Behavioural Brain Research 112 (2000) 127 – 134
www.elsevier.com/locate/bbr
Research report
Sucrose and quinine intake by maternally-deprived and control
rhesus monkeys
Ian A. Paul *, Justin A. English, Angelos Halaris
Department of Psychiatry, Di6ision of Neurobiology and Beha6ior Research, Laboratory of Neurobeha6ioral Pharmacology and Immunology,
Uni6ersity of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216 -4505, USA
Received 10 December 1999; received in revised form 9 February 2000; accepted 12 February 2000
Abstract
Clinical depression is often characterized by a loss of interest or pleasure in formerly enjoyable activities. Analogs of anhedonia
are established in rats, but the generality of this phenomenon to other species is unknown. Maternally-deprived rhesus macaques
show a wide range of behavioral abnormalities that are reversed by chronic antidepressant treatment. We tested consumption by
maternally deprived versus control macaques of sweetened (seven sucrose concentrations) or bitter water (four quinine
concentrations) versus plain water to evaluate a non-human primate model of depression for signs of anhedonia. All monkeys
consumed more sweetened than tap water, but maternally-deprived monkeys had a diminished preference for sweetened water
than did controls. However, maternally deprived animals consumed more bitter water than did controls. Baseline fluid
consumption did not differ. The data suggest that ‘anhedonia’ in animal models may be secondary to a generally attenuated
responsiveness to stimuli, rather than a unitary reduction in responsiveness to the appetitive properties of stimuli. We conclude
that maternally-deprived rhesus monkeys do not display gustatory signs of anhedonia, but rather of insensitivity to gustatory
stimuli. © 2000 Elsevier Science B.V. All rights reserved.
Keywords: Animal model; Anhedonia depression; Maternal deprivation; Monkey; Sucrose; Quinine
1. Introduction
Major depressive disorders are characterized by diverse symptoms including melancholia, suicidal ideation, to changes in appetitive behaviors, sleep patterns
and sexual behavior. The clinical presentation of individual cases varies widely with respect to the extent to
which any of these symptoms predominates. Many
classification and diagnostic systems for depressive disorders exist, and each diagnostic system defines a variety of subtypes of depressive disorders. Nevertheless,
certain core features or symptoms can be considered
defining or cardinal features of depression. One feature
that has received substantial attention is anhedonia, a
loss of interest or pleasure in acts that are normally
* Corresponding author. Tel.: +1-601-9845898; fax: + 1-6019845899.
E-mail address: [email protected] (I.A. Paul)
enjoyable. A recent field trial of the DSM-IV [3]
showed that anhedonia was present in 95% of patients
with major depressive disorder, and in 54% of dysthymic patients [20].
Unlike some clinical features of depressive disorders,
anhedonia can be readily operationalized in animal
models. Rats presented with a chronic regimen of variable mild stressors (CMS) will display progressive reductions
in
intracranial
self-stimulation
and
consumption of sweetened water. These reductions can
be attained with relatively brief (1 week) [16–18] or
more prolonged (5–9 weeks) stress, [38–42] are reversed by chronic treatment with some antidepressants,
and can be considered to be a rodent analog of anhedonia. Although similar results are reported with the brief
and chronic stress procedures, it has been suggested
that the briefer, more intensive exposure to stressors
might better model post-traumatic stress disorder than
major depression or dysthymia [2].
0166-4328/00/$ - see front matter © 2000 Elsevier Science B.V. All rights reserved.
PII: S 0 1 6 6 - 4 3 2 8 ( 0 0 ) 0 0 1 7 3 - X
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I.A. Paul et al. / Beha6ioural Brain Research 112 (2000) 127–134
Animal analogs of major depressive disorders (e.g.
forced swim test, DRL-72 and chronic mild stress)
generally use rodents as subjects. These analogs have
considerable predictive validity as behavioral screening
tools for identification of potential antidepressant treatments. Nonetheless, the extent to which such analogs
can model major depression is limited by at least two
factors: the etiology of major depressive disorders is
unknown and the range of affective expression of rodents is limited and difficult to equate with human
emotional expression [37].
An alternative to procedures using rodents, the maternally-deprived rhesus monkey, has also been proposed as an animal model of depression [8,9]. In the
maternal-deprivation model, newborn monkeys are separated from their mothers and reared in a nursery
environment with minimal social contact. Maternallydeprived macques develop persistent behavioral abnormalities including inappropriate or ambivalent response
to social situations, gaze aversion, huddling and self-injurious behaviors [22,28,33,35]. Early studies indicated
that at least some of these deficits could be reversed or
ameliorated with chronic tricyclic, monoamine oxidase
inhibitor and electroconvulsive antidepressant treatments [23,25,36]. Likewise, repeated contact with a
‘therapist’ monkey reduces the presentation of these
behaviors [32,34]. Nonetheless, predictive validation of
this model has been quite limited, with only a few
antidepressant therapies tested. Thus, considerable controversy exists as to the nature of the effects of neonatal
maternal deprivation and their relevance to major depressive disorders [25,27].
The present study was designed to determine if a
diminished response to pleasurable stimuli like that
observed in rodents (i.e. reduction in sucrose solution
consumption) could be observed in maternally-deprived
macaques. We also measured response to a presumably
aversive stimulus (i.e. quinine solution consumption), to
test the hypothesis that decreases in sucrose solution
consumption could reflect a general decrease in responsiveness to gustatory stimuli. In the present study,
maternally-deprived macaques consumed less of a normally preferred sweetened solution than did controls.
Moreover, maternally-deprived macaques consumed a
normally aversive bitter solution as avidly as they did
tap water. These effects were concentration dependent
and were accompanied by compensatory reductions or
increases in the consumption of tap water.
2. Methods and materials
Four maternally-deprived rhesus macaques (Macaca
mulatta, three female; one male, Harlow Primate Center, Madison, WI) and five normally-reared controls
(five females, Oregon Regional Primate Center)
matched for age and body weight (5–8 kg, 4– 5 years
old) were individually housed in stainless steel cages.
Maternally-deprived macaques were removed from
their mothers at 3 days postpartum and were hand- or
nursery-reared by human caregivers until the age of 6
months. Once trained to self-feed from a bottle, they
were raised on Similac formula. At 3–5 months of age,
they were transferred to Purina monkey chow. At 7
months of age, all but one monkey (AL-67) were
pair-housed. They experienced repeated separations
from the partner and were singly-housed for the course
of these experiments. The male macaque (AL-67) was
single-housed at the Harlow Laboratories for experimental purposes but, did have daily interactions with
humans. All monkeys had been involved in previous
experimental procedures as follows: controls — subjected to one to two bone marrow biopsies; female
maternally-separated (AO72, AO74, AO77) — observation of separation-induced behavior; male maternally-separated (AL67) — trained and tested in the
WGTA. All monkeys were undisturbed except for shipping for 6–12 months prior to the beginning of our
preference studies.
After arrival and quarantine in the UMC Laboratory
Animal Facilities, all monkeys were single-housed with
visual access to several other cohort members. All
animals were placed on a 12 h light/dark cycle (on at
07:00 h) and were fed monkey biscuits (Harlan
LabraDiet (25%) 12–15 biscuits/day) supplemented
with fruit to maintain normal body weight. Three
months after their arrival, all animals were acclimated
to a 23 h/day water restriction schedule. Animals had
access to tap water in two identical bottles for 1 h/day.
Bottles were placed such that the spouts were approximately 35 cm from the cage floor and approximately 15
cm from either wall of the front of the cage. After
acclimation to the restriction schedule and between
experiments, baseline water consumption was monitored daily. The UMMC Animal Care and Use Committee monitored all procedures. Animals were healthy
throughout the study and unrestrained with the exception of those occasions when the monkeys were anesthetized with ketamine for physical examination and
tuberculin skin testing (3–4 times throughout the
study).
All maternally-deprived animals displayed consistent
affective display confusion, huddling, fearfulness, agitation and, in one case, sham self-biting throughout the
course of experimentation. Normally-reared animals
displayed no such behavioral signs and reacted normally to human presence in the colony room. No
increase or diminution of aberrant behavior among the
maternally-deprived animals was observed over the
course of experimentation. However, animals were not
formally rated during these experiments.
In the first experiment, one bottle contained one
of seven sucrose concentrations (0.375–6.0% – i.e.
I.A. Paul et al. / Beha6ioural Brain Research 112 (2000) 127–134
129
followed by Tukey’s HSD to identify between-cell differences (SPSS Windows, v. 5.05, SPSS Inc., Chicago,
IL).
3. Results
Fig. 1. Flavored water intake during sucrose presentation experiments.
Open symbols and solid lines represent control subjects, filled symbols
and broken lines represent maternally-deprived monkeys. Trials are
bracketed by presentation conditions (Baseline =tap water in both
bottles, 0.375, 0.75, 1.5, 3.0, 6.0% = percent sucrose in flavored bottle).
Data represent the mean of five controls and four maternally-deprived
macaques per group. Although not shown for clarity, S.E.M. values
were typically 15 – 25% of the mean value on any trial.
All monkeys displayed a stable baseline of water
consumption when presented with two bottles of tap
water. Baseline total water consumption did not differ
as a function of group (controls= 1609 5 ml/kg, n=
100 observations; deprived= 1489 5 ml/kg, n=80 observations) or bottle position (data not shown).
Because of the relatively small number of animals
available for testing, presentation of the various concentrations of sucrose were conducted repeatedly over
the course of 4 months. The initial data reduction is
shown in Fig. 1. As is evident on inspection, maternally-deprived monkeys consumed less of any sweetened solution with a concentration greater than 0.75%
sucrose. After the initial presentation of 3 and 6%
sucrose solutions (trials 1–24), the monkeys were re-
2.74–175.0 mM), randomly presented. The bottles were
refilled 30 min after the start of the access period to
accommodate the increased consumption of sweetened
water. The second experiment was similar to the first,
except that one of five quinine – HCl concentrations
(0.1 –5.0 mM) was presented for 4 days as described for
sucrose. Bottle positions were alternated daily to control for position preference. Fluid consumption was
measured at the middle and end of access. Because
baseline fluid consumption is correlated with body
weight (data obtained over 20 baseline observation
days, r 2 =0.48, F1,6 =5.46, P = 0.058), fluid intake for
each bottle was analyzed as ml consumed per kg body
weight.
Sucrose was obtained from commercial sources as
cane sugar while quinine – HCl was obtained from
Sigma (St. Louis, MO). Sucrose or quinine was diluted
with house tap water. All bottles were thoroughly
washed and sanitized between presentations. Sucrose
and quinine solutions were prepared fresh every 2–4
days in sanitized containers.
Data were collected for 8 – 30 days per [sucrose] or 2
days per [quinine] from all animals. We have presented
data both by trial and condition. However, in order to
reduce variance and simplify data analysis each condition’s data for all animals in a group were pooled. Thus
n= observations= (number of subjects)×(number of
trials) per condition. Although this technique tends to
obscure individual variance, it best describes the performance of each group of animals when presented with a
particular concentration of either sucrose or quinine.
Data were subsequently analyzed with two-factor analysis of variance (group ×[sucrose] or group×[quinine]
Fig. 2. Effect of concentration on flavored water intake (pooled into
four trial blocks). Open symbols or bars represent control, filled
symbols and bars represent maternally-deprived subjects. Data for each
animal were pooled in blocks of four trials. The mean9S.E.M. of five
control and four maternally-deprived monkeys for each block within
a given sucrose concentration are presented.
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I.A. Paul et al. / Beha6ioural Brain Research 112 (2000) 127–134
Fig. 3. Flavored water intake pooled by sucrose concentration. Open symbols and solid lines represent controls, filled symbols and broken lines
represent maternally-deprived macaques. Data are presented as the mean 9 S.E.M. of all subject-trials within a given sucrose presentation
concentration. Inset: Concentration–response relationship for sucrose to facilitate fluid consumption from the sucrose-containing bottle. Data
were analyzed using a single-site sigmoidal model. R 2 \ 0.9 for both control and maternally-deprived. Points labeled a are significantly different
from the within-group baseline; points labeled b indicate significant between-group differences.
turned to baseline (tap water in both bottles) from trials
27 – 46. The animals were retested with similar results
(trials 47–76) and the sensitivity to sucrose concentration was extended (trials 77 – 118).
As shown in Fig. 2, relatively little difference between
control and maternally-deprived monkeys was observable at concentrations of sucrose less than 1.5% and
greater than 3%. However, at concentrations of 1.5 and
3% sucrose, maternally-deprived monkeys repeatedly
consumed less of the flavored solutions than did
controls.
In summary, when presented with a choice between a
sweetened solution and tap water all monkeys concentration-dependently increased their consumption from
the bottle containing sucrose (Fig. 3). When analyzed
as a concentration-response function (Fig. 3, inset) it is
clear that maternally-deprived monkeys were both less
sensitive to sucrose (increased EC50) and less responsive
to sucrose (reduced EMAX) than controls. Likewise, all
monkeys reduced tap water consumption when presented with sweetened water (Fig. 6A). However, except
at very high sucrose concentrations, no difference in tap
water intake was observed between controls and deprived (Fig. 6A). Thus, total fluid intake increased in
both groups up to 3% sucrose (data not shown).
Presentation of quinine-flavored water was conducted in a manner similar to that of sucrose presentation (Fig. 4). However, owing to our concern for
inducing a conditioned-taste aversion in either group,
quinine was presented for shorter intervals (no more
than 2 sequential trials/concentration and no more than
10 sequential trials of quinine. As with the sucrose
presentation, quinine concentrations were presented
twice separated by a 4 trial return to baseline (tap water
in both bottles) conditions.
When presented with quinine-flavored water, control
monkeys rapidly reduced consumption from the bitter
Fig. 4. Flavored water intake during quinine presentation experiments. Open symbols and solid lines represent control subjects, filled
symbols and broken lines represent maternally-deprived monkeys.
Trials are bracketed by presentation conditions (Baseline = tap water
in both bottles, 0.1, 0.3, 1.0, 3.0 and 5.0 =mM quinine in flavored
bottle). Data represent the mean of five controls and four maternallydeprived macaques per group. Although not shown for clarity,
S.E.M. values were typically 15 – 25% of the mean value on any trial.
I.A. Paul et al. / Beha6ioural Brain Research 112 (2000) 127–134
131
4. Discussion
Fig. 5. Flavored water intake pooled by quinine concentration. Open
symbols and solid lines represent controls, filled symbols and broken
lines represent maternally-deprived macaques. Data are presented as
the mean 9S.E.M. of all subject-trials within a given sucrose presentation concentration. Panel A: Untransformed scale. Concentrationresponse relationship for quinine to inhibit fluid consumption from
the quinine-containing bottle. Panel B: Log-transformed scale. Data
were analyzed using a single-site sigmoidal model. R 2 \ 0.9 for
control. No curve could be resolved for maternally-deprived
macaques. Points labeled a are significantly different from the withingroup baseline.
flavored bottle and increased consumption of water
from the unflavored bottle (Figs. 5 and 6B). In contrast,
maternally-deprived monkeys continued to consume
from the quinine-spiked bottle even at concentrations
that effectively eliminated control consumption (Fig. 5).
Moreover, maternally-deprived monkeys did not display significant increases in tap water consumption
when presented with a choice between unflavored and
quinine-flavored water (Fig. 6B). Thus, the EC50 for
quinine suppression of consumption by controls was
2.69 0.12 mM and quinine produced more than 50%
inhibition of consumption from the flavored bottle
compared to tap water (Fig. 5B).
The maternal deprivation model has been much less
widely used than the CMS model. This neglect likely
has two causes: maternal-deprivation (especially in nonhuman primates) is difficult and time consuming, and
many reports of maternal-deprivation’s effects adopted
a fundamentally psychodynamic perspective — a direct
analogy with presumptive anaclitic depression resulting
from an infant’s separation from its mother [13,19,31].
Nevertheless, behavioral effects of maternal deprivation can be considered from a non-psychodynamic
viewpoint. For example Hennessy reported that maternal deprivation in the squirrel monkey reduces consumption of novel sweetened liquids [10]. Hennessy
interpreted these data as indicating neophobia, noting
that maternally-deprived animals’ consumption tended
to increase after four presentations. However, the animals were only followed for four presentations and
only sweetened liquids (various fruit juices) were presented to the monkeys. Thus, these data do not permit
a systematic separation between neophobia, anhedonia,
or changes in taste preference or sensitivity as causes of
changes in consumption.
In the present study, we have tried to determine
which of these possible causes might produce reduced
sweet solution consumption. Thus, the present experiment included multiple concentrations of both sweet
(presumably appetitive) and bitter (presumably aversive) solutions, and followed animals over a large number of trials so that the role of neophobia could be
more clearly understood. The data support several conclusions. First, although neophobia may influence the
consumption during the first few days of novel stimulus
presentation, the reduced consumption of sweet solutions is not readily accounted for by this phenomenon,
because reduced consumption is maintained over a
chronic course. Second, reduced sweet solution consumption can be accounted for by anhedonia, but this
is not a satisfactory explanation of the data on bitter
solution consumption. Likewise, a general shift in the
overall hedonic qualities of particular classes of gustatory stimuli was not apparent in our data. Maternallydeprived animals showed relatively less preference for
the sweet solutions than did controls, but nevertheless
consumed more of the sweetened solutions than tap
water, preserving the general pattern shown by controls. Similarly, making the solution bitter by addition
of quinine suppressed consumption by maternally deprived monkeys only at much higher concentrations
than those that suppressed it in controls.
Previous studies have demonstrated that plasma corticosterone concentrations ([CORT]P) are inversely correlated with fluid consumption. Moreover, under a
water restriction schedule, [CORT]P is rapidly reduced
during water presentation [11,12]. Likewise, [CORT]P
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I.A. Paul et al. / Beha6ioural Brain Research 112 (2000) 127–134
Fig. 6. Consumption of tap water as a function of sucrose (Panel A) or quinine (Panel B) concentration. Open symbols and solid lines represent
controls, filled symbols and broken lines represent maternally-deprived macaques. Data are presented as the mean 9S.E.M. of all subject-trials
within a given sucrose presentation concentration. Points labeled a are significantly different from the within-group baseline; points labeled b
indicate significant between-group differences.
increases under schedule-induced polydipsia (SIP)
paradigms and exogenous elevation of [CORT]P by
direct administration [6] or indirectly by brief stress
presentation [14] facilitates acquisition of SIP. In contrast, inescapable stress exposure retards SIP acquisition
[5] as does isolation rearing in rats [15]. However, in this
latter study, isolation-reared rats actually displayed increased water consumption under non-SIP conditions
[15]. Notably, in the human dexamethasone supression
test, nonsuppressors are typically polydipsic [7].
Thus, polydipsia is associated with both depressogenic environmental conditions in non-humans and depressive symptomatology. In the present study, then, we
might expect polydipsia if, indeed, maternally-separated
macaques displayed a non-human primate analog of
depression. No such polydipsia was evident in either the
sucrose- or quinine-presentation studies. In fact, there is
some evidence at near detection limit concentrations of
sucrose or quinine that the maternally-separated animals might be somewhat adipsic.
I.A. Paul et al. / Beha6ioural Brain Research 112 (2000) 127–134
The simplest explanation of the data we report is that
the maternally-deprived animals are not simply anhedo
nic, but instead are less responsive overall to gustatory
stimuli. Any observed reduction in sweet solution consumption (anhedonia) is likely to be mediated by this
reduced responsiveness. In summary, we note that the
apparent anhedonia observed in this and other animal
models of depressive disorders may be secondary to a
sensory deficit.
Although not included as a diagnostic criterion for
depressive disorders in the current DSM-IV, a flattening of affective response is considered a characteristic
symptom of schizophrenia, although the exact nature of
this symptom is itself controversial [1,4,24,26,29,30].
Likewise, it has been suggested previously that there are
similarities between the behavior of maternally-deprived monkeys and schizophrenic symptoms [21].
Thus, our data would be congruent with the hypothesis
that maternal deprivation in nonhuman primates results in appetitive conditions more analogous to
schizophrenia than to depression.
A more concrete observation is that research on
animal models of anhedonia should be improved by the
inclusion of the appropriate control conditions with
regard to the presumed hedonic properties of stimuli.
Our data demonstrate that anhedonia is likely not an
isolated phenomenon, but instead may reflect a generally attenuated sensory response to stimuli. It will be of
interest in future studies to determine if a similar phenomenon can be demonstrated in rodents, and perhaps
to examine the effects of laboratory models of depression on behavior that is controlled by stimuli with
mixed hedonic properties, for example, sucrose – quinine
combinations. The latter would be particularly interesting, because clinical presentation of depression also
frequently includes a tendency for the patient to focus
on the negative or aversive properties of events that
also have positive and appetitive components.
Acknowledgements
The authors thank Drs William Woolverton and
Michael Weed for their advice and comments regarding
non-human primate experiments.
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