Psychopharmacology (2011) 217:455–473
DOI 10.1007/s00213-011-2296-2
ORIGINAL INVESTIGATION
Acute nicotine increases both impulsive choice
and behavioural disinhibition in rats
Katerina Zoe Kolokotroni & Robert J. Rodgers &
Amanda A. Harrison
Received: 1 October 2010 / Accepted: 1 April 2011 / Published online: 19 April 2011
# Springer-Verlag 2011
Abstract
Rationale Heavy smokers exhibit greater levels of impulsive
choice and behavioural disinhibition than non-smokers. To
date, however, the relationship between nicotine use and
differing dimensions of impulsivity has not been systematically
assessed.
Objectives A series of studies was designed to assess the
acute dose–response effects of nicotine and the nicotinic
receptor antagonist mecamylamine alone, and in combination with nicotine, on impulsive choice and behavioural
disinhibition in rats.
Methods Separate groups of rats were trained on a
symmetrically reinforced go/no-go task to measure levels
of disinhibition and a systematic delayed reward task to
measure levels of impulsive choice. Once trained, all
animals in each task were treated acutely with nicotine
(0.125, 0.25, 0.5 and 1.0 mg/kg), mecamylamine (0.1, 0.3
and 1.0 mg/kg) and varying doses of mecamylamine (0.1,
0.3 and 1.0 mg/kg) prior to nicotine (0.5 mg/kg). An
additional experiment assessed the effects of alterations in
primary motivation (presatiation and fasting) on performance
in both tasks.
Electronic supplementary material The online version of this article
(doi:10.1007/s00213-011-2296-2) contains supplementary material,
which is available to authorized users.
R. J. Rodgers : A. A. Harrison
Behavioural Neuroscience Laboratory, Institute of Psychological
Sciences, University of Leeds,
Leeds LS2 9JT, UK
K. Z. Kolokotroni (*)
Department of Psychology, Leeds Metropolitan University,
D420 Civic Quarter, Calverley Street,
Leeds LS1 3HE, UK
e-mail: [email protected]
Results Acute nicotine increased both impulsive choice
and behavioural disinhibition, effects that were blocked
by pre-treatment with mecamylamine. Mecamylamine when
administered alone did not alter impulsive behaviour. The lack
of effect of presatiation on performance measures suggests
that the observed nicotine-induced impulsivity cannot be
attributed to the anorectic activity of the compound.
Conclusions Present findings support the hypothesis that
heightened impulsivity in smokers may in part be a
consequence of the direct acute effects of nicotine. As
such, drug-induced changes in impulsivity may play a
critical role in the transition to and maintenance of nicotine
dependence.
Keywords Impulsivity . Drug abuse . Behavioural
inhibition . Go/no-go task . Impulsive choice . Delayed
reward task . Acute nicotine . Rats
Introduction
Impulsivity is a multidimensional concept subsuming a
failure of inhibitory control (disinhibition) and a preference
for immediate over delayed gratification (impulsive choice)
(Evenden 1999; Reynolds et al. 2006a). Increasing evidence suggests that substances of abuse, and psychostimulants in particular, increase levels of impulsive choice and
disinhibition in humans and laboratory animals (e.g. Anker
et al. 2009; Fillmore et al. 2002; Harrison et al. 1997;
Helms et al. 2006; Paine and Olmstead 2004; Stanis et al.
2008; Van Gaalen et al. 2006; but see De Wit et al. 2002;
Cardinal et al. 2000; Fillmore et al. 2006). Such findings
suggest that psychostimulant abuse may itself lead to the
heightened impulsivity often observed in chronic drug
abusers (e.g. Kirby and Petry 2004; Monterosso et al.
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2005; for review, see Perry and Carroll 2008). To date,
however, the effects of nicotine on impulsivity/impulsive
choice, have been less well documented.
Pharmacologically, nicotine produces its effects via
nicotinic acetylcholine receptors (nAChRs) located throughout the CNS (e.g. Mansvelder et al. 2009; Nashmi and
Lester 2006; Nayak et al; 2000; Woolterton et al. 2003).
Of particular relevance in the present context, nAChRs are
present in many brain regions implicated in the modulation of impulsivity (e.g. the ventral tegmental area,
striatum, nucleus accumbens, prefrontal cortex and amygdala;
Aron et al. 2004; Cardinal et al. 2001; Christakou et al. 2004;
Churchwell et al. 2009; Eagle et al. 2008; Hariri et al. 2006;
Koob and Volkow 2010; Winstanley et al. 2004). Extensive
research on smokers suggests a strong association between
nicotine dependence and impulsivity. For example, smokers
consistently discount the value of delayed rewards at a
steeper rate than non-smokers (e.g. Bickel et al. 1999; Bickel
et al. 2008; Fields et al. 2009; Reynolds et al. 2004;
Reynolds et al. 2009). This greater sensitivity to delayed
gratification in smokers has been demonstrated across
differing magnitudes of reward, when considering both
losses and gains (Baker et al. 2003) and making choices
regarding a range of commodities (Odum and Rainaud
2003). Consistent with other psychostimulant drugdependent populations, smokers display more pronounced
delay discounting of their drug of abuse (i.e. cigarettes vs.
other reward commodities) suggesting that the delayed drug
of abuse loses its subjective value to a greater extent than
other delayed rewards (e.g. Baker et al. 2003; Bickel et al.
1999). Disturbances in inhibitory control, as assessed by
continuous performance tasks (CPT) and go/no-go paradigms (Dinn et al. 2004; Spinella 2002; Yakir et al. 2007),
have also been documented in heavy smokers. Although this
previous research has left little doubt regarding an association between nicotine dependence and impulsivity, what
remains unclear is the direction of this relationship, i.e. is
impulsivity a cause or consequence of nicotine abuse? One
study that has attempted to explore the direction of causality
of this relationship discovered that adult smokers discount
delayed monetary rewards to a greater degree than both nonsmokers and young adolescent smokers (Reynolds et al.
2004). Adolescent smokers did not differ significantly from
the control group, supporting the hypothesis that heightened
impulsivity may be a consequence of long-term nicotine
exposure. However, for this interpretation to hold true, it
must be assumed that all the adolescent smokers will
continue smoking into adulthood.
To test the hypothesis that differences in impulsivity
between smokers and non-smokers arises due to nicotine
exposure requires research that explores directly the effects
of the stimulant on impulsivity. Despite extensive research
on the acute effects of cocaine and amphetamine, only one
Psychopharmacology (2011) 217:455–473
study to date has examined the acute effects of nicotine on
impulsive choice. In a rodent adjusting delay paradigm,
nicotine (0.03–1.0 mg/kg) produced a dose-dependent
increase in the choice of the immediate smaller reward
(Dallery and Locey 2005). The strength of these findings is,
however, limited by sample size and a failure to counterbalance for treatment order. Although a marginally greater
number of studies have assessed the acute effects of
nicotine on measures of behavioural inhibition, the results
have so far been equivocal. On the one hand, no significant
effects of acute nicotine on inhibitory control, as assessed
by the CPT and stop signal task (SST), were reported in
either non-smokers or overnight abstinent smokers (Bekker
et al. 2005; Levin et al. 1998). Conversely, amongst
neuropsychiatric populations suffering from attention-deficit
hyperactivity disorder or schizophrenia (where baseline
inhibitory control is abnormally low), acute nicotine
increased inhibitory control (Levin et al. 1996; Potter and
Newhouse 2004). These positive effects of acute nicotine on
inhibitory control in humans clearly contrast with the poor
impulse control evident in smokers and suggest that
abnormalities in this facet of impulsivity may predispose
individuals to initiate smoking. Such conclusions are
currently limited due to the small number of studies
exploring the effects of acute nicotine in both healthy
smokers and non-smokers.
Animal studies on the acute effects of nicotine on
inhibitory control have primarily focused on attentional
tasks (Carli et al. 1983). Acute nicotine has been found to
increase anticipatory responding in the five- and threechoice serial reaction time tasks (5CSRTT and 3CSRTT)
but only at low doses (0.03–0.3 mg/kg) and under task
conditions of high attentional demand which alone can
increase impulsive responding (e.g. Blondel et al. 2000;
Bizarro et al. 2004; Day et al. 2007; Harrison et al. 1997;
Mirza and Bright 2001; Mirza and Stolerman 1998;
Stolerman et al. 2000; Tsutsui-Kimura et al. 2010a). An
increase in inappropriate premature responding during a
delayed reinforcement of low levels of responding (DRL)
schedule of reinforcement has also been reported following
acute nicotine administration (Bizot 1998; Popke et al. 2000;
Kirshenbaum et al. 2009). However, this effect may be
related to nicotine’s known effects on time perception (e.g.
Carrasco et al. 1998).
In view of the above considerations, the aim of the
present study was to determine whether acute treatment
with nicotine (0.125–1.0 mg/kg) increases impulsivity in
drug-naïve rats as assessed in two behavioural tasks
designed to measure: (1) behavioural disinhibition as
assessed by a symmetrically reinforced go/no-go task and
(2) impulsive choice as assessed by a systematic delayed
reward paradigm. Mecamylamine (0.1–1.0 mg/kg), the
classical nAChR antagonist (Martin et al. 1989; Francis
Psychopharmacology (2011) 217:455–473
and Papke 1996; Varanda et al. 1985), was used to assess the
involvement of nAChRs in the mediation of nicotine-induced
impulsive behaviour. Finally, in view of the well-known
effects of nicotine on appetite, we assessed the effects of
alterations in primary motivation on performance of both
tasks.
Methods
Subjects
Subjects were 39 adult male Lister hooded rats (Charles
River, UK); 18 of which were trained on the symmetrically reinforced go/no-go task and 21 on the systematic
delayed reward task. On arrival in the laboratory, animals
were housed in pairs (46×26.5×26 cm) and maintained
under a 12-h light/dark cycle (lights on at 0700 hours) in
a temperature (21°C±3°C)- and humidity (50%±15%)controlled environment. At the start of testing, animals
weighed 300–350 g. A food deprivation schedule of
18.6 g/day (inclusive of food consumed during testing)
maintained animals at 85% of their free-feeding bodyweight.
Water was available ad libitum in home cages and feeding
occurred at the end of each day. All training and testing took
place during the animals light phase of their LD cycle between
0830 and 1800 hours.
Due to illness/and a failure to return to stable performance,
three subjects failed to complete all drug experiments and
were removed from the study. All procedures were conducted
under Home Office licence in accordance with the UK
Animals (Scientific Procedures) Act 1986.
Drugs
(−)-Nicotine hydrogen tartrate ((−)-1-methyl-2-(3-pyridyl)
pyrrolidine (+)-bitartrate salt) and mecamylamine hydrochloride (2-(methylamino)isocamphane hydrochloride;
inversine), obtained from Sigma-Aldrich (Poole, UK), were
dissolved in 0.9% saline and administered subcutaneously
(SC) in a volume of 1 ml/kg of body weight. Doses of both
compounds were chosen on the basis of the existing
literature (e.g. Stolerman et al. 2000; Harrison et al. 2001;
Dallery and Locey 2005). The pH of nicotine solutions was
adjusted to approximately six using 0.1 M NaOH. All drug
doses were calculated as free base and freshly prepared on
each test day.
Apparatus
Both behavioural tasks were performed in eight standard
operant chambers (dimensions 30.5×24.1×21 and 30.5×
24.1×29.2 cm; Med Associates Inc., USA). Each aluminium
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chamber was enclosed within a soundproof wooden box fitted
with a ventilation fan. Chambers were illuminated by a 2.8 W
house light and equipped with two retractable levers on the
front wall. Above each lever was a 2.8 W stimulus light while,
between the two levers, there was a food magazine to which
45 mg sucrose pellets (Noyes pellets, Sandown Scientific,
UK) were delivered from a pellet dispenser. The magazine
was illuminated by a white LED and head entries were
detected by an infrared photobeam. The apparatus was
controlled by Med-PC software running on a Pentium 3
Processor.
Procedure
Symmetrically reinforced go/no-go task
This task was based on that described by Harrison et al.
(1999). All animals were initially magazine-trained by
permitting access to several sucrose pellets placed in an
illuminated magazine. This phase was followed by continuous
reinforcement (CRF) training. Only one lever was presented
during these training sessions, with the position (right or left)
counterbalanced across rats. A lever press resulted in the
illumination of the magazine light which remained on
until the animal entered the magazine to receive a single
sucrose pellet. This training continued until rats earned
more than 50 pellets in 30 min on two consecutive
sessions: this usually required no more than five training
sessions.
The go/no-go task consisted of 40 go trials and 40 no-go
trials presented in random order. Animals were required to
discriminate between two visual stimuli comprising fast
(0.1 s pulses presented at 5 Hz) and slow (0.4 s pulses
presented at 0.83 Hz) synchronised flashings of the
stimulus lights. The stimulus-response contingencies were
counterbalanced in that, for half the animals, fast flashing
lights indicated a go trial while slow flashing lights
indicated a no-go trial while, for the remainder, the
converse applied. Each trial began with illumination of
the house light and the initiation of a 5-s inter-trial interval
(ITI), following which the discriminative visual stimuli
were presented for 10 s. During the first 1.2 s of stimulus
presentation (the pre-discrimination period), any lever press
was recorded as an early response but had no consequence
as this time period allowed the presentation of one complete
cycle of the slow stimulus and therefore identification of
the stimulus frequency prior to this time point was unlikely.
As go trials require an active lever response, early lever
responses were expected to be considerably greater during
these trials in comparison to no-go trials. Presentation of the
stimuli continued for a maximum period of 10 s or until
either a response on the lever occurred or animals entered
the food magazine. If animals entered the magazine during
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the 10 s stimulus presentation, a 5-s time-out period
followed and an inappropriate magazine entry was
recorded. During the time-out period, the house light was
extinguished and any further responses had no consequences. After the time-out period, the same trial was restarted.
If a lever response occurred during the 10 s stimulus
presentation period, one of two outcomes followed. During
a go trial, a lever press resulted in the stimulus lights being
turned off and the magazine being illuminated to signal the
availability of a food reward. This response was recorded as
a correct go trial. The animal then had a period of 5 s to
enter the food magazine which would in turn switch off the
magazine light and deliver a single sucrose pellet. However,
for no-go trials, a lever press resulted in the termination of
the flashing stimulus lights, followed by a 5-s time-out
period of darkness. In this case, an incorrect no-go trial was
recorded. If no lever response occurred during the 10 s
stimulus presentation then, again, then one of two outcomes
followed. If no response occurred during a no-go trial, at the
end of the stimulus presentation the magazine was illuminated
and animals had a 5-s period in which to enter the magazine
and receive a food reward. A correct no-go trial was recorded.
However, if animals failed to make a lever response during a
go trial, a 5-s time-out period of darkness followed and the
trial was recorded as an incorrect go trial.
Response latencies were also recorded for both trials and
were measured from the end of the pre-discrimination
period of the stimulus presentation until the lever was
pressed. Response latencies were recorded as correct and
incorrect during go and no-go trials, respectively. Both
correct and incorrect response latencies were used to
determine the ITI prior to the following trial. This was
achieved by subtracting the response latency from the total
possible duration of the stimulus had no lever response
occurred (i.e. 10 s). This duration was then added to the 5-s
ITI period. If no response occurred, the ITI duration was
simply 5 s. Therefore, irrespective of the type of trial that had
preceded and how the animals had responded, the duration
between trials always remained constant. This prevented a go
response being favoured due to a possible increase in rate of
delivery of reinforcement if a response bias occurred.
Magazine entry latencies were calculated from the time
of the correct response (i.e. a lever press during go trials or
following the stimulus presentation during no-go trials)
until the animal’s entry into the food magazine. If animals
failed to enter the magazine within 5 s, this was recorded as
a magazine omission and no rewards were delivered.
Training continued until animals reached a criterion of
85% total correct trials on two consecutive sessions.
Animals typically reached this level of performance
following 8 weeks of training. Once this level of accuracy
had been achieved, sessions continued for 1 week to ensure
that performance accuracy had stabilised prior to testing.
Psychopharmacology (2011) 217:455–473
All dependent variables recorded in the go/no-go task are
summarised in Table 1. The main index of disinhibition in
the paradigm was the inability to withhold responding
during no-go trials. Impulsive responding was therefore
indicated by reductions in the percentage of correctly
completed no-go trials. Enhancements of anticipatory
responses (both early responses and inappropriate magazine
entries) were also indicative of increased impulsive
responding, and these measures were utilised to provide
further support of an impulsive behavioural profile.
Systematic delayed reward task
Animals were initially magazine-trained by allowing free
access on two consecutive sessions to sucrose pellets in the
illuminated magazine. CRF lever training then commenced,
during which animals were trained to press the right and
left lever on alternate training sessions. Responding on a
lever resulted in illumination of the magazine light and
delivery of a single sucrose pellet. CRF training on each
lever continued until 100 pellets had been earned within a
20-min period on two consecutive sessions.
Animals were then trained on a simplified version of the
full delayed reward task. Each trial was 40 s in duration and
commenced with the illumination of the house and
magazine lights and retraction of both levers. Animals
were required to enter the magazine within 10 s in order for
a single lever to be presented and the magazine light to be
turned off. If the animal failed to nose poke the magazine,
the trial was aborted and the chamber returned to darkness
for the remainder of the current trial. When presented with
a lever, a response was required within 10 s or the chamber
returned to darkness and the lever retracted until the
following trial was initiated. If the animal did respond on
the lever, a single pellet was delivered and the magazine
light was illuminated until either the pellet was collected or
6 s had elapsed. Trials were presented in pairs so that each
lever was presented once. The order of presentation during
each pair of trials was randomised. This stage of training
continued until 60 trials had been successfully completed
within 1 h for two consecutive sessions. Animals were then
transferred to the full task where delays and small versus
larger rewards were introduced.
The delayed reinforcement task was based on behavioural
procedures described by Evenden and Ryan (1996) and
Cardinal et al. (2000) and comprised a total of 60 trials each
of 100 s duration. Animals were trained to make a choice
between one of two levers, one delivering a single pellet
immediately, the other five pellets after a programmed delay.
The delayed reward task was ‘systematic’ in nature as the
delay to the delivery of the larger reward was under
experimenter control and was either increased or decreased
systematically during the testing session. The initiation of
Psychopharmacology (2011) 217:455–473
Table 1 Summary of dependent
measures in the symmetrically
reinforced go/no-go task and
systematic delayed reward task
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Behavioural measures in go/no-go task
Accuracy of responding
Total percentage of correct trials (no. of correct go trials+correct no-go
trials/80×100)
Percentage correct go trials (no. of correct go trials/40×100)
Percentage correct no-go trials (no. of correct no-go trials/40×100)
Anticipatory responding
No. of go trials with early responses
No. of no-go trials with early responses
No. of go trials with inappropriate magazine entries
No. of no-go trials with inappropriate magazine entries
Speed of responding
Correct response latency during go trials (s)
Incorrect response latency during no-go trials (s)
Magazine latency following correct go trials (s)
Magazine latency following correct no-go trials (s)
Omissions
No. of magazine omissions following correct go trials
No. of magazine omissions following correct no-go trials
Behavioural measures in delayed reward task
Choice behaviour
Overall percent choice of delayed lever (no. of delayed reward lever
responses/(50−no. of omissions)×100)
Percentage choice of delayed lever by delay (0, 10, 20, 40 and 60; no.
of delayed reward lever responses/(10−no. of omissions)×100)
Speed of responding
Trial initiation latency (s)
‘Delayed’ reward choice latency (s)
‘Immediate’ choice latency (s)
Magazine latency following delayed reward choice (s)
Magazine latency following immediate reward choice (s)
Omissions
No. of trial omissions
No. of choice omissions
No. of magazine omissions following immediate choice
No. of magazine omissions following delayed choice
each trial was signalled by the illumination of the house and
magazine lights. Animals were required to nose poke the
magazine within 10 s, which resulted in the magazine light
being extinguished and both levers being inserted into the
test chamber. This ensured that the animal was centrally
located between both levers prior to making a response
choice. The latency to enter the magazine was recorded as
the trial initiation latency. If the animal failed to make a nose
poke response during this time period, the trial was recorded
as a ‘trial’ omission and the chamber returned to darkness
until commencement of the following trial.
When the levers were presented in the test chamber,
animals were required to respond on either lever within a
10-s period. If no lever response occurred, the levers were
retracted, the house light extinguished and the chamber
returned to the ITI for the remainder of the trial. This
behaviour was then recorded as a ‘choice’ omission. One
lever was designated the ‘immediate’ lever the other the
‘delayed’ lever for each animal, with this designation
counterbalanced left or right across animals. When a lever
response was made, both levers were withdrawn and the
house light turned off. A response on the ‘immediate’ lever
resulted in the immediate delivery of a single food pellet. A
response on the ‘delayed’ lever resulted in the delivery of
five food pellets, delivered 1 s apart, following a programmed
delay (of either 0, 10, 20, 40, 60 s). The latency to choose a
lever was recorded as the choice latency and was
measured as the time between trial initiation (nose-poking
the magazine) and lever responding. During the delivery
of sucrose pellets, the magazine light was illuminated
until either the animal entered the magazine to collect the
reward or until 6 s had passed. The chamber then entered
the ITI period for the remainder of the 100 s until the
initiation of the following trial. Initiation and response
latencies were used to calculate the length of the ITI
period to ensure that, regardless of behaviour in each trial, the
duration of all 60 trials remained constant. If collection of the
pellets occurred prior to the initiation of the next trial, the
magazine latency was calculated from the time of delivery of
the first pellet until a magazine entry was detected. Failure to
collect pellets prior to the next trial was recorded as a
‘magazine’ omission.
Each session comprised five blocks of 12 trials. Delays
varied for each block (0, 10, 20 40 and 60 s) with the
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direction of delays counterbalanced across animals, i.e. for
equal numbers of animals, delays either ascended or
descended in a step-wise manner across the session. Each
block of trials began with two forced trials followed by ten
free-choice trials. During forced trials (no choice available),
only one lever was presented. Each lever was presented
once in a randomised order during one of the forced trials.
Implementing forced trials ensured that animals had
experienced the delay as well as the large and small
rewards prior to the free-choice trials. During free-choice
trials, both levers were presented. Each session length was
100 min and animals received one session per day.
Immediate and delayed lever choices were recorded
during free-choice trials, thereby enabling calculation of the
percentage choice of the delayed lever (no. of delayed lever
responses/total number of responses) across the various
delays. Impulsive choice can be measured as a decrease in
choice of the delayed lever. Omissions were excluded from
choice calculations. Training continued until animals displayed stable, delay-dependent behaviour across three
consecutive sessions. This required approximately 10 weeks
of training. All dependent variables recorded during the
delayed reward task are summarised in Table 1.
Three experiments were conducted, each employing a
within-subjects design. Experiment 1 examined the acute
effects of NIC and MEC, alone and in combination, on
performance in the go/no-go task. Experiment 2 assessed
the effects of these manipulations in the delayed reward
task. Experiment 3 employed separate groups of trained
animals to examine the influence of alterations in primary
motivation on task performance. For experiments 1 and 2,
the animals were habituated to injection procedures prior to
drug testing. Within each phase (NIC, MEC and combination)
of experiments 1 and 2, treatments were administered
according to a Latin square design with a minimum interval
of 72 h between successive drug treatments. Between
successive phases of experiments 1 and 2, a minimum 1 week
‘wash-out’ period was used to minimise the possibility of drug
carry-over effects. Throughout all phases of each experiment,
animal’s task performance had returned to baseline levels
prior to drug treatments. Baseline performance in go/no-go
task was defined as accuracy deviating by no more than 5%
from that reached by the subject by the end of the training
phase. Baseline in the delayed reward task was defined as
impulsive choice deviating by no more than 10% from that
exhibited by the subject by the end of training.
Experiment 1: effect of acute nicotinic manipulations on
performance of the go/no-go task Phase 1 of this experiment assessed the dose–response effects of NIC (0, 0.125,
0.25, 0.5 and 1.0 mg/kg, SC, 10 min prior to testing) in a
group of 12 trained animals. Phase 2 assessed the dose–
response effects of MEC (0, 0.1, 0.3 and 1.0 mg/kg, SC,
Psychopharmacology (2011) 217:455–473
20 min prior to testing). In phase 3, a 0.5 mg/kg dose of NIC
was selected on the basis that it significantly increased
behavioural disinhibition in phase 1, while the lack of
behavioural disruption seen with MEC (phase 2) justified
the use of three ‘silent’ doses (0.1, 0.3 and 1.0 mg/kg, SC) of
the antagonist. This resulted in the following treatment
combinations: saline/saline, saline/NIC0.5mg/kg, MEC0.1mg/kg/
NIC0.5mg/kg, MEC0.3mg/kg/NIC0.5mg/kg and MEC1.0mg/kg/
NIC0.5mg/kg. Animals were pretreated with saline or MEC
10 min prior to NIC, with testing commencing after a further
10 min.
Experiment 2: effect of acute nicotinic manipulations on
performance of the systematic delayed reward task Phase 1
of this experiment examined the dose–response effects of
NIC (0, 0.125, 0.25 and 0.5 mg/kg, SC, 10 min prior to
testing) in a group of 11 trained animals. Each dose of
NIC was administered twice to each animal in order to
increase the number of choice trials at each delay to 20.
In phase 2, the dose–response effects of MEC (0, 0.1,
0.3, and 1.0 mg/kg, SC, 20 min prior to testing) on
performance in the delayed reward task were assessed.
Dose–response data from phases 1 and 2 were used to select
doses for phase 3 resulting in the following treatment
conditions: saline/saline, saline/NIC0.5mg/kg, MEC0.1mg/kg/
NIC0.5mg/kg, MEC0.3mg/kg/NIC0.5mg/kg and MEC1.0mg/kg/
NIC0.5mg/kg. Animals were pretreated with saline or MEC
10 min prior to NIC, with testing commencing after a further
10 min.
Experiment 3: effect of alterations in primary motivation on
performance of the go/no-go and delayed reward tasks Previous (unpublished) data indicated that acute administration
of either 0.125 or 0.5 mg/kg nicotine significantly reduced
food intake during a 1 h free-feeding study in animals (N=
10) of a comparable age and weight (350–370 g). This
anorectic effect was observed following doses of nicotine
that significantly increased impulsivity in experiments 1
and 2. Therefore to assess the effects of alterations in
primary motivation (i.e. hunger) on task performance, this
study examined the effects of presatiation and fasting on
performance in the go/no-go task (N=6) and delayed
reward task (N=10). The sequence of manipulations was
determined by a Latin square and, between manipulations,
an inter-test interval of at least 6 days elapsed during which
subjects were maintained under their normal baseline
operant testing and feeding regimen.
Phase 1: decrease in primary motivation
The potential influence of reduced hunger on task performance was assessed in two ways; firstly, by allowing 1 h of
Psychopharmacology (2011) 217:455–473
free access to a pre-weighed amount of normal rat chow
(Rat & Mouse Standard I Diet, Bantin & Kingman, Hull,
UK) immediately prior to operant testing and, secondly,
by allowing 30 min free access to a pre-weighed amount
of sucrose pellets (the reward used in operant tasks)
immediately prior to operant testing. The shorter period of
access to sucrose was adopted on the basis of preliminary
observations indicating a much greater and more rapid
consumption of sucrose pellets relative to normal chow.
Animals were individually housed during these prefeeding
sessions with water available ad libitum. Each animal’s
bodyweight was measured immediately prior to and following
the prefeeding period (1 h or 30 min), and the amount of food
consumed was calculated.
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Experiment 3 (Hunger manipulations: go/no-go and
delayed reward tasks) Data from each motivational manipulation were compared to the preceding 5-day average
baseline performance to assess the behavioural effects of
alterations in primary motivation. With the exception of
choice by delay in the delayed reward task, analysis of
all parameters of both tasks was conducted using a
repeated measures t test. Data for the choice of reward by
delay were analysed by a two-way repeated measures
ANOVA, with delay and motivational level as the withinsubject factors. Weight gain was assessed both as a change
in absolute bodyweight (g) and as a percentage change
from the weight recorded either immediately prior to the
prefeeding period or, for fasting, the day prior to the
feeding manipulation.
Phase 2: increase in primary motivation
The effect of increasing hunger on task performance was
assessed by reducing the normal daily food allowance to
9.3 g (i.e. a 50% reduction) on the day prior to testing. To
quantify loss of bodyweight, animals were weighed
immediately prior to operant testing.
Results
Experiment 1
Phase 1: nicotine dose response
Statistical analysis
All data were initially evaluated for normality and
sphericity. In cases where sphericity was violated, the
Greenhouse–Geisser correction was applied and the degrees
of freedom adjusted to more conservative values. Data that
violated normality were subjected to appropriate transformations: arcsine transformations were used for proportional data (percentage correct trials and percentage choice
data) while all other datasets were subjected to square root,
log10 or inverse transformations. If data could not be
transformed, then the non-parametric Friedman test was
employed and followed, where appropriate, by Wilcoxon
signed-rank tests. In all cases, values of p<0.05 were
deemed statistically significant.
Experiments 1 and 2 (effect of acute nicotinic manipulations on performance: go/no-go and delayed reward
tasks)For all drug phases, behavioural data were analysed
using a one-way repeated measures analysis of variance
(ANOVA). All significant main effects were assessed further
by Bonferroni post hoc comparisons. In experiment 2,
analysis of the choice of reward by delay was also conducted
using a two-way repeated measures ANOVA with treatment
condition and delay (0, 10, 20, 40 and 60 s) as within-subject
factors. Significant interactions were explored by simple
effects analysis. In the case of significant treatment×delay
interactions, one-way ANOVAs were used to examine
the main effects of dose across each of the five delay
conditions.
Performance accuracy Acute NIC produced a significant
deficit in overall performance in the go/no-go task (F(4, 44)=
5.769, p=0.001). Bonferroni comparisons demonstrated a
significant reduction in accuracy with 0.5 mg/kg (p<0.05)
and 1.0 mg/kg (p<0.05) NIC relative to the saline control
(see Electronic supplementary materials, Fig. 1a). Separate
assessment of performance accuracy on go and no-go trials
revealed a significant NIC-induced reduction in accuracy
on both types of trial (F(4, 44)=12.264, p<0.001; F(4,
44) = 2.802, p = 0.037, respectively). As illustrated in
Fig. 1a, performance during go trials was reduced following
1.0 mg/kg NIC when compared both to the saline control
and lower doses (0.125 and 0.25 mg/kg) of NIC (all p<
0.01). In contrast, 0.5 mg/kg NIC selectively impaired the
ability to withhold a response on no-go trials (p<0.05)
(see Fig. 1b).
Anticipatory responding With the exception of the highest
dose, NIC increased the number of go trials with early
responses (F(4, 44)=9.368, p<0.001). Post hoc analysis
revealed that, following 0.125 mg/kg NIC, early responses
significantly increased compared to both saline and 1.0 mg/kg
NIC (all p<0.05). The frequency of early responding
observed at 1.0 mg/kg NIC also differed significantly from
the lower dose of 0.5 mg/kg (p<0.01) (see Fig. 2a). Analysis
of early responding during no-go trials also confirmed a
main effect of treatment (F(4, 44)=3.187, p=0.022).
However, despite evidence of an increased frequency of
early responding at the 0.25 mg/kg dose, post hoc tests failed
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Psychopharmacology (2011) 217:455–473
Fig. 1 a–b Accuracy of
responding: the effects of acute
nicotine on percentage correct
go trials (a) and no-go trials (b).
Each bar represents the mean
percentage correct trials±SEM.
*p<0.05; **p<0.01 (as
compared to vehicle control);
†p<0.05; ††p<0.01 (as compared to the highest dose
(1.0 mg/kg))
to reach significance (see Fig. 2b). The number of go trials
with inappropriate magazine entries during the stimulus
presentation (Fig. 2c) increased following NIC (χ²=15.159,
df=4, p=0.004), a dose-related effect that reached significance at 0.5 mg/kg (p<0.05) and 1.0 mg/kg (p<0.01) in
comparison to the saline control. Furthermore, the increase
in this anticipatory measure observed after the highest dose
of NIC was significantly greater than that seen in response to
Fig. 2 a–f Anticipatory
responses and speed of
responding: the effects of acute
nicotine on early responses
during go trials (a) and no-go
trials (b), inappropriate magazine entries during go trials (c)
and no-go trials (d) and latency
in seconds to respond correctly
during go trials (e) and incorrectly during no-go trials (f). In
the case of anticipatory
responding, each point represents the mean number of trials
±SEM. In the case of speed of
responding, each point represents mean latency in seconds±
SEM. *p<0.05; **p<0.01
(as compared to vehicle
control); †p<0.05; ††p<0.01
(as compared to the highest
dose (1.0 mg/kg))
the 0.125 and 0.25 mg/kg treatment conditions. NIC had no
significant effect on inappropriate magazine entries during
no-go trials (F(4, 44)=1.427, N.S.) (see Fig. 2d).
Speed of responding Analysis revealed a significant main
effect of NIC on the latency to respond correctly during go
trials (F(4, 44)=6.203, p<0.001). Further post hoc analysis
revealed that 1.0 mg/kg NIC resulted in significantly slower
Psychopharmacology (2011) 217:455–473
lever responding in comparison to both the saline control
and 0.125 mg/kg NIC (all p<0.05). In contrast, the effect of
treatment on incorrect response latencies during no-go trials
failed to reach significance (F(4, 44)=0.774, N.S.) (see
Fig. 2e–f). Acute NIC had no significant effect on
latencies to collect the reward during either go or no-go
trials (F(1.831, 20.141)=2.882, p=N.S.; χ²=9.067, df=4,
p=N.S., respectively).
Phase 2: mecamylamine dose–response
Performance accuracy MEC had no significant effect on
overall performance accuracy in the go/no-go task (F(3, 30)=
1.571, N.S.) nor did the nicotinic antagonist affect accuracy
when data for go and no-go trials were independently
analysed (F(3, 30)=0.807, N.S.; F(3, 30)=1.463, N.S.
respectively) (see Electronic supplementary materials,
Table 1).
Anticipatory responding MEC did not alter the frequency
of early responding during go trials (F(3, 30)=0.117, N.S.)
and no-go trials (F(3, 30)=0.898, N.S.). The frequency of
magazine entries during go trials also remained unchanged
(F(3, 30)=0.240, N.S.) and, although a significant effect
was observed on this behaviour during no-go trials (F(3,
30)=3.882, p=0.020), post hoc tests failed to identify any
significant differences between drug conditions and the
saline control (see Electronic supplementary materials,
Table 1).
Speed of responding Although MEC did not significantly
affect correct response latencies (F(3, 30)=0.741, N.S.), a
significant main effect of treatment was observed for
incorrect response latencies during no-go trials (F(3, 30)=
5.577, p=0.004). Incorrect response latencies at 0.1 mg/kg
MEC were significantly faster compared with 0.3 and
1.0 mg/kg MEC (all p<0.05). No significant treatment
effects were observed on magazine latencies during either
go or no-go trials (F(1.180, 11.802)=1.731, N.S.; F(1.910,
19.096)=0.510, N.S., respectively) (see Electronic supplementary materials, Table 1).
Phase 3: mecamylamine antagonism of nicotine effects
Performance accuracy ANOVA indicated a significant
main effect of treatment on overall accuracy of performance
in the go/no-go task (F(4, 40)=18.761, p<0.001). Post hoc
analysis revealed that NIC alone significantly reduced the
number of correct trials in comparison to the saline/saline
control condition (p<0.01). Pre-treatment with MEC, at all
dose levels, significantly antagonised these effects of NIC,
463
with none of the drug combinations differing significantly
from the saline/saline control. In addition, overall performance accuracy following all MEC/NIC combinations was
significantly greater than performance following NIC alone
(all p <0.01) (see Electronic supplementary materials,
Fig. 1b).
Accuracy of performance on go trials was not affected
by any drug combination (F(4, 40)=2.945, N.S.). In direct
contrast, accuracy of performance on no-go trials revealed a
highly significant main effect of treatment (F(4, 40)=
20.512, p<0.001). When administered alone, NIC significantly decreased the percentage of correct no-go trials
relative to saline/saline control (p<0.01). Post hoc analysis
revealed that pre-treatment with MEC across all doses
blocked this effect of NIC, as demonstrated by the lack of
difference relative to the saline/saline control. Furthermore,
NIC treatment alone was significantly lower than all MEC/
NIC combinations (all p<0.01) (see Fig. 3a–b).
Anticipatory responding ANOVA failed to reveal any
treatment effects on the frequency of early responding or
inappropriate magazine entries on either go and no-go trials
(all F(4, 40)≤1.461, N.S.).
Speed of responding Whilst no significant effects of treatment were observed on the speed at which animals responded
on the lever during go trials (F(4, 40)=0.320, N.S.), analysis
did reveal a significant treatment effect on incorrect
response latencies during no-go trials (F(4, 40)=5.694,
p=0.001). Post hoc analysis showed that whilst NIC alone
slowed the speed of incorrect responses relative to saline
control (p<0.05), no significant differences were observed
between saline control and MEC/NIC combination treatments (all p>0.05 vs saline/saline). No significant treatment effects were observed on magazine latencies during
either go or no-go trials (F(1.765, 17.647)=2.300, N.S.;
F(2.196, 21.917)=1.781, N.S., respectively) (see Electronic
supplementary materials, Table 2).
Experiment 2
Across all phases of experiment 2, choice behaviour
remained highly delay sensitive as indicated by the main
effect of delay (phase 1: F(1.653, 16.528)=74.188, p<
0.001; phase 2: F(2.05, 18.493)=31.101, p<0.001; phase 3:
F(2.315, 20.839)=59.861, p<0.001).
Phase 1: nicotine dose–response
Choice behaviour A marked dose-related decrease in the
choice of the delayed reward was found following acute
administration of NIC (F(3, 30)=30.478, p<0.001). All
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Psychopharmacology (2011) 217:455–473
Fig. 3 a–b Accuracy of
responding: the effects of
combined mecamylamine and
nicotine treatment on percentage
correct go trials (a) and no-go
trials (b). Each bar represents
the mean percentage correct
trials±SEM. **p<0.01 (as
compared to vehicle control);
##p<0.01 (as compared to
nicotine treatment alone)
doses of NIC significantly decreased the overall choice of
delayed reward in comparison to saline control (all p<
0.01), with the greatest reduction observed at the highest
dose tested (0.5 mg/kg). Furthermore, the choice of delayed
reward at the highest dose was significantly lower than that
observed at lower doses (0.125 and 0.25 mg/kg; all p<0.01)
(see Electronic supplementary materials, Fig. 2a).
Analysis of choice by delay again demonstrated a highly
significant main effect of treatment (F(3, 30)=25.610, p<
0.001). Analysis revealed a significant treatment×delay
interaction, suggesting that NIC differentially affected
choice of the larger reward by delay (F(12, 120)=5.016,
p<0.001). A series of one-way ANOVAs (see Fig. 4a)
failed to find a significant effect of NIC at the 0-s delay, the
predominant choice being that of the larger reward at all
doses (F(3, 30)=0.897, N.S.). In marked contrast, significant main effects of NIC were found at the 10-, 20-, 40- and
60-s delays (all F(3, 30)≥6.550, p≤0.002). Post hoc
comparisons showed that, relative to saline control, choice
of delayed reward following 0.125 mg/kg NIC was
significantly lower only during 40-s delay trials (p<0.05),
choice of the delayed reward following 0.25 mg/kg was
significantly lower at the 40- and 60-s delays (all p<0.01),
and choice of the delayed reward following the highest
0.5 mg/kg dose was significantly lower at 10-, 20-, 40- and
60-s delays (all p<0.01). Furthermore, the reduction in
choice seen with 0.5 mg/kg NIC during the 10-s delay trials
was significantly different to that observed at 0.125 mg/kg
(p<0.05), while the reduction in choice at the high dose
during the 20-s delay trials was significantly different
compared with both lower doses (all p<0.05).
Speed of responding NIC decreased the latency to initiate
trials in the task (F(3,30)=8.101, p<0.001), an effect that
reached significance versus saline control at 0.25 mg/kg
(p<0.05) and 0.5 mg/kg (p<0.01)(See Fig. 5). However,
NIC did not affect the speed with which animals made a
choice between the rewards. This lack of effect on choice
latency was seen for both types of reward (immediate: F
(3,30)=1.631, N.S.; delayed: F(1.535, 15.351)=1.875, N.S.)
(see Fig. 5). Although the speed with which animals
collected food reward following an immediate choice was
not affected by NIC (F(3,30)=0.118, N.S.), 0.5 mg/kg NIC
significantly reduced the latency to collect reward following
a delay (χ2 =11.182, df=3, p=0.011). As well as differing
from saline control (p<0.01), 0.5 mg/kg NIC significantly
reduced delayed magazine latency relative to the lower dose
of 0.25 mg/kg (p<0.05) (see Fig. 5).
Omissions No significant effect of treatment was observed
on omissions to initiate trials (χ2 =5.947, df=3, N.S.).
However, the highest 0.5 mg/kg dose of NIC significantly
decreased magazine omissions to collect delayed reward
relative to saline control (χ2 =9.720, df=3, p =0.021).
Phase 2: mecamylamine dose–response
Choice behaviour Although a significant main effect of
MEC was observed on overall choice of delayed lever
(F(3,27) = 30.478, p = 0.011), post hoc analysis failed
reveal any significant differences between MEC doses
and saline control. The main effect instead reflected a
marginal, though significant (p<0.05) difference between
0.1 mg/kg and 1.0 mg/kg conditions (see Electronic
supplementary materials, Fig. 2b). Analysis of choice by
delay also demonstrated a main effect of MEC treatment
(F(3,27)=3.246, p=0.037). However, post hoc comparisons
again failed to identify significant differences between drug
groups and the saline control A significant dose x delay
interaction was also found (F (12, 108)=2.098, p=0.028).
As illustrated in Fig. 4(b), choice of the delayed reward
differed only at the 20-s delay (F(3,27)=4.063, p=0.017),
post hoc analysis revealing that the highest dose of MEC
decreased preference for the delayed reward in comparison
to 0.3 mg/kg (p=0.05) and not saline control.
Speed of responding MEC did not affect the latency to
initiate trials (F(3,26)=0.487, N.S.), the latency with which
animals chose either the delayed or immediate reward (all F
Psychopharmacology (2011) 217:455–473
465
0.286, N.S., respectively) (see Electronic supplementary
materials, Table 3).
Omissions MEC did not affect the frequency of trial
omissions or failure to collect reward following a delayed
reward choice (all χ2 ≤1.737, df=9, N.S.).
Phase 3: mecamylamine antagonism of nicotine effects
Fig. 4 a–c Choice behaviour: the effects of acute nicotine (a), acute
mecamylamine (b) and combined nicotine and mecamylamine
treatment (c) on percentage choice of delayed reward across delay
condition. Each point represents the mean percentage choice±
SEM. *p < 0.05; **p < 0.01; ***p < 0.001 (compared to vehicle
control); †p< 0.05; ††p< 0.01 (as compared to the highest nicotine
dose (0.5 mg/kg)); §p<0.05 (as compared with the 0.3 mg/kg
mecamylamine dose (0.3 mg/kg)).; #p<0.05; ##p<0.01 (as compared to
the combination treatment of saline and nicotine (0.3/0.5 mg/kg))
(3,27)≤1.381, N.S.), or the speed with which animals
collected reward following the choice of either an immediate
of delayed reward (F(1.722, 15.497)=1.381, N.S.; F(3,27)=
Choice behaviour ANOVA revealed a significant treatment
effect on overall choice of delayed reward (F(4, 26)=
17.487, p<0.001). NIC alone significantly reduced the
choice of the delayed reward relative to saline control (p<
0.01), an effect that was dose-dependently influenced by
MEC pre-treatment. Thus, while overall choice of delayed
reward was also significantly reduced following cotreatment with NIC and 0.1 mg/kg MEC (p<0.05), it was
not different to saline control when animals were co-treated
with NIC and 0.3 mg/kg MEC. Furthermore, choice of the
delayed reward in the latter condition was significantly
greater than following NIC alone (p<0.01). Finally, the coadministration of NIC and 1.0 mg/kg MEC significantly
decreased the choice of the delayed reward in comparison
to saline treatment. In addition, the overall choice of
delayed reward following co-administration of NIC and
either 0.1 or 1.0 mg/kg MEC was significantly lower than
that following co-administration of NIC and 0.3 mg/kg
MEC (all p<0.05) (see Electronic supplementary materials,
Fig. 2c).
This dose-related antagonism of nicotine’s effects on
choice behaviour was further supported by the significant
main effect of treatment on choice by delay (F(4, 36)=
20.248, p<0.001). Analysis additionally revealed a dose x
delay interaction (F(12,120) = 2.317, p = 0.005) (see
Fig. 4c). A series of one-way ANOVAs indicated that the
main effects of treatment across delay conditions reached
significance at all delays except the 0-s condition (all F(4,
36)≥4.742, p≤0.004). Post hoc analyses showed that,
compared to saline control, NIC alone significantly reduced
the choice of the delayed larger reward at 20- and 40-s
delays (all p<0.05). In contrast, pre-treatment with 0.1 and
1.0 mg/kg MEC decreased the choice of the delayed reward
significantly at the 20-s delay only (all p<0.05). However,
the co-administration of 0.3 mg/kg MEC and NIC resulted
in a choice of delayed reward across all delays that did not
differ from saline control (all p>0.05). In addition, the
choice of delayed reward at the 20-, 40-, and 60-s delays
following co-treatment with 0.3 mg/kg MEC and NIC was
significantly greater than choice at these delays following
NIC alone. Post hoc analysis also highlighted that,
following pre-treatment with 0.3 mg/kg MEC, choice of
delayed reward during the 10-s delay condition was
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Psychopharmacology (2011) 217:455–473
Fig. 5 Speed of responding: the
effects of acute nicotine on
latency in seconds to initiate
trials, to choose an immediate or
delayed reward and on latency
in seconds to collect reward
following and immediate and
delayed choice. Each bar represents the mean percentage
correct trials±SEM.*p<0.05;
**p<0.01 (as compared to
vehicle control). †p<0.05 (as
compared to the highest
nicotine dose (0.5 mg/kg))
significantly greater than choice at this delay following pretreatment with the lowest dose of MEC (p<0.05) (see
Fig. 4c).
Speed of responding Analysis revealed a significant treatment effect on latency to initiate trials in the task (F(4, 36)=
4.788, p=0.003). NIC alone decreased latencies relative to
saline control (p<0.05), an effect not seen in any of the
combined NIC/MEC treatment conditions (all p>0.05). No
treatment effects were found for the speed with which the
animals responded on the lever to select their reward, or the
latency with which they collected their reward following an
immediate or delayed reward choice (all F(4, 36)≤2.127,
N.S.) (see Electronic supplementary materials, Table 4).
Omissions No treatment effects were found for the frequency
of trial omissions or failure to collect reward following a
delayed reward choice (all χ2 ≤7.800, df=4, N.S.)
rewards following the completion of no-go trials did
however increase significantly in response to prefeeding
with both normal chow (Z=−1.997, p=0.046) and sucrose
pellets (Z=−2.201, p=0.028). All earned food pellets were
however consumed in the task following both feeding
manipulations.
Phase 2: increase in primary motivation
With the exception of a significant decrease in the latency
to incorrect responds during no-go trials (t=3.526, df=6,
p=0.012), food restriction had no effect on performance
accuracy, anticipatory responding, speed of responding or
frequency of omissions in the task (all t≤−1.655, df=6, N.S.).
Systematic delayed reward task
Phase 1: decrease in primary motivation
Experiment 3
For further details, see Electronic supplementary materials
(results section; Tables 5 and 6).
Go/no-go task
Phase 1: decrease in primary motivation
No significant effect on accuracy of performance, anticipatory responding or speed of responding was observed
following prefeeding with either normal rat chow or
sucrose pellets (all t≤2.127, df=5, N.S.). Failure to collect
Although choice behaviour remained delay sensitive (all F
(4, 36)≥35.766, p<0.001), prefeeding with chow or sucrose
had no significant effects on choice behaviour (main effect
of level of motivation all F(1, 9)≤2.289, N.S.; motivation×
delay interaction F(4, 36)≤0.791, N.S.). The latency to
initiate trials did however significantly increase following
both prefeeding manipulations (all t≥−2.998, df=9, p≤
0.015), as did the speed with which the immediate reward
was chosen (t=−2.326, df=9, p=0.045) and the delayed
reward was collected from the magazine (t=−3.229, df=9,
p=0.009), following prefeeding of chow and sucrose
respectively. Other speed of responding measures (all t≤−
1.655, d=9, N.S.), and frequency of omissions (all Z≤
1.389, N=10; N.S.) remained unchanged. Following both
Psychopharmacology (2011) 217:455–473
feedings manipulations, all food rewards were consumed in
the task.
Phase 2: increase in primary motivation
Following food restriction animals’ choice behaviour
remained delay sensitive (F(4, 36)=32.826, p<0.001), and
an increase in preference for the immediate reward was
observed in comparison to baseline (F(4, 36)=8.253, p=
0.018). A significant motivation×delay interaction (F(4,
36)=5.688, p=0.001) indicated that at the 10-s delay
preference for the immediate reward increased (t=−5.577,
df=9, p<0.001) (see Electronic supplementary materials,
Fig. 3). Increasing primary motivation also significantly
decreased both the magazine latency following a delayed
reward choice (t=1.905, df=9, p=0.045) and failures to
initiate trials (Z=−2.060, N=10, p=0.039). All of speed of
responding measures (all t≤ −1.189, df = 9, N.S.) and
omissions (Z=0.001, N=10, N.S.) were unaffected.
Discussion
Although the association between impulsivity and smoking
is well established, what is currently unclear is the extent to
which pre-existing differences in impulsivity and/or nicotine exposure may account for the heightened impulsive
choice and disinhibition observed in smokers. The present
research systematically assessed the effects of nicotine
administration on two different measure of impulsive
behaviour, that of impulsive choice and behavioural
disinhibition, in an attempt to explore the direct effects of
the drug on impulsive behaviour. The findings demonstrated
that acute exposure of drug-naïve animals to NIC elevated
both these dimensions of impulsivity. There were, however,
profound differences in the sensitivity of task behaviour to
nicotine, with impulsive choice being considerably more
sensitive to nicotine than behavioural disinhibition. Furthermore, as the observed modulation of impulsivity in both tasks
was antagonised by MEC, these behavioural effects of NIC
appear to be mediated by nAChRs.
Although acute challenges with NIC (0.5 and 1.0 mg/kg)
led to impairments in performance of the go/no-go task, the
specific behavioural profile differed as a function of dose.
At the highest dose (1.0 mg/kg), the reduction in accuracy
can be attributed to an inability to actively respond during
go trials without affecting the ability to withhold responding
during no-go trials. Although inappropriate magazine
entries increased during go trials, a significant slowing of
correct lever responding coupled with a reduction in
early responding suggests that 1.0 mg/kg NIC significantly disrupted basic task performance. Comparable
deficits in general operant behaviour have been previously
467
reported following this dose in the 5CSRTT procedure (e.g.
Hoyle et al. 2006) and is most likely attributable to the often
profound locomotor depression observed at higher acute
doses of the drug (e.g. Clarke and Kumar 1983; Stolerman
et al. 1973). Conversely, the reduction in overall accuracy
observed at 0.5 mg/kg NIC is clearly related to a significant
and selective decrease in the ability to withhold responding
on no-go trials. This pattern of responding reflects a clear
manifestation of NIC-induced behavioural disinhibition
(Fletcher 1993), an interpretation supported by a concurrent
enhancement of anticipatory responding (i.e. increased
inappropriate magazine entries during go trials). The lack
of effect of 0.5 mg/kg NIC on latencies suggests that the
drug-induced changes in impulsive responding reflect a
genuine deficit in inhibitory control over behaviour rather
than a more basic change in locomotor activity (Clarke and
Kumar 1983).
Present data agree well with previous preclinical
research demonstrating enhanced premature responding in
the 5CSRTT and DRL in rodents following acute NIC (e.g.
Bizot 1998; Bizarro et al. 2004; Blondel et al. 2000; Hahn
et al. 2002; Kirshenbaum et al. 2009; Mirza and Stolerman
1998; Popke et al. 2000; Stolerman et al. 2000; TsutsuiKimura et al. 2010a, b). However, they are at variance with
several other 5CSRTT studies that have failed to observe an
increase in anticipatory responding (Day et al. 2007; Hahn
et al. 2003; Mirza and Bright 2001). This inconsistency in
the acute effects of NIC on impulsive responding in the
5CSRTT may be accounted for by the generally lower dose
range of NIC (0.001–0.4 mg/kg) as used in the negative
reports. Furthermore, unlike the go/no-go task, the 5CSRTT
is primarily a model of sustained attention as opposed to
behavioural inhibition. Our findings also appear to be at
odds with the human literature where both a lack of effect
and an increase in inhibitory control on the CPT and SST
have been reported following acute NIC administration
(Bekker et al. 2005; Levin et al. 1996; Levin et al. 1998;
Potter and Newhouse 2004). Such discrepancies are most
likely attributable to major methodological differences in
the measurement of inhibitory control. Firstly, in past
research utilising the CPT, the profound effects of NIC on
sustained attention may have masked any effects of the
drug on behavioural disinhibition (Levin et al. 1996; Levin
et al. 1998; Bekker et al. 2005). Secondly, although the SST
and go/no-go task primarily assess inhibitory control,
contrasting effects of drugs of abuse in each of these
paradigms is not uncommon (e.g. Reynolds, et al. 2006b).
The go/no-go task requires the ability to wait and withhold
inappropriate responding whereas the SST requires the
ability to stop an already initiated response and switch to an
alternative behaviour. It may be that NIC impairs only the
former of these processes, an argument supported by that
fact that the two behaviours can be dissociated at both the
468
neuroanatomical and pharmacological level (e.g. Eagle
et al. 2008; 2009; Winstanley et al. 2006).
Nicotine induced changes in motivation (e.g. Grunberg
et al. 1986; Miyata et al. 1999; Zhang et al. 2001) are
unlikely to explain the observed increase in impulsive
responding. Neither decreasing motivation through prefeeding (either normal chow or sucrose pellets) nor
increasing motivation through reduction in daily food
allowance, had significant effects on accuracy of responding
or on anticipatory behaviour in the go/no-go task. Acutely
decreasing motivation did however significantly increase
failures to collect the food reward during no-go trials,
while increasing motivation led to faster incorrect lever
responses during these trials. Although magazine latency
has traditionally been used to index motivation (Robbins
2002), it has been argued that task omissions and response
latencies more consistently reflect the level of motivation
for reward in paradigms such as the 5CSRTT (Bizarro and
Stolerman 2003; Grottick and Higgins 2002). It can
therefore be argued that motivation for food reward was
effectively manipulated under these conditions. However,
these findings are inconsistent with the reported significant decreases and increases in anticipatory responding
reported in the 5CSRTT following presatiation and
increased deprivation levels, respectively (e.g. Bizarro
and Stolerman 2003; Grottick and Higgins 2002; Harrison
et al. 1997). The possibility that the prefeeding manipulations
in the present research did not reduce motivation to a great
enough extent to observe alterations in performance, cannot
easily account for the discrepancy in findings. Thus, in most
previous research, animals consumed less food (4–5 g) prior
to testing than did animals in the current study (12–12.6 g),
suggesting that motivation was actually reduced to a greater
extent in our animals. As such, the variation in findings is
more likely to be the result of methodological differences
between the paradigms used to measure inhibitory control.
In the delayed reward task, acute NIC led to a profound
dose-related decrease in overall choice of the delayed,
larger reward. The reduction in choice was also delay
dependent. Closer examination of choice behaviour revealed
that the effects of NIC were not due to an alteration in
preference of the delayed reward during 0-s delay trials but
rather to reductions in the choice of the delayed reward at the
10-, 20-, 40- and 60-s delays. With increasing doses, the NICinduced reduction in the choice of the delayed reward
was observed at a greater number of delays, thereby
supporting the dose-dependent effect of the drug on
choice behaviour (see Fig 4a). Further evidence that NICinduced greater impulsivity in the task was provided by
the more rapid speed at which trials were initiated
following the 0.25 and 0.5 mg/kg doses. The current
finding that NIC robustly increased impulsive choice is
consistent with the heightened sensitivity to delayed
Psychopharmacology (2011) 217:455–473
gratification that has been observed in heavy smokers
(Bickel et al. 1999; 2008; Fields et al. 2009; Reynolds et
al. 2004; 2009) and extends previous preclinical reports of
NIC-induced intolerance to delayed rewards in an adjusting
delay procedure (Dallery and Locey 2005). Moreover, present
results are consistent with the increased impulsive choice
observed following acute administration of other drugs of
abuse (i.e. cocaine, amphetamine and alcohol) in comparable
delayed reward tasks in both animals and humans (e.g.
Anker et al. 2009; Cardinal et al. 2000; Evenden and
Ryan 1996; Helms et al. 2006; Reynolds et al. 2006b;
Stanis et al. 2008).
Once again, NIC’s known anorectic effects cannot easily
account for the observed NIC-induced impulsive choice. In
agreement with previous research, acute prefeeding of
normal chow or sucrose pellets had no significant effect
on preference for the delayed reward in the task (e.g.
Cardinal et al. 2000; Logue and Pena-Correal 1985;
Richards et al. 1997). Speed of responding was however
reduced following prefeeding, providing evidence of
changes in motivation for the reward. Prefeeding prior to
testing also significantly increased the latency to initiate
trials and slowed the speed with which the immediate
reward was chosen and the delayed reward collected
following consumption of chow and sucrose pellets,
respectively. These findings indicate that speed of responding
and choice behaviour in the task can be altered independently and that measures of speed are more sensitive to
manipulations that reduce motivation. Conversely, acutely
increasing the deprivation state of animals significantly
increased the overall choice of delayed reward in comparison
to baseline. The enhanced preference of the delayed larger
reward was delay dependent, significantly increasing choice
of the delayed reward during the 10-s delay trials. An
increased preference for delayed reward observed following
the acute increase in deprivation state is in agreement with
some (e.g. Ho et al. 1997; Wogar et al. 1992) but not all (e.g.
Cardinal et al. 2000; Logue and Pena-Correal 1985) previous
studies in this area. Again, discrepant results most likely
reflect significant methodological variations in the delayed
reward paradigms as well as specific food and water
rewards. The lack of effect of prefeeding on choice
behaviour provides a strong argument against the possibility
that NIC’s known anorectic effects may have caused the
observed shift in preference from the larger delayed to the
smaller immediate reward. This conclusion is further
supported by the observed significant decrease in both the
latency to collect the delayed reward and the frequency of
omissions at the NIC dose that increased impulsivity most
profoundly.
Importantly, these effects are also unlikely to be related
to drug-induced changes in the sensitivity to reward
magnitude rather than delay. In contrast to the human
Psychopharmacology (2011) 217:455–473
literature (Green et al. 1997; Johnson and Bickel 2002),
there is limited evidence to indicate that choice behaviour is
sensitive to changes in reward magnitude in animal models
of delayed reward (e.g. Farrar et al. 2003; Green et al. 2004;
Richards et al. 1997). The fact that NIC-treated animals
continued to select the delayed larger reward on almost
100% of trials at the 0-s delay suggests that they were still
sensitive to the difference in magnitude of the rewards and
able to discriminate effectively between them. It is therefore
more likely that the NIC-induced preference for the
immediate reward is due to a hypersensitivity to delay.
It is important to acknowledge that the observed
enhancements in impulsive choice in the present study
could be due to effects of NIC on time perception (Bizot
1997; Carrasco et al. 1998). Nicotine is known to increase
‘internal clock’ speed, i.e. overestimate the passage of time.
In the delayed reward task, the delay to the delivery of the
larger reward is therefore likely to have been perceived as
longer following NIC treatment. As delayed reward is
discounted to a greater extent with increasing delay (e.g.
Bickel and Marsch 2001), the observed increased preference for the immediate reward may have been mediated by
drug-induced alterations in timing mechanisms. This
hypothesis is indirectly supported by the finding that, at
the highest dose tested (0.5 mg/kg), the latency to collect
the delayed reward was significantly reduced, as were
failures to collect the delayed reward. These data might
indicate that animals had overestimated the passage of time
during the delay period, and had prematurely approached
the magazine to await reward delivery. Although the current
data do not permit any firm conclusions, it seems likely that
there is a close association between time perception and
delay discounting.
In contrast to NIC, the nicotinic receptor antagonist
MEC was without significant effect on performance in the
go/no-go or delayed reward tasks. Whilst there was
evidence of a decrease in delayed reward preference at the
highest MEC dose (1.0 mg/kg), this failed to reach
significance in comparison to the saline control. In both
tasks other parameters including anticipatory responding,
speed of responding and omissions also remained unchanged
following MEC treatment. However, when co-administered
with NIC (0.5 mg/kg), all ‘silent’ doses of MEC antagonised
the NIC-induced loss of inhibitory control and decrease in
incorrect response latencies in the go/no-go task. Conversely,
only 0.3 mg/kg MEC fully antagonised the NIC-induced
hypersensitivity to delay observed in the delayed reward task.
In the MEC0.3mg/kg/NIC0.5mg/kg treatment condition, neither
overall choice of delayed reward nor choice by delay
differed from the saline control, thereby supporting the
complete reversal of NIC effects on impulsive choice.
Co-administration of either 0.1 and 1.0 mg/kg MEC
failed to block NIC’s effects on choice behaviour, with
469
both combinations significantly reducing choice of delayed
reward in comparison to the control. Replicating the effects on
task performance in phase 1, NIC alone once again
significantly decreased latency to initiate trials; intriguingly,
however, this effect was blocked by all doses of MEC.
Together, present findings suggest that the acute pharmacological effects of NIC both on impulsive choice and
behavioural disinhibition are mediated by nAChRs, extending
previous findings in the 5CSRTT (e.g. Blondel et al. 2000). In
terms of impulsive choice, our preclinical data are the first to
suggest that an optimal dose of MEC is required to block
NIC’s effects on choice behaviour, a finding that may
perhaps indicate competitive antagonism of this component
of impulsivity. Although MEC is generally believed to be
non-competitive in its action, it has been reported to also
exhibit some competitive properties, for example on
behaviours such as locomotor activity (Francis and Papke
1996; Martin et al. 1989; Varanda et al. 1985). Although
the lack of receptor subtype selectivity of MEC does not
permit conclusions regarding the specific nAChR subtypes
involved in NIC-induced effects on impulsivity, there is
some evidence to suggest that α4β2 and α7 receptors may
play a fundamental role in behavioural disinhibition. For
example, several studies have reported that administration
of the competitive antagonist DHβE, which has relative
selectivity for the α4β2 and α4β4 receptors (ChavezNoriega et al. 1997; Harvey and Luetje 1996), can reduce
impulsive action in the 3CSRTT (Tsutsui-Kimura et al.
2010b) and block the effects of NIC on anticipatory
responding in 5CSRTT (Blondel et al. 2000; Grottick and
Higgins 2000). This observation, combined with the
finding that stimulation of the α4β2 receptors by the
agonist SIB 1765F is capable of increasing premature
responding in the task (Grottick and Higgins 2000),
provides strong evidence for the involvement of the α4β2
receptor in NIC-induced disinhibition in the 5CSRTT. More
recent interest has focused on the homomeric α7 receptor.
Thus, in behavioural models comparable to the 5CSRTT,
α7 nicotinic knockout mice display significantly increased anticipatory responding relative to wild type
controls (Hoyle et al. 2006; Keller et al. 2005, but see
Tsutsui-Kimura et al. 2010b). At present, however, it is
not known whether the nicotinic receptors that govern
anticipatory responding in the 5CSRTT also influence
disinhibited behaviour in the go/no-go task or whether
these receptor subtypes are also involved in the modulation of impulsive choice. Extensive research suggests that
subcomponents of impulsive choice and disinhibition are
often dissociated at the level of receptor subtype, as is the
case for serotonin and dopamine (Talpos et al. 2006; Van
Gaalen et al. 2006; Wade et al. 2000; see Pattij and
Vanderschuren 2008 for a review). As such, future
research on NIC should employ more selective antagonists
470
(such as DHβE) to further delineate the role/s of specific
nicotinic receptor subtypes in various subcomponents of
impulsivity and in mechanisms downstream of these
receptors, e.g. mesocorticolimbic dopamine projections.
The neurochemical events beyond the nicotinic receptor
were not investigated in the present research. However,
when considering the neural systems that may be mediating
nicotine-induced elevations in impulsivity, the mesocorticolimbic DA system is a likely candidate (see Pattij and
Vanderschuren 2008 for review). As with other psychostimulants, acute treatment with nicotine enhances striatal
dopaminergic neurotransmission (e.g. Di Chiara and Imperato
1988). More specifically, stimulation of nAChRs receptors
located within the ventral tegmental area lead to a dosedependent increase in extracellular levels of dopamine (DA)
in the shell of the nucleus accumbens (NAc) and in the
prefrontal cortex (Benwell and Balfour 1992; Di Chiara and
Imperato 1988; Nisell et al. 1996). Interestingly both the β2
(e.g. Picciotto et al. 1998) and α7 (Schilstrom et al. 1998)
receptor subtypes have been implicated in acute nicotineinduced DA release in the NAc and may be involved in the
mediation of nicotine’s effects on inhibitory control (Blondel
et al. 2000; Grottick and Higgins 2000; Hoyle et al. 2006).
This suggests that nicotine-induced disinhibition may
depend heavily on the stimulation of DA activity within
the NAc via the α7, β2 nicotinic receptors. Lending
support to this theory is the finding that blockade of the
DA D1 and D2 receptors significantly attenuated nicotine-,
cocaine- and amphetamine-induced impulsive responding in
the 5CSRTT and 2CSRTT (e.g. Pattij et al. 2007; Van Gaalen
et al. 2006; 2009). To what extent dopaminergic systems are
involved in the nicotine-induced heightened impulsive
choice is less clear. The majority of research investigating
the effect of increasing synaptic levels of DA has been most
widely studied through the administration of the indirect
dopaminergic agonist, amphetamine. In both the human and
animal literature, acute doses of d-amphetamine have yielded
mixed results in delayed reward models; with both increases
(e.g. Cardinal et al. 2000; Evenden and Ryan 1996; Hand
et al. 2009; Helms et al. 2006) and decreases (e.g. Cardinal
et al. 2000; de Wit et al. 2002; Richards et al. 1997; Wade
et al. 2000; see Perry et al. 2008 for review) in impulsivity
reported. These contradictory findings can be attributed to a
number of procedural differences, including differences in
baseline impulsivity (see Perry et al. 2008) and the presence
or absence of a reward-predicting cue during the delay to
delivery of the larger reward (Cardinal et al. 2000).
Interestingly, in the absence of a reward-predicting
cue, as in the case of SDRT adopted in the present
study, d-amphetamine elevated impulsive choice (Cardinal
et al. 2000). Indeed, areas of the NAc and orbitofrontal
cortex within which nicotine is known to elevate DA (e.g.
Benwell and Balfour 1992; Cadoni and Di Chiara 2000;
Psychopharmacology (2011) 217:455–473
Nisell et al. 1996) have long been implicated in the neuronal
processes underlying impulsive choice (e.g. Bezzina et al.
2008; Cardinal et al. 2001; Khermin et al. 2002; Winstanley
et al. 2004; see Basar et al. 2010 for review).
In summary, current findings show that acute NIC
treatment results in behavioural disinhibition and a profound heightened sensitivity to delayed gratification. These
effects moreover appear to be mediated by nAChRs. Our
findings suggest that exposure to NIC during the early
stages of the addiction cycle may result in a discounting of
the longer-term social and health benefits associated with a
continued drug-free lifestyle in favour of the immediate
reinforcing properties of NIC. This heightened impulsive
choice, combined with inability to effectively inhibit drugseeking and drug-taking behaviour, is likely to promote
continued smoking and to increase the likelihood of the
transition to drug dependence. Although increasing evidence in both humans and animals suggests that impulsivity
is a predisposing factor in the initiation and maintenance of
addiction to drugs of abuse, including NIC (e.g. AudrainMcGovern et al. 2009; Diergaarde et al. 2008; for reviews,
see Perry and Carroll 2008; Verdejo-Garcia et al. 2008), the
present findings suggest that the acute effects of NIC on
impulsivity may also play a crucial role in maintaining drug
use. Whether pre-existing differences in impulsivity come
to interact with the effects of NIC on impulsivity is an
avenue for future research. Indeed, initial pilot data from
our laboratory suggest that low ‘trait’ impulsive animals
may be more sensitive to nicotine-induced impulsive
choice, whilst others have reported differential effects of
amphetamine in high and low impulsive animals (e.g. Feola
et al. 2000; Perry et al. 2008). Nevertheless, the present
data suggest that pharmacological and behavioural interventions designed to improve self-control may be successful in reducing susceptibility to and maintenance of NIC
addiction. However, given the often contrasting effects of
acute and chronic psychostimulant administration on
impulsivity (e.g. Richards et al. 1999; Stanis et al. 2008),
it is important that further research also assesses chronic
drug regimes that model more precisely the pattern of drug
use in dependent smokers.
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