-conditioned place preference is reduced in dopamine
D2 receptor-deficient mice. Pharmacol Biochem Behav 67:693-699.
Currie PJ, Mirza A, Fuld R, Park D, Vasselli JR. 2005. Ghrelin is an orexigenic and metabolic signaling peptide in the arcuate and paraventricular
nuclei. Am J Physiol Regul Integr Comp Physiol 289:R353-R358.
Dahchour A, Quertemont E, De Witte P. 1994. Acute ethanol increases taurine but neither glutamate nor GABA in the nucleus accumbens of male
rats: A microdialysis study. Alcohol Alcohol 29:485-487.
Volume 53, Number 1
2012
Dahlstrom A, Fuxe K. 1964. Localization of monoamines in the lower brain
stem. Experientia 20:398-399.
de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE,
Fukuhara C, Battenberg EL, Gautvik VT, Bartlett FS, 2nd, Frankel WN,
van den Pol AN, Bloom FE, Gautvik KM, Sutcliffe JG. 1998. The hypocretins: Hypothalamus-specific peptides with neuroexcitatory activity.
Proc Natl Acad Sci U S A 95:322-327.
Deng C, Li KY, Zhou C, Ye JH. 2009. Ethanol enhances glutamate transmission by retrograde dopamine signaling in a postsynaptic neuron/synaptic
bouton preparation from the ventral tegmental area. Neuropsychopharmacology 34:1233-1244.
Devaud LL, Smith FD, Grayson DR, Morrow AL. 1995. Chronic ethanol
consumption differentially alters the expression of gamma-aminobutyric
acidA receptor subunit mRNAs in rat cerebral cortex: Competitive,
quantitative reverse transcriptase-polymerase chain reaction analysis.
Mol Pharmacol 48:861-868.
Di Chiara G, Imperato A. 1988. Drugs abused by humans preferentially increase synaptic dopamine concentrations in the mesolimbic system of
freely moving rats. Proc Natl Acad Sci U S A 85:5274-5278.
Dickson PR, Vaccarino FJ. 1990. Characterization of feeding behavior induced by central injection of GRF. Am J Physiol 259(3 Pt 2):R651R657.
Dickson PR, Vaccarino FJ. 1994. GRF-induced feeding: Evidence for protein selectivity and opiate involvement. Peptides 15:1343-1352.
Dube MG, Kalra SP, Kalra PS. 1999. Food intake elicited by central administration of orexins/hypocretins: Identification of hypothalamic sites of
action. Brain Res 842:473-477.
Duncan EA, Proulx K, Woods SC. 2005. Central administration of melaninconcentrating hormone increases alcohol and sucrose/quinine intake in
rats. Alcohol Clin Exp Res 29:958-964.
Duncan EA, Rider TR, Jandacek RJ, Clegg DJ, Benoit SC, Tso P, Woods
SC. 2006. The regulation of alcohol intake by melanin-concentrating
hormone in rats. Pharmacol Biochem Behav 85:728-735.
Duncan EA, Sorrell JE, Adamantidis A, Rider T, Jandacek RJ, Seeley RJ,
Lakaye B, Woods SC. 2007. Alcohol drinking in MCH receptor-1-deficient
mice. Alcohol Clin Exp Res 31:1325-1337.
Dziedzic B, Szemraj J, Bartkowiak J, Walczewska A. 2007. Various dietary
fats differentially change the gene expression of neuropeptides involved
in body weight regulation in rats. J Neuroendocrinol 19:364-373.
Eiler WJ, 2nd, June HL. 2007. Blockade of GABA(A) receptors within the
extended amygdala attenuates D(2) regulation of alcohol-motivated behaviors in the ventral tegmental area of alcohol-preferring (P) rats. Neuropharmacology 52:1570-1579.
Elliott JC, Harrold JA, Brodin P, Enquist K, Backman A, Bystrom M, Lindgren
K, King P, Williams G. 2004. Increases in melanin-concentrating hormone
and MCH receptor levels in the hypothalamus of dietary-obese rats.
Brain Res Mol Brain Res 128:150-159.
Engleman EA, Ingraham CM, McBride WJ, Lumeng L, Murphy JM. 2006.
Extracellular dopamine levels are lower in the medial prefrontal cortex
of alcohol-preferring rats compared to Wistar rats. Alcohol 38:5-12.
Eny KM, Corey PN, El-Sohemy A. 2009. Dopamine D2 receptor genotype
(C957T) and habitual consumption of sugars in a free-living population
of men and women. J Nutrigenet Nutrigenomics 2:235-242.
Evans KR, Vaccarino FJ. 1986. Intra-nucleus accumbens amphetamine:
Dose-dependent effects on food intake. Pharmacol Biochem Behav
25:1149-1151.
Fadel J, Deutch AY. 2002. Anatomical substrates of orexin-dopamine interactions: Lateral hypothalamic projections to the ventral tegmental area.
Neuroscience 111:379-387.
Ferrer B, Bermudez-Silva FJ, Bilbao A, Alvarez-Jaimes L, Sanchez-Vera I,
Giuffrida A, Serrano A, Baixeras E, Khaturia S, Navarro M, Parsons
LH, Piomelli D, Rodriguez de Fonseca F. 2007. Regulation of brain
anandamide by acute administration of ethanol. Biochem J 404:97-104.
Fintini D, Alba M, Schally AV, Bowers CY, Parlow AF, Salvatori R. 2005.
Effects of combined long-term treatment with a growth hormone-releasing
hormone analogue and a growth hormone secretagogue in the growth
hormone-releasing hormone knock out mouse. Neuroendocrinology 82:
198-207.
51
Fisler JS, Shimizu H, Bray GA. 1989. Brain 3-hydroxybutyrate, glutamate,
and GABA in a rat model of dietary obesity. Physiol Behav 45:571-577.
Flegal KM, Carroll MD, Ogden CL, Johnson CL. 2002. Prevalence and
trends in obesity among US adults, 1999-2000. JAMA 288:1723-1727.
Foster KL, McKay PF, Seyoum R, Milbourne D, Yin W, Sarma PV, Cook
JM, June HL. 2004. GABA(A) and opioid receptors of the central nucleus of the amygdala selectively regulate ethanol-maintained behaviors. Neuropsychopharmacology 29:269-284.
Frank GK, Kaye WH, Sahu A, Fernstrom J, McConaha C. 2001. Could reduced cerebrospinal fluid (csf) galanin contribute to restricted eating in
anorexia nervosa? Neuropsychopharmacology 24:706-709.
Funato H, Tsai AL, Willie JT, Kisanuki Y, Williams SC, Sakurai T, Yanagisawa
M. 2009. Enhanced orexin receptor-2 signaling prevents diet-induced obesity and improves leptin sensitivity. Cell Metab 9:64-76.
Furieri FA, Nakamura-Palacios EM. 2007. Gabapentin reduces alcohol consumption and craving: A randomized, double-blind, placebo-controlled
trial. J Clin Psychiatry 68:1691-1700.
Furudono Y, Ando C, Yamamoto C, Kobashi M, Yamamoto T. 2006. Involvement of specific orexigenic neuropeptides in sweetener-induced
overconsumption in rats. Behav Brain Res 175:241-248.
Garcia-Tornadu I, Diaz-Torga G, Risso GS, Silveyra P, Cataldi N, Ramirez
MC, Low MJ, Libertun C, Becu-Villalobos D. 2009. Hypothalamic
orexin, OX1, alphaMSH, NPY and MCRs expression in dopaminergic
D2R knockout mice. Neuropeptides 43:267-274.
Garcia-Tornadu I, Perez-Millan MI, Recouvreux V, Ramirez MC, Luque G,
Risso GS, Ornstein AM, Cristina C, Diaz-Torga G, Becu-Villalobos D.
2010. New insights into the endocrine and metabolic roles of dopamine
D2 receptors gained from the Drd2 mouse. Neuroendocrinology 92:
207-214.
Gardiner JV, Campbell D, Patterson M, Kent A, Ghatei MA, Bloom SR,
Bewick GA. 2010. The hyperphagic effect of ghrelin is inhibited in
mice by a diet high in fat. Gastroenterology 138:2468-2476, 2476
e2461.
Gaysinskaya VA, Karatayev O, Chang GQ, Leibowitz SF. 2007. Increased
caloric intake after a high-fat preload: Relation to circulating triglycerides and orexigenic peptides. Physiol Behav 91:142-153.
Geiger BM, Behr GG, Frank LE, Caldera-Siu AD, Beinfeld MC, Kokkotou
EG, Pothos EN. 2008. Evidence for defective mesolimbic dopamine
exocytosis in obesity-prone rats. FASEB J 22:2740-2746.
Gelernter J, Gueorguieva R, Kranzler HR, Zhang H, Cramer J, Rosenheck
R, Krystal JH. 2007. Opioid receptor gene (OPRM1, OPRK1, and
OPRD1) variants and response to naltrexone treatment for alcohol dependence: Results from the VA Cooperative Study. Alcohol Clin Exp
Res 31:555-563.
Georgescu D, Sears RM, Hommel JD, Barrot M, Bolanos CA, Marsh DJ,
Bednarek MA, Bibb JA, Maratos-Flier E, Nestler EJ, DiLeone RJ. 2005.
The hypothalamic neuropeptide melanin-concentrating hormone acts in
the nucleus accumbens to modulate feeding behavior and forced-swim
performance. J Neurosci 25:2933-2940.
Gibson WT, Pissios P, Trombly DJ, Luan J, Keogh J, Wareham NJ, MaratosFlier E, O’Rahilly S, Farooqi IS. 2004. Melanin-concentrating hormone
receptor mutations and human obesity: Functional analysis. Obes Res
12:743-749.
Gilpin NW, Misra K, Koob GF. 2008a. Neuropeptide Y in the central nucleus of the amygdala suppresses dependence-induced increases in alcohol drinking. Pharmacol Biochem Behav 90:475-480.
Gilpin NW, Richardson HN, Cole M, Koob GF. 2008b. Vapor inhalation of
alcohol in rats. Curr Protoc Neurosci Chapter 9:Unit 9:29.
Giraudo SQ, Kotz CM, Grace MK, Levine AS, Billington CJ. 1994. Rat
hypothalamic NPY mRNA and brown fat uncoupling protein mRNA
after high-carbohydrate or high-fat diets. Am J Physiol 266:R1578R1583.
Gomori A, Ishihara A, Ito M, Mashiko S, Matsushita H, Yumoto M, Tanaka
T, Tokita S, Moriya M, Iwaasa H, Kanatani A. 2003. Chronic intracerebroventricular infusion of MCH causes obesity in mice: Melanin-concentrating
hormone. Am J Physiol Endocrinol Metab 284:E583-E588.
Gosnell BA. 1988. Involvement of mu opioid receptors in the amygdala in
the control of feeding. Neuropharmacology 27:319-326.
52
Graham M, Shutter JR, Sarmiento U, Sarosi I, Stark KL. 1997. Overexpression of Agrt leads to obesity in transgenic mice. Nat Genet 17:
273-274.
Guilleminault C, Carskadon M, Dement WC. 1974. On the treatment of
rapid eye movement narcolepsy. Arch Neurol 30:90-93.
Hagan MM, Rushing PA, Benoit SC, Woods SC, Seeley RJ. 2001. Opioid
receptor involvement in the effect of AgRP- (83-132) on food intake and
food selection. Am J Physiol Regul Integr Comp Physiol 280:R814R821.
Hajnal A, Smith GP, Norgren R. 2004. Oral sucrose stimulation increases
accumbens dopamine in the rat. Am J Physiol Regul Integr Comp
Physiol 286:R31-R37.
Hall FS, Sora I, Uhl GR. 2001. Ethanol consumption and reward are decreased in mu-opiate receptor knockout mice. Psychopharmacology
(Berl) 154:43-49.
Hansson AC, Bermudez-Silva FJ, Malinen H, Hyytia P, Sanchez-Vera I,
Rimondini R, Rodriguez de Fonseca F, Kunos G, Sommer WH, Heilig M.
2007. Genetic impairment of frontocortical endocannabinoid degradation
and high alcohol preference. Neuropsychopharmacology 32:117-126.
Harris GC, Aston-Jones G. 2006. Arousal and reward: A dichotomy in
orexin function. Trends Neurosci 29:571-577.
Hayes DM, Knapp DJ, Breese GR, Thiele TE. 2005. Comparison of basal
neuropeptide Y and corticotropin releasing factor levels between the
high ethanol drinking C57BL/6J and low ethanol drinking DBA/2J inbred mouse strains. Alcohol Clin Exp Res 29:721-729.
Hayward MD, Hansen ST, Pintar JE, Low MJ. 2004. Operant self-administration
of ethanol in C57BL/6 mice lacking beta-endorphin and enkephalin.
Pharmacol Biochem Behav 79:171-181.
Hayward MD, Pintar JE, Low MJ. 2002. Selective reward deficit in mice
lacking beta-endorphin and enkephalin. J Neurosci 22:8251-8258.
Heidbreder C, De Witte P. 1993. Ethanol differentially affects extracellular
monoamines and GABA in the nucleus accumbens. Pharmacol Biochem Behav 46:477-481.
Hendrickson LM, Zhao-Shea R, Tapper AR. 2009. Modulation of ethanol
drinking-in-the-dark by mecamylamine and nicotinic acetylcholine receptor agonists in C57BL/6J mice. Psychopharmacology (Berl) 204:
563-572.
Heyser CJ, Roberts AJ, Schulteis G, Koob GF. 1999. Central administration
of an opiate antagonist decreases oral ethanol self-administration in rats.
Alcohol Clin Exp Res 23:1468-1476.
Higuchi S, Ohji M, Araki M, Furuta R, Katsuki M, Yamaguchi R, Akitake
Y, Matsuyama K, Irie K, Mishima K, Iwasaki K, Fujiwara M. 2011.
Increment of hypothalamic 2-arachidonoylglycerol induces the preference for a high-fat diet via activation of cannabinoid 1 receptors. Behav
Brain Res 216:477-480.
Hinney A, Hoch A, Geller F, Schafer H, Siegfried W, Goldschmidt H,
Remschmidt H, Hebebrand J. 2002. Ghrelin gene: Identification of missense variants and a frameshift mutation in extremely obese children
and adolescents and healthy normal weight students. J Clin Endocrinol
Metab 87:2716.
Hodge CW, Chappelle AM, Samson HH. 1995. GABAergic transmission in
the nucleus accumbens is involved in the termination of ethanol selfadministration in rats. Alcohol Clin Exp Res 19:1486-1493.
Hodge CW, Samson HH, Tolliver GA, Haraguchi M. 1994. Effects of intraaccumbens injections of dopamine agonists and antagonists on sucrose and sucrose-ethanol reinforced responding. Pharmacol Biochem
Behav 48:141-150.
Hohmann JG, Krasnow SM, Teklemichael DN, Clifton DK, Wynick D,
Steiner RA. 2003. Neuroendocrine profiles in galanin-overexpressing
and knockout mice. Neuroendocrinology 77:354-366.
Hong CJ, Liou YJ, Bai YM, Chen TT, Wang YC, Tsai SJ. 2010. Dopamine
receptor D2 gene is associated with weight gain in schizophrenic patients under long-term atypical antipsychotic treatment. Pharmacogenet
Genomics 20:359-366.
Hoover WB, Vertes RP. 2007. Anatomical analysis of afferent projections to
the medial prefrontal cortex in the rat. Brain Struct Funct 212:149-179.
Hungund BL, Basavarajappa BS. 2000. Distinct differences in the cannabinoid receptor binding in the brain of C57BL/6 and DBA/2 mice,
ILAR Journal
selected for their differences in voluntary ethanol consumption. J Neurosci Res 60:122-128.
Hutchison KE, Haughey H, Niculescu M, Schacht J, Kaiser A, Stitzel J,
Horton WJ, Filbey F. 2008. The incentive salience of alcohol: Translating
the effects of genetic variant in CNR1. Arch Gen Psychiatry 65:841-850.
Hwang BH, Zhang JK, Ehlers CL, Lumeng L, Li TK. 1999. Innate differences of neuropeptide Y (NPY) in hypothalamic nuclei and central
nucleus of the amygdala between selectively bred rats with high and
low alcohol preference. Alcohol Clin Exp Res 23:1023-1030.
Ingman K, Kupila J, Hyytia P, Korpi ER. 2006. Effects of aripiprazole on
alcohol intake in an animal model of high-alcohol drinking. Alcohol
Alcohol 41:391-398.
Jaeger JP, Mattevi VS, Callegari-Jacques SM, Hutz MH. 2008. Cannabinoid
type-1 receptor gene polymorphisms are associated with central obesity
in a Southern Brazilian population. Dis Markers 25:67-74.
Jamensky NT, Gianoulakis C. 1999. Comparison of the proopiomelanocortin and proenkephalin opioid peptide systems in brain regions of the
alcohol-preferring C57BL/6 and alcohol-avoiding DBA/2 mice. Alcohol 18:177-187.
Jean C, Fromentin G, Tome D, Larue-Achagiotis C. 2002. Wistar rats allowed to self-select macronutrients from weaning to maturity choose a
high-protein, high-lipid diet. Physiol Behav 76:65-73.
Jerlhag E, Egecioglu E, Dickson SL, Douhan A, Svensson L, Engel JA.
2007. Ghrelin administration into tegmental areas stimulates locomotor
activity and increases extracellular concentration of dopamine in the
nucleus accumbens. Addict Biol 12:6-16.
Jerlhag E, Egecioglu E, Landgren S, Salome N, Heilig M, Moechars D,
Datta R, Perrissoud D, Dickson SL, Engel JA. 2009. Requirement of
central ghrelin signaling for alcohol reward. Proc Natl Acad Sci U S A
106:11318-11323.
June HL, Torres L, Cason CR, Hwang BH, Braun MR, Murphy JM. 1998a.
The novel benzodiazepine inverse agonist RO19-4603 antagonizes ethanol motivated behaviors: Neuropharmacological studies. Brain Res 784:
256-275.
June HL, Zuccarelli D, Torres L, Craig KS, DeLong J, Allen A, Braun MR,
Cason CR, Murphy JM. 1998b. High-affinity benzodiazepine antagonists reduce responding maintained by ethanol presentation in ethanolpreferring rats. J Pharmacol Exp Ther 284:1006-1014.
Kaga T, Inui A, Okita M, Asakawa A, Ueno N, Kasuga M, Fujimiya M,
Nishimura N, Dobashi R, Morimoto Y, Liu IM, Cheng JT. 2001. Modest
overexpression of neuropeptide Y in the brain leads to obesity after
high-sucrose feeding. Diabetes 50:1206-1210.
Kalivas PW, Churchill L, Klitenick MA. 1993. GABA and enkephalin projection from the nucleus accumbens and ventral pallidum to the ventral
tegmental area. Neuroscience 57:1047-1060.
Kalnina I, Kapa I, Pirags V, Ignatovica V, Schioth HB, Klovins J. 2009. Association between a rare SNP in the second intron of human agouti related protein gene and increased BMI. BMC Med Genet 10:63.
Kalra SP, Dube MG, Sahu A, Phelps CP, Kalra PS. 1991. Neuropeptide Y
secretion increases in the paraventricular nucleus in association with
increased appetite for food. Proc Natl Acad Sci U S A 88:10931-10935.
Kampe J, Tschop MH, Hollis JH, Oldfield BJ. 2009. An anatomic basis for
the communication of hypothalamic, cortical and mesolimbic circuitry
in the regulation of energy balance. Eur J Neurosci 30:415-430.
Karatayev O, Barson JR, Carr AJ, Baylan J, Chen YW, Leibowitz SF. 2010a.
Predictors of ethanol consumption in adult Sprague-Dawley rats:
Relation to hypothalamic peptides that stimulate ethanol intake. Alcohol 44:323-334.
Karatayev O, Baylan J, Leibowitz SF. 2009a. Increased intake of ethanol
and dietary fat in galanin overexpressing mice. Alcohol 43:571-580.
Karatayev O, Baylan J, Weed V, Chang S, Wynick D, Leibowitz SF. 2010b.
Galanin knockout mice show disturbances in ethanol consumption and
expression of hypothalamic peptides that stimulate ethanol intake. Alcohol Clin Exp Res 34:72-80.
Karatayev O, Gaysinskaya V, Chang GQ, Leibowitz SF. 2009b. Circulating triglycerides after a high-fat meal: Predictor of increased caloric intake,
orexigenic peptide expression, and dietary obesity. Brain Res 1298:
111-122.
Volume 53, Number 1
2012
Katner SN, Weiss F. 2001. Neurochemical characteristics associated
with ethanol preference in selected alcohol-preferring and -nonpreferring
rats: A quantitative microdialysis study. Alcohol Clin Exp Res 25:198205.
Kauhanen J, Karvonen MK, Pesonen U, Koulu M, Tuomainen TP, Uusitupa
MI, Salonen JT. 2000. Neuropeptide Y polymorphism and alcohol consumption in middle-aged men. Am J Med Genet 93:117-121.
Kaur S, Ryabinin AE. 2010. Ghrelin receptor antagonism decreases alcohol
consumption and activation of perioculomotor urocortin-containing
neurons. Alcohol Clin Exp Res 34:1525-1534.
Kaur S, Thankachan S, Begum S, Blanco-Centurion C, Sakurai T, Yanagisawa
M, Shiromani PJ. 2008. Entrainment of temperature and activity
rhythms to restricted feeding in orexin knock out mice. Brain Res
1205:47-54.
Kelley AE, Domesick VB, Nauta WJ. 1982. The amygdalostriatal projection in the rat---An anatomical study by anterograde and retrograde tracing methods. Neuroscience 7:615-630.
Kelley AE, Will MJ, Steininger TL, Zhang M, Haber SN. 2003. Restricted
daily consumption of a highly palatable food (chocolate Ensure(R))
alters striatal enkephalin gene expression. Eur J Neurosci 18:25922598.
Kemppainen H, Raivio N, Nurmi H, Kiianmaa K. 2010. GABA and glutamate
overflow in the VTA and ventral pallidum of alcohol-preferring AA and
alcohol-avoiding ANA rats after ethanol. Alcohol Alcohol 45:111-118.
Kim DJ, Yoon SJ, Choi B, Kim TS, Woo YS, Kim W, Myrick H, Peterson
BS, Choi YB, Kim YK, Jeong J. 2005. Increased fasting plasma ghrelin
levels during alcohol abstinence. Alcohol Alcohol 40:76-79.
Kim EM, Quinn JG, Levine AS, O’Hare E. 2004. A bi-directional mu-opioidopioid connection between the nucleus of the accumbens shell and the
central nucleus of the amygdala in the rat. Brain Res 1029:135-139.
Kim MS, Rossi M, Abusnana S, Sunter D, Morgan DG, Small CJ, Edwards
CM, Heath MM, Stanley SA, Seal LJ, Bhatti JR, Smith DM, Ghatei
MA, Bloom SR. 2000. Hypothalamic localization of the feeding effect
of agouti-related peptide and alpha-melanocyte-stimulating hormone.
Diabetes 49:177-182.
Kim SH, Mauron J, Gleason R, Wurtman R. 1991. Selection of carbohydrate to protein ratio and correlations with weight gain and body fat in
rats allowed three dietary choices. Int J Vitam Nutr Res 61:166-179.
Kinoshita H, Harbuz MS, Nishiguchi M, Ouchi H, Minami T, Utsumi T,
Motomura H, Hishida S. 2004. High alcohol preferring (HAP) and low
alcohol preferring (LAP) rats show altered proopiomelanocortin (POMC)
messenger RNA expression in the arcuate nucleus. Alcohol Alcohol
39:406-409.
Kinoshita H, Jessop DS, Finn DP, Coventry TL, Roberts DJ, Ameno K, Ijiri
I, Harbuz MS. 2000. Acute ethanol decreases NPY mRNA but not
POMC mRNA in the arcuate nucleus. Neuroreport 11:3517-3519.
Kita H, Oomura Y. 1981. Reciprocal connections between the lateral hypothalamus and the frontal complex in the rat: Electrophysiological and
anatomical observations. Brain Res 213:1-16.
Kluge M, Schuld A, Himmerich H, Dalal M, Schacht A, Wehmeier PM, HinzeSelch D, Kraus T, Dittmann RW, Pollmacher T. 2007. Clozapine and olanzapine are associated with food craving and binge eating: Results from a
randomized double-blind study. J Clin Psychopharmacol 27:662-666.
Koch JE. 2001. Delta(9)-THC stimulates food intake in Lewis rats: Effects
on chow, high-fat and sweet high-fat diets. Pharmacol Biochem Behav
68:539-543.
Koenig HN, Olive MF. 2002. Ethanol consumption patterns and conditioned place preference in mice lacking preproenkephalin. Neurosci
Lett 325:75-78.
Koliaki C, Kokkinos A, Tentolouris N, Katsilambros N. 2010. The effect of
ingested macronutrients on postprandial ghrelin response: A critical review of existing literature data. Int J Pept 2010:1-9.
Koros E, Piasecki J, Kostowski W, Bienkowski P. 1998. Saccharin drinking
rather than open field behaviour predicts initial ethanol acceptance in
Wistar rats. Alcohol Alcohol 33:131-140.
Kraus T, Schanze A, Groschl M, Bayerlein K, Hillemacher T, Reulbach U,
Kornhuber J, Bleich S. 2005. Ghrelin levels are increased in alcoholism.
Alcohol Clin Exp Res 29:2154-2157.
53
Kyrkouli SE, Stanley BG, Seirafi RD, Leibowitz SF. 1990. Stimulation of
feeding by galanin: Anatomical localization and behavioral specificity
of this peptide’s effects in the brain. Peptides 11:995-1001.
Lallemand F, de Witte P. 2005. Ethanol induces higher BEC in CB1 cannabinoid receptor knockout mice while decreasing ethanol preference.
Alcohol Alcohol 40:54-62.
Landgren S, Jerlhag E, Zetterberg H, Gonzalez-Quintela A, Campos J,
Olofsson U, Nilsson S, Blennow K, Engel JA. 2008. Association of proghrelin and GHS-R1A gene polymorphisms and haplotypes with heavy
alcohol use and body mass. Alcohol Clin Exp Res 32:2054-2061.
Lappalainen J, Kranzler HR, Malison R, Price LH, Van Dyck C, Rosenheck
RA, Cramer J, Southwick S, Charney D, Krystal J, Gelernter J. 2002. A
functional neuropeptide Y Leu7Pro polymorphism associated with alcohol dependence in a large population sample from the United States.
Arch Gen Psychiatry 59:825-831.
Lavebratt C, Alpman A, Persson B, Arner P, Hoffstedt J. 2006. Common
neuropeptide Y2 receptor gene variant is protective against obesity
among Swedish men. Int J Obes (Lond) 30:453-459.
Lawrence AJ, Cowen MS, Yang HJ, Chen F, Oldfield B. 2006. The orexin
system regulates alcohol-seeking in rats. Br J Pharmacol 148:752-759.
Laycock JF. 1976. Review: The Brattleboro rat with hereditary hypothalamic
diabetes insipidus as an ideal experimental model. Lab Anim 10:261-270.
Legradi G, Lechan RM. 1998. The arcuate nucleus is the major source
for neuropeptide Y-innervation of thyrotropin-releasing hormone neurons in the hypothalamic paraventricular nucleus. Endocrinology 139:
3262-3270.
Leibowitz SF, Akabayashi A, Alexander J, Karatayev O, Chang GQ. 2009.
Puberty onset in female rats: Relationship with fat intake, ovarian steroids and the peptides, galanin and enkephalin, in the paraventricular
and medial preoptic nuclei. J Neuroendocrinol 21:538-549.
Leibowitz SF, Akabayashi A, Alexander JT, Wang J. 1998. Gonadal steroids
and hypothalamic galanin and neuropeptide Y: Role in eating behavior
and body weight control in female rats. Endocrinology 139:1771-1780.
Leibowitz SF, Avena NM, Chang GQ, Karatayev O, Chau DT, Hoebel BG.
2003. Ethanol intake increases galanin mRNA in the hypothalamus and
withdrawal decreases it. Physiol Behav 79:103-111.
LeSage MG, Perry JL, Kotz CM, Shelley D, Corrigall WA. 2010. Nicotine
self-administration in the rat: Effects of hypocretin antagonists and
changes in hypocretin mRNA. Psychopharmacology (Berl) 209:203-212.
Levin BE. 1999. Arcuate NPY neurons and energy homeostasis in dietinduced obese and resistant rats. Am J Physiol 276:R382-R387.
Levin BE, Dunn-Meynell AA, Balkan B, Keesey RE. 1997. Selective breeding for diet-induced obesity and resistance in Sprague-Dawley rats. Am
J Physiol 273:R725-R730.
Levin BE, Magnan C, Migrenne S, Chua SC, Jr., Dunn-Meynell AA. 2005.
F-DIO obesity-prone rat is insulin resistant before obesity onset. Am J
Physiol Regul Integr Comp Physiol 289:R704-R711.
Lewis MJ, Johnson DF, Waldman D, Leibowitz SF, Hoebel BG. 2004.
Galanin microinjection in the third ventricle increases voluntary ethanol
intake. Alcohol Clin Exp Res 28:1822-1828.
Li TK, Lumeng L, Doolittle DP. 1993. Selective breeding for alcohol preference and associated responses. Behav Genet 23:163-170.
Lindholm S, Ploj K, Franck J, Nylander I. 2000. Repeated ethanol administration induces short- and long-term changes in enkephalin and dynorphin tissue concentrations in rat brain. Alcohol 22:165-171.
Lindqvist A, Baelemans A, Erlanson-Albertsson C. 2008. Effects of sucrose, glucose and fructose on peripheral and central appetite signals.
Regul Pept 150:26-32.
Linsenbardt DN, Boehm SL, 2nd. 2009. Agonism of the endocannabinoid system modulates binge-like alcohol intake in male C57BL/6J mice: Involvement of the posterior ventral tegmental area. Neuroscience 164:424-434.
Liu M, Shen L, Liu Y, Woods SC, Seeley RJ, D’Alessio D, Tso P. 2004a.
Obesity induced by a high-fat diet downregulates apolipoprotein A-IV
gene expression in rat hypothalamus. Am J Physiol Endocrinol Metab
287:E366-E370.
Liu X, York DA, Bray GA. 2004b. Regulation of ghrelin gene expression in
stomach and feeding response to a ghrelin analogue in two strains of
rats. Peptides 25:2171-2177.
54
Lograno DE, Matteo F, Trabucchi M, Govoni S, Cagiano R, Lacomba C,
Cuomo V. 1993. Effects of chronic ethanol intake at a low dose on the
rat brain dopaminergic system. Alcohol 10:45-49.
Loos RJ, Rankinen T, Rice T, Rao DC, Leon AS, Skinner JS, Bouchard C,
Argyropoulos G. 2005. Two ethnic-specific polymorphisms in the
human agouti-related protein gene are associated with macronutrient
intake. Am J Clin Nutr 82:1097-1101.
Lucas LA, McMillen BA. 2004. Effect of neuropeptide Y microinjected into
the hypothalamus on ethanol consumption. Peptides 25:2139-2145.
Lucchi L, Moresco RM, Govoni S, Trabucchi M. 1988. Effect of chronic
ethanol treatment on dopamine receptor subtypes in rat striatum. Brain
Res 449:347-351.
Ludwig DS, Tritos NA, Mastaitis JW, Kulkarni R, Kokkotou E, Elmquist J,
Lowell B, Flier JS, Maratos-Flier E. 2001. Melanin-concentrating hormone overexpression in transgenic mice leads to obesity and insulin
resistance. J Clin Invest 107:379-386.
Lumeng L, Li TK. 1986. The development of metabolic tolerance in the
alcohol-preferring P rats: Comparison of forced and free-choice drinking of ethanol. Pharmacol Biochem Behav 25:1013-1020.
Luquet S, Perez FA, Hnasko TS, Palmiter RD. 2005. NPY/AgRP neurons
are essential for feeding in adult mice but can be ablated in neonates.
Science 310:683-685.
Lyons AM, Lowery EG, Sparta DR, Thiele TE. 2008. Effects of food availability and administration of orexigenic and anorectic agents on elevated ethanol drinking associated with drinking in the dark procedures.
Alcohol Clin Exp Res 32:1962-1968.
Magoul R, Dubourg P, Benjelloun W, Tramu G. 1993. Direct and indirect
enkephalinergic synaptic inputs to the rat arcuate nucleus studied by
combination of retrograde tracing and immunocytochemistry. Neuroscience 55:1055-1066.
Mahler SV, Smith KS, Berridge KC. 2007. Endocannabinoid hedonic hotspot
for sensory pleasure: Anandamide in nucleus accumbens shell enhances
“liking” of a sweet reward. Neuropsychopharmacology 32:2267-2278.
Marks JL, Li M, Schwartz M, Porte D, Jr., Baskin DG. 1992. Effect of fasting
on regional levels of neuropeptide Y mRNA and insulin receptors in the rat
hypothalamus: An autoradiographic study. Mol Cell Neurosci 3:199-205.
Marmonier C, Chapelot D, Louis-Sylvestre J. 2000. Effects of macronutrient content and energy density of snacks consumed in a satiety state on
the onset of the next meal. Appetite 34:161-168.
Mathieu-Kia AM, Besson MJ. 1998. Repeated administration of cocaine,
nicotine and ethanol: effects on preprodynorphin, preprotachykinin A
and preproenkephalin mRNA expression in the dorsal and the ventral
striatum of the rat. Brain Res Mol Brain Res 54:141-151.
McDonald AJ, Mascagni F, Guo L. 1996. Projections of the medial and
lateral prefrontal cortices to the amygdala: A Phaseolus vulgaris leucoagglutinin study in the rat. Neuroscience 71:55-75.
McQuade JA, Benoit SC, Xu M, Woods SC, Seeley RJ. 2004. High-fat diet
induced adiposity in mice with targeted disruption of the dopamine-3
receptor gene. Behav Brain Res 151:313-319.
Melis M, Pillolla G, Perra S, Colombo G, Muntoni AL, Pistis M. 2009.
Electrophysiological properties of dopamine neurons in the ventral tegmental area of Sardinian alcohol-preferring rats. Psychopharmacology
(Berl) 201:471-481.
Mena JD, Baldo BA. 2009. DAMGO-induced stimulation of mu-opioid receptors in the mPFC leads to increases in food intake and a fragmentation of feeding microstructure. Neuroscience Meeting Planner. Chicago:
Society for Neuroscience. Program no. 755.7.
Mendez M, Morales-Mulia M. 2006. Ethanol exposure differentially alters
pro-enkephalin mRNA expression in regions of the mesocorticolimbic
system. Psychopharmacology (Berl) 189:117-124.
Meredith GE. 1999. The synaptic framework for chemical signaling in nucleus accumbens. Ann N Y Acad Sci 877:140-156.
Middaugh LD, Szumlinski KK, Van Patten Y, Marlowe AL, Kalivas PW. 2003.
Chronic ethanol consumption by C57BL/6 mice promotes tolerance to
its interoceptive cues and increases extracellular dopamine, an effect
blocked by naltrexone. Alcohol Clin Exp Res 27:1892-1900.
Milewicz A, Bidzinska B, Mikulski E, Demissie M, Tworowska U.
2000. Influence of obesity and menopausal status on serum leptin,
ILAR Journal
cholecystokinin, galanin and neuropeptide Y levels. Gynecol Endocrinol 14:196-203.
Minano FJ, Meneres Sancho MS, Sancibrian M, Salinas P, Myers RD.
1992. GABAA receptors in the amygdala: Role in feeding in fasted and
satiated rats. Brain Res 586:104-110.
Miraglia del Giudice E, Santoro N, Cirillo G, Raimondo P, Grandone A,
D’Aniello A, Di Nardo M, Perrone L. 2004. Molecular screening of the
ghrelin gene in Italian obese children: The Leu72Met variant is associated with an earlier onset of obesity. Int J Obes Relat Metab Disord
28:447-450.
Moghaddam B, Bolinao ML. 1994. Biphasic effect of ethanol on extracellular accumulation of glutamate in the hippocampus and the nucleus
accumbens. Neurosci Lett 178:99-102.
Moore EM, Boehm SL 2nd. 2009. Site-specific microinjection of baclofen
into the anterior ventral tegmental area reduces binge-like ethanol intake in male C57BL/6J mice. Behav Neurosci 123:555-563.
Moorman DE, Aston-Jones G. 2009. Orexin-1 receptor antagonism decreases
ethanol consumption and preference selectively in high-ethanol-preferring
Sprague--Dawley rats. Alcohol 43:379-386.
Morganstern I, Chang GQ, Barson JR, Ye Z, Karatayev O, Leibowitz SF.
2010a. Differential effects of acute and chronic ethanol exposure on
orexin expression in the perifornical lateral hypothalamus. Alcohol Clin
Exp Res 34:886-896.
Morganstern I, Chang GQ, Chen YW, Barson JR, Zhiyu Y, Hoebel BG,
Leibowitz SF. 2010b. Role of melanin-concentrating hormone in the
control of ethanol consumption: Region-specific effects revealed by expression and injection studies. Physiol Behav 101:428-437.
Morganstern I, Chang GQ, Karatayev O, Leibowitz SF. 2010c. Increased
orexin and melanin-concentrating hormone expression in the perifornical lateral hypothalamus of rats prone to overconsuming a fat-rich diet.
Pharmacol Biochem Behav 96:413-422.
Morzorati SL, Marunde RL, Downey D. 2010. Limited access to ethanol
increases the number of spontaneously active dopamine neurons in the
posterior ventral tegmental area of nondependent P rats. Alcohol 44:
257-264.
Mottagui-Tabar S, Prince JA, Wahlestedt C, Zhu G, Goldman D, Heilig M.
2005. A novel single nucleotide polymorphism of the neuropeptide Y
(NPY) gene associated with alcohol dependence. Alcohol Clin Exp Res
29:702-707.
Mucha RF, Iversen SD. 1986. Increased food intake after opioid microinjections into nucleus accumbens and ventral tegmental area of rat. Brain
Res 397:214-224.
Muller DJ, Zai CC, Sicard M, Remington E, Souza RP, Tiwari AK, Hwang
R, Likhodi O, Shaikh S, Freeman N, Arenovich T, Heinz A, Meltzer HY,
Lieberman JA, Kennedy JL. 2010. Systematic analysis of dopamine receptor genes (DRD1-DRD5) in antipsychotic-induced weight gain.
Pharmacogenomics J 12:156-164.
Naassila M, Pierrefiche O, Ledent C, Daoust M. 2004. Decreased alcohol
self-administration and increased alcohol sensitivity and withdrawal in
CB1 receptor knockout mice. Neuropharmacology 46:243-253.
Nadal R, Armario A, Janak PH. 2002. Positive relationship between activity
in a novel environment and operant ethanol self-administration in rats.
Psychopharmacology (Berl) 162:333-338.
Nagase H, Nakajima A, Sekihara H, York DA, Bray GA. 2002. Regulation
of feeding behavior, gastric emptying, and sympathetic nerve activity to
interscapular brown adipose tissue by galanin and enterostatin: The involvement of vagal-central nervous system interactions. J Gastroenterol
37(Suppl 14):118-127.
Nakashima Y. 2008. Fish-oil high-fat diet intake of dams after day 5 of
pregnancy and during lactation guards against excessive fat consumption of their weaning pups. J Nutr Sci Vitaminol (Tokyo) 54:46-53.
Naleid AM, Grace MK, Chimukangara M, Billington CJ, Levine AS. 2007.
Paraventricular opioids alter intake of high-fat but not high-sucrose diet
depending on diet preference in a binge model of feeding. Am J Physiol
Regul Integr Comp Physiol 293:R99-R105.
Navarro M, Cubero I, Chen AS, Chen HY, Knapp DJ, Breese GR, Marsh
DJ, Thiele TE. 2005. Effects of melanocortin receptor activation and
blockade on ethanol intake: A possible role for the melanocortin-4 receptor.
Alcohol Clin Exp Res 29:949-957.
Volume 53, Number 1
2012
Navarro M, Cubero I, Knapp DJ, Breese GR, Thiele TE. 2008. Decreased
immunoreactivity of the melanocortin neuropeptide alpha-melanocytestimulating hormone (alpha-MSH) after chronic ethanol exposure in
Sprague-Dawley rats. Alcohol Clin Exp Res 32:266-276.
Navarro M, Cubero I, Knapp DJ, Thiele TE. 2003. MTII-induced reduction
of voluntary ethanol drinking is blocked by pretreatment with AgRP(83-132). Neuropeptides 37:338-344.
Navarro M, Cubero I, Ko L, Thiele TE. 2009. Deletion of agouti-related
protein blunts ethanol self-administration and binge-like drinking in
mice. Genes Brain Behav 8:450-458.
Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E. 2000. Hypocretin
(orexin) deficiency in human narcolepsy. Lancet 355:39-40.
Nishizawa D, Han W, Hasegawa J, Ishida T, Numata Y, Sato T, Kawai A,
Ikeda K. 2006. Association of mu-opioid receptor gene polymorphism
A118G with alcohol dependence in a Japanese population. Neuropsychobiology 53:137-141.
Noto T, Hepler JR, Myers RD. 1984. Profile of amino acid synthesis in rat
hippocampus during push-pull perfusion of ethanol or morphine. Neuroscience 13:367-376.
Nylander I, Hyytia P, Forsander O, Terenius L. 1994. Differences between
alcohol-preferring (AA) and alcohol-avoiding (ANA) rats in the prodynorphin and proenkephalin systems. Alcohol Clin Exp Res 18:1272-1279.
O’Dell LE, Roberts AJ, Smith RT, Koob GF. 2004. Enhanced alcohol selfadministration after intermittent versus continuous alcohol vapor exposure. Alcohol Clin Exp Res 28:1676-1682.
Oades RD, Halliday GM. 1987. Ventral tegmental (A10) system: Neurobiology. 1. Anatomy and connectivity. Brain Res 434:117-165.
Obara I, Bell RL, Goulding SP, Reyes CM, Larson LA, Ary AW, Truitt WA,
Szumlinski KK. 2009. Differential effects of chronic ethanol consumption
and withdrawal on homer/glutamate receptor expression in subregions of
the accumbens and amygdala of P rats. Alcohol Clin Exp Res 33:1924-1934.
Odorizzi M, Max JP, Tankosic P, Burlet C, Burlet A. 1999. Dietary preferences of Brattleboro rats correlated with an overexpression of galanin in
the hypothalamus. Eur J Neurosci 11:3005-3014.
Oliva JM, Manzanares J. 2007. Gene transcription alterations associated
with decrease of ethanol intake induced by naltrexone in the brain of
Wistar rats. Neuropsychopharmacology 32:1358-1369.
Ollmann MM, Wilson BD, Yang YK, Kerns JA, Chen Y, Gantz I, Barsh GS.
1997. Antagonism of central melanocortin receptors in vitro and in vivo
by agouti-related protein. Science 278:135-138.
Olszewski PK, Shaw TJ, Grace MK, Hoglund CE, Fredriksson R, Schioth
HB, Levine AS. 2009. Complexity of neural mechanisms underlying
overconsumption of sugar in scheduled feeding: Involvement of opioids, orexin, oxytocin and NPY. Peptides 30:226-233.
Orosco M, Rouch C, Dauge V. 2002. Behavioral responses to ingestion of
different sources of fat. Involvement of serotonin? Behav Brain Res
132:103-109.
Ortiz S, Oliva JM, Perez-Rial S, Palomo T, Manzanares J. 2004. Differences
in basal cannabinoid CB1 receptor function in selective brain areas and
vulnerability to voluntary alcohol consumption in Fawn Hooded and
Wistar rats. Alcohol Alcohol 39:297-302.
Overstreet DH, Kampov-Polevoy AB, Rezvani AH, Murrelle L, Halikas JA,
Janowsky DS. 1993. Saccharin intake predicts ethanol intake in genetically heterogeneous rats as well as different rat strains. Alcohol Clin
Exp Res 17:366-369.
Palou M, Sanchez J, Rodriguez AM, Priego T, Pico C, Palou A. 2009. Induction of NPY/AgRP orexigenic peptide expression in rat hypothalamus is an early event in fasting: Relationship with circulating leptin,
insulin and glucose. Cell Physiol Biochem 23:115-124.
Papaleo F, Kieffer BL, Tabarin A, Contarino A. 2007. Decreased motivation to
eat in mu-opioid receptor-deficient mice. Eur J Neurosci 25:3398-3405.
Parkes JD, Baraitser M, Marsden CD, Asselman P. 1975. Natural history,
symptoms and treatment of the narcoleptic syndrome. Acta Neurol
Scand 52:337-353.
Pecina S, Berridge KC. 2005. Hedonic hot spot in nucleus accumbens shell:
Where do mu-opioids cause increased hedonic impact of sweetness? J
Neurosci 25:11777-11786.
Pereira RM, Aguiar-Oliveira MH, Sagazio A, Oliveira CR, Oliveira FT, Campos
VC, Farias CT, Vicente TA, Gois MB, Jr., Oliveira JL, Marques-Santos
55
C, Rocha IE, Barreto-Filho JA, Salvatori R. 2007. Heterozygosity for
a mutation in the growth hormone-releasing hormone receptor gene
does not influence adult stature, but affects body composition.
J Clin Endocrinol Metab 92:2353-2357.
Phillips TJ, Brown KJ, Burkhart-Kasch S, Wenger CD, Kelly MA,
Rubinstein M, Grandy DK, Low MJ. 1998. Alcohol preference and sensitivity are markedly reduced in mice lacking dopamine D2 receptors.
Nat Neurosci 1:610-615.
Phillipson OT, Griffiths AC. 1985. The topographic order of inputs to nucleus accumbens in the rat. Neuroscience 16:275-296.
Pickering C, Avesson L, Liljequist S, Lindblom J, Schioth HB. 2007. The role
of hypothalamic peptide gene expression in alcohol self-administration
behavior. Peptides 28:2361-2371.
Piepponen TP, Kiianmaa K, Ahtee L. 2002. Effects of ethanol on the accumbal output of dopamine, GABA and glutamate in alcohol-tolerant
and alcohol-nontolerant rats. Pharmacol Biochem Behav 74:21-30.
Pietzak ER, Wilce PA, Shanley BC. 1988. The effect of chronic ethanol consumption on muscarinic receptors in rat brain. Neurochem Int 12:447-452.
Polidori C, Geary N, Massi M. 2006. Effect of the melanocortin receptor
stimulation or inhibition on ethanol intake in alcohol-preferring rats.
Peptides 27:144-149.
Poncelet M, Maruani J, Calassi R, Soubrie P. 2003. Overeating, alcohol and
sucrose consumption decrease in CB1 receptor deleted mice. Neurosci
Lett 343:216-218.
Quintanilla ME, Perez E, Tampier L. 2008. Baclofen reduces ethanol intake
in high-alcohol-drinking University of Chile bibulous rats. Addict Biol
13:326-336.
Rabin RA, Wolfe BB, Dibner MD, Zahniser NR, Melchior C, Molinoff PB.
1980. Effects of ethanol administration and withdrawal on neurotransmitter receptor systems in C57 mice. J Pharmacol Exp Ther 213:491-496.
Rada P, Avena NM, Leibowitz SF, Hoebel BG. 2004. Ethanol intake is increased by injection of galanin in the paraventricular nucleus and reduced by a galanin antagonist. Alcohol 33:91-97.
Rada P, Bocarsly ME, Barson JR, Hoebel BG, Leibowitz SF. 2010. Reduced
accumbens dopamine in Sprague-Dawley rats prone to overeating a fatrich diet. Physiol Behav 101:394-400.
Rains TM, Mangian HF, Liang T, Cole AC, Beverly JL, Shay NF. 2001.
Growth hormone-releasing factor affects macronutrient intake during
the anabolic phase of zinc repletion: Total hypothalamic growth hormonereleasing factor content and growth hormone-releasing factor immunoneutralization during zinc repletion. Nutr Neurosci 4:283-293.
Rao RE, Wojnicki FH, Coupland J, Ghosh S, Corwin RL. 2008a. Baclofen, raclopride, and naltrexone differentially reduce solid fat emulsion intake under limited access conditions. Pharmacol Biochem Behav 89:581-590.
Rao Y, Lu M, Ge F, Marsh DJ, Qian S, Wang AH, Picciotto MR, Gao XB.
2008b. Regulation of synaptic efficacy in hypocretin/orexin-containing
neurons by melanin concentrating hormone in the lateral hypothalamus.
J Neurosci 28:9101-9110.
Rassnick S, Pulvirenti L, Koob GF. 1992. Oral ethanol self-administration
in rats is reduced by the administration of dopamine and glutamate receptor antagonists into the nucleus accumbens. Psychopharmacology
(Berl) 109:92-98.
Ravinet Trillou C, Delgorge C, Menet C, Arnone M, Soubrie P. 2004. CB1
cannabinoid receptor knockout in mice leads to leanness, resistance to
diet-induced obesity and enhanced leptin sensitivity. Int J Obes Relat
Metab Disord 28:640-648.
Reed JA, Benoit SC, Pfluger PT, Tschop MH, D’Alessio DA, Seeley RJ. 2008.
Mice with chronically increased circulating ghrelin develop age-related
glucose intolerance. Am J Physiol Endocrinol Metab 294:E752-E760.
Rhodes JS, Best K, Belknap JK, Finn DA, Crabbe JC. 2005. Evaluation of
a simple model of ethanol drinking to intoxication in C57BL/6J mice.
Physiol Behav 84:53-63.
Rice HB, Greenberg D, Corwin RL. 2000. Different preferences for oils
with similar fatty acid profiles. Physiol Behav 68:755-759.
Richards JK, Simms JA, Steensland P, Taha SA, Borgland SL, Bonci A,
Bartlett SE. 2008. Inhibition of orexin-1/hypocretin-1 receptors inhibits
yohimbine-induced reinstatement of ethanol and sucrose seeking in
Long-Evans rats. Psychopharmacology (Berl) 199:109-117.
56
Rodaros D, Caruana DA, Amir S, Stewart J. 2007. Corticotropin-releasing
factor projections from limbic forebrain and paraventricular nucleus of
the hypothalamus to the region of the ventral tegmental area. Neuroscience 150:8-13.
Rossi M, Beak SA, Choi SJ, Small CJ, Morgan DG, Ghatei MA, Smith DM,
Bloom SR. 1999. Investigation of the feeding effects of melanin concentrating hormone on food intake---Action independent of galanin and
the melanocortin receptors. Brain Res 846:164-170.
Roy A, Pandey SC. 2002. The decreased cellular expression of neuropeptide Y protein in rat brain structures during ethanol withdrawal after
chronic ethanol exposure. Alcohol Clin Exp Res 26:796-803.
Rubio M, de Miguel R, Fernandez-Ruiz J, Gutierrez-Lopez D, Carai MA,
Ramos JA. 2009. Effects of a short-term exposure to alcohol in rats on
FAAH enzyme and CB1 receptor in different brain areas. Drug Alcohol
Depend 99:354-358.
Rubio M, McHugh D, Fernandez-Ruiz J, Bradshaw H, Walker JM. 2007. Shortterm exposure to alcohol in rats affects brain levels of anandamide, other Nacylethanolamines and 2-arachidonoyl-glycerol. Neurosci Lett 421:270-274.
Russo P, Strazzullo P, Cappuccio FP, Tregouet DA, Lauria F, Loguercio M,
Barba G, Versiero M, Siani A. 2007. Genetic variations at the endocannabinoid type 1 receptor gene (CNR1) are associated with obesity phenotypes in men. J Clin Endocrinol Metab 92:2382-2386.
Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H,
Williams SC, Richarson JA, Kozlowski GP, Wilson S, Arch JR,
Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu WS,
Terrett JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M. 1998. Orexins
and orexin receptors: A family of hypothalamic neuropeptides and G
protein-coupled receptors that regulate feeding behavior. Cell 92:573-585.
Sakurai T, Mieda M, Tsujino N. 2010. The orexin system: Roles in sleep/
wake regulation. Ann N Y Acad Sci 1200:149-161.
Samson HH. 1986. Initiation of ethanol reinforcement using a sucrosesubstitution procedure in food- and water-sated rats. Alcohol Clin Exp
Res 10:436-442.
Samson HH, Chappell A. 2003. Dopaminergic involvement in medial prefrontal cortex and core of the nucleus accumbens in the regulation of
ethanol self-administration: A dual-site microinjection study in the rat.
Physiol Behav 79:581-590.
Samson HH, Chappell AM. 1999. Effects of microinjection of the D2 dopamine antagonist raclopride into the ventral tegmental area on ethanol
and sucrose self-administration. Alcohol Clin Exp Res 23:421-426.
Sanchez J, Cladera MM, Llopis M, Palou A, Pico C. 2010. The different
satiating capacity of CHO and fats can be mediated by different effects
on leptin and ghrelin systems. Behav Brain Res 213:183-188.
Sandbak T, Murison R. 1996. Voluntary alcohol consumption in rats: Relationships to defensive burying and stress gastric erosions. Physiol Behav 59:983-989.
Saulskaya NB, Mikhailova MO. 2002. Feeding-induced decrease in extracellular glutamate level in the rat nucleus accumbens: Dependence on
glutamate uptake. Neuroscience 112:791-801.
Schauble N, Reichwald K, Grassl W, Bechstein H, Muller HC, Scherag A,
Geller F, Utting M, Siegfried W, Goldschmidt H, Blundell J, Lawton C,
Alam R, Whybrow S, Stubbs J, Platzer M, Hebebrand J, Hinney A. 2005.
Human galanin (GAL) and galanin 1 receptor (GALR1) variations are not
involved in fat intake and early onset obesity. J Nutr 135:1387-1392.
Schmidt LG, Samochowiec J, Finckh U, Fiszer-Piosik E, Horodnicki J,
Wendel B, Rommelspacher H, Hoehe MR. 2002. Association of a CB1
cannabinoid receptor gene (CNR1) polymorphism with severe alcohol
dependence. Drug Alcohol Depend 65:221-224.
Schneider ER, Rada P, Darby RD, Leibowitz SF, Hoebel BG. 2007. Orexigenic peptides and alcohol intake: Differential effects of orexin, galanin,
and ghrelin. Alcohol Clin Exp Res 31:1858-1865.
Schramm-Sapyta NL, Kingsley MA, Rezvani AH, Propst K, Swartzwelder
HS, Kuhn CM. 2008. Early ethanol consumption predicts relapselike behavior in adolescent male rats. Alcohol Clin Exp Res 32:
754-762.
Schroeder JP, Olive F, Koenig H, Hodge CW. 2003. Intra-amygdala infusion
of the NPY Y1 receptor antagonist BIBP 3226 attenuates operant ethanol self-administration. Alcohol Clin Exp Res 27:1884-1891.
ILAR Journal
Seilicovich A, Duvilanski BH, Lasaga M, Debeljuk L, Diaz MC. 1988.
Effect of ethanol on GABA uptake and release from hypothalamic fragments. Psychopharmacology (Berl) 95:418-422.
Seilicovich A, Rubio M, Duvilanski B, Munoz Maines V, Rettori V. 1985.
Inhibition by naloxone of the rise in hypothalamic dopamine and serum
prolactin induced by ethanol. Psychopharmacology (Berl) 87:461-463.
Serra S, Carai MA, Brunetti G, Gomez R, Melis S, Vacca G, Colombo G,
Gessa GL. 2001. The cannabinoid receptor antagonist SR 141716 prevents acquisition of drinking behavior in alcohol-preferring rats. Eur J
Pharmacol 430:369-371.
Sesack SR, Pickel VM. 1992. Prefrontal cortical efferents in the rat synapse
on unlabeled neuronal targets of catecholamine terminals in the nucleus
accumbens septi and on dopamine neurons in the ventral tegmental area.
J Comp Neurol 320:145-160.
Sharf R, Sarhan M, Brayton CE, Guarnieri DJ, Taylor JR, DiLeone RJ.
2010. Orexin signaling via the orexin 1 receptor mediates operant responding for food reinforcement. Biol Psychiatry 67:753-760.
Shen CP, Wu KK, Shearman LP, Camacho R, Tota MR, Fong TM, Van der
Ploeg LH. 2002. Plasma agouti-related protein level: A possible correlation with fasted and fed states in humans and rats. J Neuroendocrinol
14:607-610.
Shiiya T, Nakazato M, Mizuta M, Date Y, Mondal MS, Tanaka M, Nozoe S,
Hosoda H, Kangawa K, Matsukura S. 2002. Plasma ghrelin levels in
lean and obese humans and the effect of glucose on ghrelin secretion.
J Clin Endocrinol Metab 87:240-244.
Shimada M, Tritos NA, Lowell BB, Flier JS, Maratos-Flier E. 1998. Mice
lacking melanin-concentrating hormone are hypophagic and lean. Nature
396:670-674.
Shinohara M, Mizushima H, Hirano M, Shioe K, Nakazawa M, Hiejima Y,
Ono Y, Kanba S. 2004. Eating disorders with binge-eating behaviour are
associated with the s allele of the 3’-UTR VNTR polymorphism of the
dopamine transporter gene. J Psychiatry Neurosci 29:134-137.
Shoblock JR, Welty N, Aluisio L, Fraser I, Motley ST, Morton K, Palmer
J, Bonaventure P, Carruthers NI, Lovenberg TW, Boggs J, Galici R.
2011. Selective blockade of the orexin-2 receptor attenuates ethanol
self-administration, place preference, and reinstatement. Psychopharmacology (Berl) 215:191-203.
Shor-Posner G, Brennan G, Ian C, Jasaitis R, Madhu K, Leibowitz SF.
1994. Meal patterns of macronutrient intake in rats with particular dietary preferences. Am J Physiol 266:R1395-R1402.
Short JL, Drago J, Lawrence AJ. 2006. Comparison of ethanol preference and
neurochemical measures of mesolimbic dopamine and adenosine systems
across different strains of mice. Alcohol Clin Exp Res 30:606-620.
Silverman AJ, Hoffman DL, Zimmerman EA. 1981. The descending afferent connections of the paraventricular nucleus of the hypothalamus
(PVN). Brain Res Bull 6:47-61.
Sinclair JD, Kampov-Polevoy A, Stewart R, Li TK. 1992. Taste preferences in
rat lines selected for low and high alcohol consumption. Alcohol 9:155-160.
Sindelar DK, Palmiter RD, Woods SC, Schwartz MW. 2005. Attenuated
feeding responses to circadian and palatability cues in mice lacking neuropeptide Y. Peptides 26:2597-2602.
Skofitsch G, Jacobowitz DM, Zamir N. 1985. Immunohistochemical localization of a melanin concentrating hormone-like peptide in the rat brain.
Brain Res Bull 15:635-649.
Smith BK, Berthoud HR, York DA, Bray GA. 1997. Differential effects of
baseline macronutrient preferences on macronutrient selection after
galanin, NPY, and an overnight fast. Peptides 18:207-211.
Smith BK, York DA, Bray GA. 1994. Chronic cerebroventricular galanin
does not induce sustained hyperphagia or obesity. Peptides 15:
1267-1272.
Sommer W, Hyytia P, Kiianmaa K. 2006. The alcohol-preferring AA and
alcohol-avoiding ANA rats: Neurobiology of the regulation of alcohol
drinking. Addict Biol 11:289-309.
Soszynski PA, Frohman LA. 1992. Inhibitory effects of ethanol on the
growth hormone (GH)-releasing hormone-GH-insulin-like growth
factor-I axis in the rat. Endocrinology 131:2603-2608.
South T, Huang XF. 2008. Temporal and site-specific brain alterations in
CB1 receptor binding in high fat diet-induced obesity in C57Bl/6 mice.
J Neuroendocrinol 20:1288-1294.
Volume 53, Number 1
2012
Sparta DR, Fee JR, Hayes DM, Knapp DJ, MacNeil DJ, Thiele TE. 2004.
Peripheral and central administration of a selective neuropeptide Y Y1
receptor antagonist suppresses ethanol intake by C57BL/6J mice. Alcohol Clin Exp Res 28:1324-1330.
Stanley BG, Chin AS, Leibowitz SF. 1985a. Feeding and drinking elicited
by central injection of neuropeptide Y: Evidence for a hypothalamic
site(s) of action. Brain Res Bull 14:521-524.
Stanley BG, Daniel DR, Chin AS, Leibowitz SF. 1985b. Paraventricular
nucleus injections of peptide YY and neuropeptide Y preferentially enhance carbohydrate ingestion. Peptides 6:1205-1211.
Stanley BG, Ha LH, Spears LC, Dee MG, 2nd. 1993. Lateral hypothalamic
injections of glutamate, kainic acid, D,L-alpha-amino-3-hydroxy-5-methylisoxazole propionic acid or N-methyl-D-aspartic acid rapidly elicit intense transient eating in rats. Brain Res 613:88-95.
Stanley BG, Lanthier D, Leibowitz SF. 1988. Multiple brain sites sensitive
to feeding stimulation by opioid agonists: A cannula-mapping study.
Pharmacol Biochem Behav 31:825-832.
Steiner JC, LaPaglia N, Hansen M, Emanuele NV, Emanuele MA. 1997.
Effect of chronic ethanol on reproductive and growth hormones in the
peripubertal male rat. J Endocrinol 154:363-370.
Stratford TR, Kelley AE. 1997. GABA in the nucleus accumbens shell participates in the central regulation of feeding behavior. J Neurosci 17:4434-4440.
Stratford TR, Swanson CJ, Kelley A. 1998. Specific changes in food intake
elicited by blockade or activation of glutamate receptors in the nucleus
accumbens shell. Behav Brain Res 93:43-50.
Stratford TR, Wirtshafter D. 2010. Opposite effects on the ingestion of
ethanol and sucrose solutions after injections of muscimol into the nucleus accumbens shell. Behav Brain Res 216:514-518.
Sun Y, Ahmed S, Smith RG. 2003. Deletion of ghrelin impairs neither
growth nor appetite. Mol Cell Biol 23:7973-7981.
Sun Y, Butte NF, Garcia JM, Smith RG. 2008. Characterization of adult
ghrelin and ghrelin receptor knockout mice under positive and negative
energy balance. Endocrinology 149:843-850.
Swanson LW. 1982. The projections of the ventral tegmental area and adjacent regions: A combined fluorescent retrograde tracer and immunofluorescence study in the rat. Brain Res Bull 9:321-353.
Szentirmai E, Kapas L, Krueger JM. 2007. Ghrelin microinjection into forebrain sites induces wakefulness and feeding in rats. Am J Physiol Regul
Integr Comp Physiol 292:R575-R585.
Szumlinski KK, Diab ME, Friedman R, Henze LM, Lominac KD, Bowers
MS. 2007. Accumbens neurochemical adaptations produced by bingelike alcohol consumption. Psychopharmacology (Berl) 190:415-431.
Tanaka Y, Egawa M, Inoue S, Takamura Y. 1991. Effect of hypothalamic
administration of growth hormone-releasing factor (GRF) on feeding
behavior in rats. Brain Res 558:273-279.
Tempel DL, Leibowitz KJ, Leibowitz SF. 1988. Effects of PVN galanin on
macronutrient selection. Peptides 9:309-314.
Tempesta E, Janiri L, Bignamini A, Chabac S, Potgieter A. 2000. Acamprosate and relapse prevention in the treatment of alcohol dependence: A
placebo-controlled study. Alcohol Alcohol 35:202-209.
Tentler JJ, LaPaglia N, Steiner J, Williams D, Castelli M, Kelley MR,
Emanuele NV, Emanuele MA. 1997. Ethanol, growth hormone and testosterone in peripubertal rats. J Endocrinol 152:477-487.
Teske JA, Levine AS, Kuskowski M, Levine JA, Kotz CM. 2006. Elevated
hypothalamic orexin signaling, sensitivity to orexin A, and spontaneous
physical activity in obesity-resistant rats. Am J Physiol Regul Integr
Comp Physiol 291:R889-R899.
Theisen FM, Haberhausen M, Firnges MA, Gregory P, Reinders JH,
Remschmidt H, Hebebrand J, Antel J. 2007. No evidence for binding of
clozapine, olanzapine and/or haloperidol to selected receptors involved
in body weight regulation. Pharmacogenomics J 7:275-281.
Thiele TE, Koh MT, Pedrazzini T. 2002. Voluntary alcohol consumption is
controlled via the neuropeptide Y Y1 receptor. J Neurosci 22:RC208.
Thiele TE, Marsh DJ, Ste Marie L, Bernstein IL, Palmiter RD. 1998. Ethanol consumption and resistance are inversely related to neuropeptide Y
levels. Nature 396:366-369.
Thiele TE, Naveilhan P, Ernfors P. 2004. Assessment of ethanol consumption and water drinking by NPY Y(2) receptor knockout mice. Peptides
25:975-983.
57
Thielen RJ, McBride WJ, Chernet E, Lumeng L, Li TK. 1997. Regional
densities of benzodiazepine sites in the CNS of alcohol-naive P and NP
rats. Pharmacol Biochem Behav 57:875-882.
Thongkhao-on K, Wirtshafter D, Shippy SA. 2008. Feeding specific glutamate surge in the rat lateral hypothalamus revealed by low-flow pushpull perfusion. Pharmacol Biochem Behav 89:591-597.
Thornton-Jones ZD, Kennett GA, Vickers SP, Clifton PG. 2007. A comparison of the effects of the CB(1) receptor antagonist SR141716A, prefeeding and changed palatability on the microstructure of ingestive
behaviour. Psychopharmacology (Berl) 193:1-9.
Thorpe AJ, Kotz CM. 2005. Orexin A in the nucleus accumbens stimulates
feeding and locomotor activity. Brain Res 1050:156-162.
Ticku MK, Burch TP, Davis WC. 1983. The interactions of ethanol with the
benzodiazepine-GABA receptor-ionophore complex. Pharmacol Biochem Behav 18(Suppl 1):15-18.
Town T, Abdullah L, Crawford F, Schinka J, Ordorica PI, Francis E, Hughes P,
Duara R, Mullan M. 1999. Association of a functional mu-opioid receptor
allele (+118A) with alcohol dependency. Am J Med Genet 88:458-461.
Tsujii S, Bray GA. 1991. GABA-related feeding control in genetically
obese rats. Brain Res 540:48-54.
Tuomainen P, Patsenka A, Hyytia P, Grinevich V, Kiianmaa K. 2003. Extracellular levels of dopamine in the nucleus accumbens in AA and ANA
rats after reverse microdialysis of ethanol into the nucleus accumbens or
ventral tegmental area. Alcohol 29:117-124.
Turenius CI, Htut MM, Prodon DA, Ebersole PL, Ngo PT, Lara RN, Wilczynski
JL, Stanley BG. 2009. GABA(A) receptors in the lateral hypothalamus as
mediators of satiety and body weight regulation. Brain Res 1262:16-24.
Ujike H, Nomura A, Morita Y, Morio A, Okahisa Y, Kotaka T, Kodama M,
Ishihara T, Kuroda S. 2008. Multiple genetic factors in olanzapineinduced weight gain in schizophrenia patients: A cohort study. J Clin
Psychiatry 69:1416-1422.
Van Bockstaele EJ, Pickel VM. 1995. GABA-containing neurons in the
ventral tegmental area project to the nucleus accumbens in rat brain.
Brain Res 682:215-221.
Verty AN, McGregor IS, Mallet PE. 2005. Paraventricular hypothalamic CB(1)
cannabinoid receptors are involved in the feeding stimulatory effects of
delta(9)-tetrahydrocannabinol. Neuropharmacology 49:1101-1109.
Walker BM, Koob GF. 2007. The gamma-aminobutyric acid-B receptor
agonist baclofen attenuates responding for ethanol in ethanol-dependent
rats. Alcohol Clin Exp Res 31:11-18.
Wallace DM, Magnuson DJ, Gray TS. 1992. Organization of amygdaloid
projections to brainstem dopaminergic, noradrenergic, and adrenergic
cell groups in the rat. Brain Res Bull 28:447-454.
Waller MB, McBride WJ, Lumeng L, Li TK. 1982. Induction of dependence on ethanol by free-choice drinking in alcohol-preferring rats.
Pharmacol Biochem Behav 16:501-507.
Wang H, Storlien LH, Huang XF. 2002. Effects of dietary fat types on body
fatness, leptin, and ARC leptin receptor, NPY, and AgRP mRNA expression. Am J Physiol Endocrinol Metab 282:E1352-E1359.
Wang J, Akabayashi A, Dourmashkin J, Yu HJ, Alexander JT, Chae HJ,
Leibowitz SF. 1998. Neuropeptide Y in relation to carbohydrate intake,
corticosterone and dietary obesity. Brain Res 802:75-88.
Wang L, Liu J, Harvey-White J, Zimmer A, Kunos G. 2003. Endocannabinoid signaling via cannabinoid receptor 1 is involved in ethanol preference and its age-dependent decline in mice. Proc Natl Acad Sci
U S A 100:1393-1398.
Warwick ZS, Synowski SJ, Rice KD, Smart AB. 2003. Independent effects
of diet palatability and fat content on bout size and daily intake in rats.
Physiol Behav 80:253-258.
Wenger T, Gerendai I, Fezza F, Gonzalez S, Bisogno T, Fernandez-Ruiz J,
Di Marzo V. 2002. The hypothalamic levels of the endocannabinoid,
anandamide, peak immediately before the onset of puberty in female
rats. Life Sci 70:1407-1414.
Wermter AK, Reichwald K, Buch T, Geller F, Platzer C, Huse K, Hess C,
Remschmidt H, Gudermann T, Preibisch G, Siegfried W, Goldschmidt
HP, Li WD, Price RA, Biebermann H, Krude H, Vollmert C, Wichmann
HE, Illig T, Sorensen TI, Astrup A, Larsen LH, Pedersen O, Eberle D,
Clement K, Blundell J, Wabitsch M, Schafer H, Platzer M, Hinney A,
58
Hebebrand J. 2005. Mutation analysis of the MCHR1 gene in human
obesity. Eur J Endocrinol 152:851-862.
White BD, Du F, Higginbotham DA. 2003. Low dietary protein is associated with an increase in food intake and a decrease in the in vitro release
of radiolabeled glutamate and GABA from the lateral hypothalamus.
Nutr Neurosci 6:361-367.
White CL, Ishii Y, Mendoza T, Upton N, Stasi LP, Bray GA, York DA. 2005.
Effect of a selective OX1R antagonist on food intake and body weight
in two strains of rats that differ in susceptibility to dietary-induced obesity. Peptides 26:2331-2338.
White JD, Kershaw M, Bruno JF, Olchovsky D, Song J, Camp P, Berelowitz
M. 1990. Localization of prepro-growth hormone releasing factor
mRNA in rat brain and regulation of its content by food deprivation and
experimental diabetes. Mol Cell Neurosci 1:183-192.
Whitworth AB, Fischer F, Lesch OM, Nimmerrichter A, Oberbauer H, Platz
T, Potgieter A, Walter H, Fleischhacker WW. 1996. Comparison of
acamprosate and placebo in long-term treatment of alcohol dependence.
Lancet 347:1438-1442.
Will MJ, Pratt WE, Kelley AE. 2006. Pharmacological characterization of
high-fat feeding induced by opioid stimulation of the ventral striatum.
Physiol Behav 89:226-234.
Wirth MM, Giraudo SQ. 2000. Agouti-related protein in the hypothalamic
paraventricular nucleus: Effect on feeding. Peptides 21:1369-1375.
Wirth MM, Giraudo SQ. 2001. Effect of agouti-related protein delivered to
the dorsomedial nucleus of the hypothalamus on intake of a preferred
versus a non-preferred diet. Brain Res 897:169-174.
Wise RA. 1973. Voluntary ethanol intake in rats following exposure to ethanol on various schedules. Psychopharmacologia 29:203-210.
Wojnicki FH, Roberts DC, Corwin RL. 2006. Effects of baclofen on operant
performance for food pellets and vegetable shortening after a history of
binge-type behavior in non-food deprived rats. Pharmacol Biochem Behav 84:197-206.
Wong KJ, Wojnicki FH, Corwin RL. 2009. Baclofen, raclopride, and naltrexone differentially affect intake of fat/sucrose mixtures under limited
access conditions. Pharmacol Biochem Behav 92:528-536.
Wortley KE, Chang GQ, Davydova Z, Leibowitz SF. 2003. Peptides that regulate
food intake: Orexin gene expression is increased during states of hypertriglyceridemia. Am J Physiol Regul Integr Comp Physiol 284:R1454-R1465.
Wright JD, Kennedy-Stephenson J, Wang CY, McDowell MA, Johnson CL,
National Center for Health Statistics C. 2004. Trends in intake of energy
and macronutrients-United States, 1971-2000. Morbidity Mortality Weekly
Report 53:80-82.
Wurst FM, Graf I, Ehrenthal HD, Klein S, Backhaus J, Blank S, Graf M,
Pridzun L, Wiesbeck GA, Junghanns K. 2007. Gender differences for
ghrelin levels in alcohol-dependent patients and differences between
alcoholics and healthy controls. Alcohol Clin Exp Res 31:2006-2011.
Yan QS, Zheng SZ, Feng MJ, Yan SE. 2005. Involvement of 5-HT1B receptors within the ventral tegmental area in ethanol-induced increases in
mesolimbic dopaminergic transmission. Brain Res 1060:126-137.
Yang ZJ, Meguid MM, Chai JK, Chen C, Oler A. 1997. Bilateral hypothalamic dopamine infusion in male Zucker rat suppresses feeding due to
reduced meal size. Pharmacol Biochem Behav 58:631-635.
Zhang M, Gosnell BA, Kelley AE. 1998. Intake of high-fat food is selectively enhanced by mu opioid receptor stimulation within the nucleus
accumbens. J Pharmacol Exp Ther 285:908-914.
Zhang M, Kelley AE. 2002. Intake of saccharin, salt, and ethanol solutions
is increased by infusion of a mu opioid agonist into the nucleus accumbens. Psychopharmacology (Berl) 159:415-423.
Zhou FC, Sahr RN, Sari Y, Behbahani K. 2006. Glutamate and dopamine
synaptic terminals in extended amygdala after 14-week chronic alcohol
drinking in inbred alcohol-preferring rats. Alcohol 39:39-49.
Zhu W, Czyzyk D, Paranjape SA, Zhou L, Horblitt A, Szabo G, Seashore
MR, Sherwin RS, Chan O. 2010. Glucose prevents the fall in ventromedial hypothalamic GABA that is required for full activation of glucose
counterregulatory responses during hypoglycemia. Am J Physiol Endocrinol Metab 298:E971-E977.
Zucker LM, Zucker TF. 1961. Fatty, a new mutation in the rat. J Heredity
52:275-278.
ILAR Journal