Psychopharmacology (2009) 204:113–125
DOI 10.1007/s00213-008-1442-y
ORIGINAL INVESTIGATION
A preclinical model of binge eating elicited by yo-yo
dieting and stressful exposure to food: effect of sibutramine,
fluoxetine, topiramate, and midazolam
Carlo Cifani & Carlo Polidori & Sergio Melotto &
Roberto Ciccocioppo & Maurizio Massi
Received: 21 October 2008 / Accepted: 10 December 2008 / Published online: 6 January 2009
# Springer-Verlag 2008
Abstract
Rationale Preclinical models are needed to investigate the
neurobiology and psychobiology of binge eating and to
identify innovative pharmacotherapeutic strategies.
Objectives A modification of the model based on the
combination of cyclic caloric restrictions and acute stress
was developed to further increase its face validity and
reliability and, for the first time, to assess its predictive value.
Materials and methods Four groups of female rats were
employed: group 1 was normally fed and not stressed on the
test day (25th); group 2 was fed normally but was exposed to
an acute stress on day 25; group 3 was exposed to three cycles
(4 days 66% of chow intake+4 days food ad libitum) of yo-yo
dieting but not stressed; and group 4 was exposed to cyclic
yo-yo dieting and then stressed. All groups were fed highly
palatable food (HPF) for 2 h on days 5–6 and 13–14. Acute
stress was elicited by exposing rats to HPF, but preventing
them from access to it for 15 min.
Results The combination of cyclic food restriction and
stressful exposure to food markedly increased HPF intake.
Sibutramine and fluoxetine inhibited food intake in all
conditions. Topiramate selectively inhibited compulsive
HPF intake in rats submitted to caloric restriction and
stress. Midazolam increased HPF intake.
Conclusions Pharmacological results suggest that this model,
in addition to face validity as an isomorphic model of human
binge eating, is endowed with good predictive validity.
C. Cifani : C. Polidori : S. Melotto : R. Ciccocioppo :
M. Massi (*)
Department of Experimental Medicine and Public Health,
University of Camerino,
Via Madonna delle Carceri,
62032 Camerino, Italy
e-mail: maurizio.massi@unicam.it
Keywords Binge eating . Caloric restriction .
Environmental stress . Palatable food . Sibutramine .
Fluoxetine . Topiramate . Midazolam . Female rats
Introduction
Binge eating episodes are characterized by uncontrollable,
distressing eating of a large amount of highly palatable food
(HPF). These episodes represent a central feature of bingeing-
related eating disorders, such as binge eating disorder, bulimia
nervosa, and binge/purge subtype anorexia nervosa (Ameri-
can Psychiatric Association 2000). Binge eating is also an
additional behavioral feature of obese individuals, signifi-
cantly contributing to their high caloric intake and finally
being overweight (Yanovski 1993; Hudson et al. 2007).
A large body of evidence suggests that dieting, stress, and
negative affective states represent possible triggers of binge
eating in patients (Freeman and Gil 2004; Wardle et al. 2000).
Indeed, dieting periods are a common finding in the history
of binge eaters, although hunger per se appears to be not
enough to induce binge eating in the absence of stress and
negative affective state (Polivy et al. 1994; Waters et al.
2001). Considerable evidence suggests that binge eating may
be caused by a unique interaction between dieting and stress;
thus, a history of cyclic food restriction and of environmental
stress may be responsible for its precipitation and mainte-
nance (Stice et al. 2001; Crowther et al. 2001; Wolff et al.
2000). Accordingly, recurring food restrictions are consis-
tently the strongest predictor of overeating in response to
stress (Wardle et al. 2000).
Also typical of binge eating in humans is the preference for
HPF. Craving, preferential selection, and ultimate overcon-
sumption of HPF are common in binge eating disorders
(Weltzin et al. 1991) and considered to play an important
114
binge-triggering role in animal models (Leigh et al. 1998;
Hagan and Moss 1997; Corwin and Buda-Levin 2004).
Preclinical models of bingeing-related eating disorders
are necessary to investigate the neurobiology and psycho-
biology of binge eating, as well as to evaluate pharmaco-
logical strategies to identify effective treatments. As
recently reviewed by Corwin and Buda-Levin (2004),
several models of binge eating have been proposed.
In line with the hypothesis that dieting and stress are
key etiological determinants of binge eating (Hudson et
al. 2007; Freeman and Gil 2004), the model proposed by
Boggiano (formerly Hagan) and coworkers (Hagan et al.
2002; Hagan et al. 2003; Artiga et al. 2007) combines
cycles of food restriction–refeeding and acute stress to
evoke binge eating for sweet HPF. In this model, rats are
submitted to cyclic caloric restriction and stressed with
electric foot shock; stress is delivered to animals that are
not in energy deficit, in keeping with the idea that binge
eating episodes usually occur in conditions of satiety and
normal body weight (Abraham and Beumont 1982). The
hyperphagic response to stress was found to be contingent
upon a minimum of three cycles of food restriction–
refeeding. In response to stress, a selective increase in
HPF intake over chow was observed. Rats, which cycled
through food restriction and refeeding in response to
stress, failed to show hyperphagia when only chow was
available. Lastly, in consideration of the high prevalence
of binge eating disorders in adolescent and young adult
females (American Psychiatric Association 2000; Hudson
et al. 2007; Spitzer at al. 1993; Spitzer et al. 1993a;
Kjelsas et al. 2004), young female rats were used. This
method is considered to have strong construct validity
(Corwin and Buda-Levin 2004) and face validity as an
isomorphic model (Smith 1989) that presents elements of
similarity with human symptomatology (Corwin and
Buda-Levin 2004; Artiga et al. 2007).
Based on the studies published by Boggiano and
coworkers, an alternative model of binge eating was
developed in which electric foot shock was substituted
with a stressful procedure characterized by exposure of
the animals to HPF, but preventing them from access to
it. Briefly, in our experiments, on the test day, animals
were prevented from getting access to HPF for 15 min
before testing, even though they were able to see it and
to smell its odor; therefore, stress was related to
temporary lack of control over the environmental
circumstances. This type of stress offers several advan-
tages over the electric foot shock stress procedure.
Firstly, it is considered a mild stress that, unlike the
electric foot shock, never induces competitive behaviors
like fear and freezing responses (Hansson et al. 2006),
but at the same time it elicits a robust behavioral
activation. Secondly, the stressful experience is related to
Psychopharmacology (2009) 204:113–125
the relationship with a HPF, as usually occurs in humans.
It may resemble the approach–avoidance stress over
“forbidden” food that is so common among human binge
eaters, thus providing a further element of face validity.
To test the predictive validity of this model, three drugs
were evaluated: sibutramine, fluoxetine, and topiramate.
They were chosen since clinical studies have reported that
they may be effective in the treatment of bingeing-related
eating disorders (McElroy et al. 2004; McElroy et al. 2007;
De Bernardi et al. 2005; Appolinario et al. 2002; Appolinario
et al. 2004; Milano et al. 2005; Wilfley et al. 2008;
Leombruni et al. 2008; Shapiro et al. 2007; Arnold et al.
2002; Carter et al. 2003; National Institute for Clinical
Excellence 2004). Sibutramine (Reductil®) is a centrally
acting serotonin–noradrenaline reuptake inhibitor. Its anti-
obesity effect has been attributed to a dual mechanism
involving reduction of food intake and increase in energy
expenditure (Padwal and Majumdar 2007). Fluoxetine
(Prozac®) is a selective serotonin reuptake inhibitor (SSRI).
It reduces food intake by affecting appetite and satiety. In
addition, fluoxetine appears to have positive effects on the
control of impulsive/compulsive symptoms associated to
some psychiatric conditions like obsessive–compulsive
disorder, bulimia nervosa, and hypochondriasis (Shapiro et
al. 2007). Topiramate (Topamax®) was developed as an
antiepileptic drug; however, it is also Food and Drug
Administration (FDA)-approved for the prevention of mi-
graine. Clinical trials have shown that this drug inhibits
binge eating (McElroy et al. 2004).
The evaluation of the effect of the three drugs was also
aimed at obtaining specific information on their ability to
influence binge eating in conditions in which it is evoked
by the combination of dieting and stress. Midazolam
(Ipnovel®) was included to assess whether an anxiolytic
benzodiazepine might reduce binge eating in response to a
stressful procedure.
Materials and methods
Animals and housing
A total of 306 female Sprague–Dawley rats (Charles River,
Calco, Como, Italy) were employed. They were 52-day-old
at the beginning of the experiment. Rats were acclimated to
individual bedded cages under a 12-h light/dark cycle
(lights on at 0800 hours) with ad libitum chow and water
for 2 weeks prior to the experiment. They were kept in a
room at constant temperature (20–22°C) and humidity (45–
55%). All procedures were conducted in adherence to the
European Community Directive for the Care and Use of
Laboratory Animals. Ethical guidelines for the investigation
of experimental pain in conscious animals were followed,
Psychopharmacology (2009) 204:113–125
and procedures were carried out according to EEC ethical
regulations for animal research (EEC Council 86/609; D.
Lgs. 27/01/1992, No. 116).
Diets
Animals were offered standard rat food pellets (4RF18,
Mucedola, Settimo Milanese, Italy; 2.6 kcal/g). The HPF
was a paste in texture, prepared by mixing:
(a) Nutella (Ferrero, Alba (TO), Italy) chocolate cream
(5.33 kcal/g; 56%, 31%, and 7% from carbohydrate,
fat, and protein, respectively),
(b) grounded food pellets (4RF18, Mucedola, Settimo
Milanese, Italy),
(c) water
in the following percent ratio: 52% Nutella, 33% food
pellets, and 15% water.
Rats were not allowed access to HPF before the
beginning of the experiments. They exhibited a pronounced
intake of the HPF; since the first exposure to it on day 5 of
the first cycle (about 5 g/rat), the intake increased on the
following day (about 9 g/rat). On days 13 and 14 of the
second cycle, HPF intake did not exhibit a further increase.
The stress procedure
For 15 min, the china coffee cup containing HPF was
placed outside the cage; the cup handle was hooked to
the top wire wall of the cage in the hollow part where
food pellets are usually offered. In these conditions, the
animal was able to see the cup in which it received
HPF on days 5, 6, 13, and 14 of the first two cycles,
was able to see in part the HPF itself, and was able to
smell its odor. In this 15-min period, the rat engaged in
repeated movements of the forepaws, head, and trunk
aimed at obtaining the HPF, but it was not able to reach
it. This expedient was adopted to generate a mild
stressful condition characterized by temporary lack of
control over the environmental circumstances. Rats
underwent the stressful procedure between 1000 and
1200 hours. After 15 min, the cup was placed inside the
cage of the rats in the stress groups (R+S and NR+S),
so that the HPF became accessible to the rat.
Drugs
Sibutramine (Reductil®, Abbott) and fluoxetine (Prozac®,
Ely Lilly) were obtained in the form of capsules for oral
administration, while topiramate (Topamax®, Janssen-
Cilag) was available in tablets, which were reduced into
powder before administration. Sibutramine was dissolved in
distilled water, while fluoxetine and topiramate were
115
dissolved in hydroxypropyl methyl cellulose 0.5% in
distilled water. It was possible to dissolve and administer
by gavage all the tested doses of the three drugs in a
volume of 2 ml/kg. Sibutramine was administered at the
doses of 1 or 3 mg/kg body weight, while fluoxetine was
given at the doses of 3 or 10 mg/kg. Topiramate was
administered at the doses of 30 or 60 mg/kg. Midazolam
(solution for injection; Ipnovel®, Roche) was administered
by intraperitoneal injection at the doses of 5 or 10 mg/kg.
Before the beginning of the experiments, animals were
made familiar with the administration procedure.
Experiment 1: effect of restriction–refeeding cycles
and stress on binge eating behavior
The rats were weight-matched (to avoid significant differ-
ence in mean body weight between groups) into one of four
groups (n=9 per group):
1. nonrestricted and not exposed to stress group (NR+NS),
2. restricted and not exposed to stress group (R+NS),
3. nonrestricted and exposed to stress group (NR+S),
4. restricted and exposed to stress group (R+S).
Once assigned to one of these groups, the rats remained
in that group throughout the experiment. The rats exposed
to stress were kept in a room different from that used for the
groups not exposed to stress to avoid exposure of the latter
to the smell of the HPF when the former was exposed to the
stressful procedure.
Rats were submitted to three consecutive 8-day cycles
followed by the final test on day 25 (see Table 1):
(a) The control group (NR+NS) had chow ad libitum for
4 days; on days 5–6, they received chow ad libitum+
HPF for 2 h; on days 7–8, they had chow ad libitum;
on day 25, they were not exposed to stress.
(b) The second group (R+NS) had chow restricted to 66%
of the normal intake for 4 days, was offered chow ad
libitum and HPF (2 h) on days 5–6 and only chow on
days 7–8; on day 25, they were not exposed to stress.
Restriction to 66% of normal chow intake was defined
for the first cycle on the basis of the intake measured
in the 6 days before the beginning of the experiment.
For the second and third cycles, 66% restriction was
defined on the basis of the intake of nonrestricted rats
during the last 2 days of the cycles in which rats
received only normal chow ad libitum.
(c) The third group had chow and HPF as controls, but
on the test day (day 25), it was exposed to stress (NR+S).
(d) The fourth group (R+S) had food available like the
second group, and on day 25, it was exposed to stress.
The 8-day cycle was repeated three times; but in the
third cycle, the animal did not have access to HPF on
116 Psychopharmacology (2009) 204:113–125

Table 1 Cycles of caloric restriction–refeeding

Group Days Days Days Days Days Days Days Days Day
1–4 5–6 7–8 9–12 13–14 15–16 17–20 21–24 25

NR+NS Ad lib chow Ad lib chow Ad lib Ad lib chow Ad lib chow Ad lib Ad lib chow Ad lib No stress+ad lib
+HPF (2 h) chow +HPF (2 h) chow chow chow+HPF
R+NS Restricted Ad lib chow Ad lib Restricted Ad lib chow Ad lib Restricted Ad lib No stress+ad lib
chow to 66% +HPF (2 h) chow chow to 66% +HPF (2 h) chow chow to 66% chow chow+HPF
NR+S Ad lib chow Ad lib chow Ad lib Ad lib chow Ad lib chow Ad lib Ad lib chow Ad lib Stress+ad lib
+HPF (2 h) chow +HPF (2 h) chow chow chow+HPF
R+S Restricted Ad lib chow Ad lib Restricted Ad lib chow Ad lib Restricted Ad lib Stress+ad lib
chow to 66% +HPF (2 h) chow chow to 66% +HPF (2 h) chow chow to 66% chow chow+HPF

days 21 and 22. On day 25, free access to HPF and chow
was offered and their intake was measured in the first 2 h
and at 24 h taking care to collect any spillage.
Body weights and food intake were recorded daily. Food
intake was expressed as mean kilocalories per kilogram
ingested±SEM. By the last day of refeeding, body weight
and food intake of restricted rats were not statistically
different from those of nonrestricted rats, thus eliminating
the potentially confounding influence of hunger or energy
deficit. A minimum of three caloric restriction and refeed-
ing cycles were run according to the method of Boggiano
and coworkers (Hagan et al. 2002; Hagan et al. 2003;
Artiga et al. 2007).
Experiment 2: effect of restriction–refeeding cycles
and stress on serum corticosterone levels
For the endocrine experiments, different female
Sprague–Dawley rats were divided into the same four
groups (NR+NS and R+NS of nine animals each, NR+S
and R+S of 18 animals each) cycled three times as
described for experiment 1.
At the end of the third cycle (day 25), the different groups
were exposed or not exposed for 15 min to the HPF without
access to it. The groups of animals exposed to stress were
named NR+S15, NR+S60, R+S15, and R+S60 (n=9 rats
each), if they were killed 15 min (S15) or 60 min (S60) after
the beginning of the stressful procedure (that is, after the
presentation of the cups containing HPF, but without access
to it). In the animals killed at 60 min, the cup containing
HPF was removed from the cage after 15 min. Animals not
exposed to stress (NR+NS and R+NS) were kept in a
different room and killed at about the same time as those
submitted to stress (between 1000 and 1200 hours).
Blood samples were collected from the trunk after rat
decapitation. To improve separation of serum from
whole blood, samples were allowed to clot at room
temperature before centrifugation (1,000×g for 10 min).
Serum was transferred into clean tubes and stored at
−20°C until the assay. Taking into account the circadian
rhythm of corticosterone, all kills were carried out
between 1000 and 1200, i.e., during the diurnal period
when its concentrations are relatively constant (Akana et
al. 1986; Vitale et al. 2006).
Assessment of serum corticosterone level was done by
means of enzyme immunoassay (EIA) using a commercially
available kit (Assay Design, Ann Arbor, MI, USA), which
utilizes a microplate reader set at 405 nm. Serum samples
were diluted 1:20 in appropriate assay buffer in order to be
within the calibration curve range and assayed in duplicate.
The detection limit of the assay was 26.7 pg/mL; intra-assay
and interassay coefficients of variations were 7.4% and 9.1%,
respectively. Levels measured in the control group (NR+NS)
were compared with those measured in the other groups at the
different times of observation.
Experiment 3: effect of pharmacological treatments
on binge eating
Fluoxetine, a SSRI, was tested in 108 female rats. As
described in experiment 1, animals were divided into four
groups of 27 animals each: a control group (NR+NS) was
submitted neither to food restriction nor to the stressful
procedure; a NR+S group was submitted only to the stressful
procedure; a R+NS group was exposed just to chow
restriction; a R+S group received both restriction and
exposure to stress. On day 25, following stress in the stressed
groups, vehicle or fluoxetine, 3 or 10 mg/kg (n=9 per group),
was given by gavage 60 min before access to food (including
the 15 min of the stressful procedure). The intake of HPF or
pellet chow was measured in the first 2 h and at 24 h after
access to HPF.
Psychopharmacology (2009) 204:113–125
Sibutramine, a centrally acting serotonin–noradrenaline
reuptake inhibitor, was tested in the same rats 10 days after the
end of the fluoxetine experiment. The same four groups of rats
received an additional 8-day cycle followed on day 9 by
sibutramine treatment. Sibutramine, 1 or 3 mg/kg, or its
vehicle was administered by gavage 60 min before access to
HPF. Rats that received the higher dose of fluoxetine in the
previous experiment received vehicle, while those treated with
vehicle in the previous experiment received the higher dose of
sibutramine.
Topiramate was tested in an additional 108 female rats,
divided into four groups of 27 rats, as in experiment 1. On
day 25, vehicle or topiramate, 30 or 60 mg/kg, was given
by gavage 60 min before access to HPF.
Midazolam, a benzodiazepine receptor agonist, was tested
in the same rats employed for topiramate. The same four-
animal groups, 10 days after the end of the topiramate
experiment, were submitted to an additional 8-day cycle
followed on day 9 by midazolam treatment. Midazolam, 5 or
10 mg/kg, or its vehicle was administered intraperitoneally 1 h
before access to HPF. Rats that received the higher dose of
topiramate in the previous experiment received vehicle, while
those treated with vehicle in the previous experiment received
the higher dose of midazolam.
Statistical analysis
The results are expressed as the mean group food intake, body
weight, or corticosterone level±SEM. Data were analyzed by
two-way analysis of variance (ANOVA), followed by post hoc
comparison carried out by the Bonferroni test. Statistical
significance was set at P<0.05.
For experiments 1 and 2, data were analyzed by two-way
ANOVA with the animal group as the between-subject
variable and time as the within-subject variable. The analysis
was aimed at evaluating whether the four groups exhibited
significant differences in HPF intake on the test day.
In experiment 3, the ANOVA was carried out for each of
the four groups of rats separately with drug treatment as the
between-subject variable and time as the within-subject
variable. Since HPF intake of the test day in the four groups
of rats was clearly different and only the R+S group exhibited
binge-type eating, the aim of the analysis was to evaluate the
effect of drug treatment separately in each group of rats.
Results
Experiment 1: effect of restriction–refeeding cycles
and stress on binge eating
The overall ANOVA revealed a highly significant differ-
ence in 2 h HPF intake in the different groups of rats [F
117
(3,32)=5.30; P<0.01]. As shown in Fig. 1, HPF intake in
the R+S group was markedly higher than that of the
control (NR+NS) group at the different times of
observation. The intake of HPF by R+S rats began
immediately after access to it was allowed; these
animals never engaged in competing behaviors, but
continuously remained over the cup containing HPF
and focused their attention on the intake. HPF intake
was very pronounced in the first 15 min of access to it.
After the first 15 min, the additional intake of the four
groups was similar; thus, at 2 h, the cumulative intake
of the R+S group remained higher than that of the other
groups. HPF intake of the groups NR+S or R+NS were
not significantly different from that of the controls. At
24 h, no significant differences in HPF intake was
observed in the four groups of rats (data not shown).
With regard to food pellet intake, the ANOVA
revealed no significant difference among groups
[F(3,32)=0.22; P>0.05]. As shown in Fig. 2, the intake
of food pellet was affected neither by food restriction, nor
by stress, nor by the combination of both.
As shown in Fig. 3, the body weight of the rats was
reduced markedly during the 4 days of food restriction,
but the animals rapidly recovered their body weight to
levels of controls by the end of each cycle. On the test day
(Fig. 4), the body weight of the four groups of animals, as
well as their food intake in the previous 24 h, were not
statistically different.
NR + NS
R + NS
NR + S
180 R+S *
*
160
**
HPF Intake (kcal/kg)
140
**
120
100
80
60
40
20
0
15 30 60 120
Time (min)
Fig. 1 HPF intake at different times after access to it on the test day
(day 25) while food pellet was freely available. *P<0.05, **P<0.01,
statistical difference from controls (NR+NS); where not indicated, the
difference was not statistically significant
118
20
NR + NS
R + NS
NR + S
15
HPF Intake (kcal/kg)
R+S
10
5 in each of the four groups of rats. At 24 h, no significant
0 The results obtained with topiramate are reported in
15 30 60
Time (min)
Fig. 2 Food pellet intake on the test day (day 25), during the 2-h access
to HPF. Statistical difference from controls (NR+NS) was never
statistically significant
Experiment 2: effect of restriction–refeeding cycles
and stress on serum corticosterone levels
As reported in Fig. 5, exposure to HPF without access to it
increased corticosterone levels in serum samples obtained
from rats killed 15 min after the beginning of the stressful
procedure, both in rats submitted to food restriction (R+S15)
[F(1,16)=13.12; P<0.05] or not submitted to restriction
(NR+S15) [F(1,16)=16.26; P<0.05].
Sixty minutes after the beginning of the stressful proce-
dure, that is 45 min after the removal of the HPF cups from the
wall of the cage (without allowing access to HPF to rats),
corticosterone levels returned to control (NR+NS) levels.
Experiment 3: effect of pharmacological treatments
on binge eating
The results obtained with fluoxetine are reported in Fig. 6.
The ANOVA revealed a highly significant difference in 2 h
HPF intake [F(3,32)=3.07; P<0.05] of the different groups
following vehicle administration. Fluoxetine reduced HPF
intake. A statistically significant drug effect was observed in
three (NR+NS, NR+S, and R+S) of the four groups of rats:
NR+NS rats [F(2,24)=5.55; P<0.05]; R+NS rats [F(2,24)=
3.30; P>0.05]; NR+S rats [F(2,24)=5.27; P<0.05]; and R+S
rats [F(2,24)=6.27; P<0.05]. Post hoc comparisons showed
statistical significant differences at the highest dose of
10 mg/kg in the three groups of rats, while the dose of
3 mg/kg induced significant reduction of HPF intake in R+S
group only. At 24 h, no significant differences in HPF intake
was observed in the four groups of rats (data not shown).
The results obtained with sibutramine are reported in
Fig. 7. The ANOVA revealed a highly significant difference
Psychopharmacology (2009) 204:113–125
in 2 h HPF intake [F(3,32)=5.57; P<0.05] of the different
groups following vehicle administration. Sibutramine re-
duced HPF intake in all groups of rats. A statistically
significant drug effect was observed in each of the four
groups of rats: NR+NS [F(2,24)=17.37; P<0.01]; R+NS
[F(2,24)=21.49; P< 0.01]; NR+S [F(2,24)=18.03; P<
0.01]; and R+S [F(2,24) = 23.11; P < 0.01]. Post hoc
comparison showed statistically significant differences from
vehicle-treated rats in response to both doses of sibutramine
differences in HPF intake was observed in the four groups
of rats (data not shown).
120 Fig. 8. Also, in this experiment, the ANOVA revealed a
highly significant difference in 2 h HPF intake [F(3,32)=
4.17; P<0.05] of the different groups following vehicle
administration. Topiramate reduced HPF intake only in the
R+S group [F(2,24)=23.11; P<0.01], but not in the other
groups: NR+NS [F(2,24)=0.68; P>0.05]; R+NS [F(2,24)=
0.04; P>0.05]; NR+S [F(2,24)=1.16; P>0.05]. At 24 h, no
significant differences in HPF intake was observed in the
four groups of rats (data not shown).
The results obtained with midazolam are reported in
Fig. 9. The ANOVA revealed a highly significant
difference in 2 h HPF intake in the different groups of
rats [F(3,32)=9.99; P<0.05] following vehicle adminis-
tration. Midazolam significantly increased HPF intake in
NR+NS [F(2,24) = 16.77; P < 0.01], R+NS [F(2,24) =
17.70; P<0.01], and NR+S groups [F(2,24)=8.22; P<
0.01] at both doses tested. In the R+S groups, midazolam
did not significantly modify HPF intake [F(2,24)=1.05;
NR + NS
260 R + NS
NR + S
R+S
240
Body Weight (g)
*
*
* **
220 **
* * ***
**
* * **
200 *
**
*
180
1 5 9 13 17 21 25
Days
Fig. 3 Effect of the three restriction–refeeding cycles on body weight
(in grams) of the four groups of female rats. *P<0.05, statistical
difference from controls (NR+NS); where not indicated, the difference
was not statistically significant
Psychopharmacology (2009) 204:113–125 119

NR + NS
2000; Hansson et al. 2006), a large variability in the
R + NS
a NR + S sensitivity of rats to electric foot shock was observed, and
60 R+S animals highly sensitive to this stressful procedure
exhibited freezing behavior that may prevent them from
24 h Food intake (kcal/kg)

50 engaging in ingestive behavior. Moreover, electric foot

shock has been usually reported to suppress food intake,
40 and only in few instances, it has been reported to induce
either no effect or small increase of the intake (Sterritt
30 1962; Robbins and Fray 1980). On the basis of these
considerations, electric foot shock stress was substituted
20 with a stressful procedure in which animals were prevented
from getting access to palatable food for 15 min, even
10 though they were able to see it and to smell its odor. Stress
was, therefore, related to temporary lack of control over the
0 environment, probably accompanied by a parallel activation
of neuronal circuits controlling reward and appetitive
b behaviors. This type of stress offers some advantages over
the electric foot shock stress procedure. Firstly, it is
250
definitely a mild stress that, unlike the electric foot shock
stress, never generates fear and freezing behavior that may
200 prevent the animal from engaging in ingestive behavior;
Body Weight (g)

indeed, it induces marked behavioral activation of the

150 animal that makes any effort to reach the HPF. Secondly, it
is generated by the relationship between the rat and the
100 HPF itself, as usually occurs in humans. It may resemble
the approach–avoidance stress over “forbidden” food that is
50 so common among human binge eaters, thus providing a
further element of face validity. In this regard, it could be
hypothesized that, since access to HPF was offered only for
0
2 h on days 5 and 6 of each cycle, also HPF withdrawal
Fig. 4 a Food pellet intake and b body weight of the four groups of might be stressful. However, all the experimental groups of
animals 24 h before the experiment. Statistical difference from rats underwent the same HPF withdrawal; therefore, it may
controls (NR+NS) was never statistically significant

800
P>0.05]. At 24 h, no significant differences in HPF intake
was observed in the four groups of rats (data not shown). 700 * *
Corticosterone (ng/ml)

600

Discussion 500

The results obtained indicate that the experimental conditions 400

adopted in the present study allow to consistently induce 300
binge eating in female rats. In animals with a history of
repeated food restrictions, a stressful exposure to HPF without 200
access to it increased HPF consumption without affecting 100
normal chow intake. HPF intake remained significantly higher
during the 2-h observation period. On the other hand, when 0
NR+NS R+NS NR+S15 R+S15 NR+S60 R+S60
repeated food restriction (R+NS group) or stressful exposure
to HPF without access to it (NR+S) were not combined Fig. 5 Corticosterone levels in rats either nonstressed (NS) or exposed
to stress (S). In the S rats, corticosterone levels were measured 15 min
together, they were not enough to induce binge eating. (S15) or 60 min (S60) after the beginning of the stressful procedure.
In our previous studies concerning stress-induced rein- *P<0.05, statistical difference from controls (NR+NS); where not
statement of alcohol-seeking behavior (Martin-Fardon et al. indicated, the difference was not statistically significant
120 Psychopharmacology (2009) 204:113–125

Vehicle
Fluoxetine 3 mg/kg
Fluoxetine 10 mg/kg

160 NR + NS 160 NR + S

140 140
HPF Intake (kcal/kg)

HPF Intake (kcal/kg)

120 120
100 100
80 ** 80
* **
60 60 * **
*
40 * 40
20 20
0 0
15 30 60 120 15 30 60 120
Time (min) Time (min)

160 R + NS 160 R+S

140 140
*
HPF Intake (kcal/kg)

HPF Intake (kcal/kg)

120 120
*
100 100
**
80 80
* **
*
60 60

40 40

20 20

0 0
15 30 60 120 15 30 60 120
Time (min) Time (min)

Fig. 6 Effect of fluoxetine (3 or 10 mg/kg) or its vehicle on HPF intake on the test day. *P<0.05, **P<0.01, statistical difference from vehicle-
treated rats in each of the four groups; where not indicated, the difference was not statistically significant

represent a contributing factor, but not the determinant for
the occurrence of binge eating in the R+S group.
Even though the adopted stressful procedure was definitely
milder, the endocrine analyses showed that it was able to
induce an increase in serum corticosterone levels, which
represents a classic stress response. Thus, the exposure to a
familiar (previously tasted and ingested) HPF, in conditions in
which the animal can see and smell it but cannot get access to
it, is a stressful determinant for the rat. The effect on
corticosterone of the stressful procedure adopted in this study
is rather short-lasting, since it is completed only 45 min after
the removal of the cup containing HPF from the wall of the
cage and without any intake of HPF. Thus, the stressful
experience delivered is not only mild but has rather short-
lasting consequences. Interestingly, the increase in corticoste-
rone levels is observed to essentially the same extent in both
the animals that experienced caloric restriction–refeeding and
in those that did not undergo cycles of caloric restriction. This
finding is different from that obtained by Artiga et al. (2007)
who observed an increase in corticosterone levels in the R+S
group, but not in the NR+S; however, in their work, electric
foot shock was administered at the end of each cycle with
the possibility that animals became acclimated to the stress.
The present results suggest that an increase in corticosterone
levels is not enough to induce binge eating per se and that it
can evoke this response only in animals that have experi-
enced periods of food restriction. Probably, repeated experi-
ences of food restriction induce neuronal adaptations that
prepare the animals to exhibit binge-type behavior in
stressful situations.
Psychopharmacology (2009) 204:113–125 121

Vehicle
Sibutramine 1 mg/kg
Sibutramine 3 mg/kg

160 NR + NS 160 NR + S

140 140
HPF Intake (kcal/kg)

HPF Intake (kcal/kg)

120 120
100 100
80 ** 80 **
60
**
** 60 **
** ** **
40 ** 40 ** **
**
** **
20 20 **
**
0 0
15 30 60 120 15 30 60 120
Time (min) Time (min)

R + NS 160 R+S
160

140 140
HPF Intake (kcal/kg)

HPF Intake (kcal/kg)

120 120

100 100
** **
80 80
** ** **
60
** 60
**
**
** ** ** ** **
40 ** 40
** **
20 20

0 0
15 30 60 120 15 30 60 120
Time (min) Time (min)

Fig. 7 Effect of sibutramine (1 or 3 mg/kg) or its vehicle on HPF intake on the test day. *P<0.05, **P<0.01, statistical difference from vehicle-
treated rats in each of the four groups; where not indicated, the difference was not statistically significant

In this experimental model of binge eating, the effect of
several pharmacological treatments was evaluated. Treat-
ment with the benzodiazepine midazolam, at anxiolytic
doses, was employed to evaluate whether the effect on
binge eating in our model might be simply related to effects
on the emotional state of the animal, thus implying that an
anxiolytic compound might be enough to abolish binge
eating. Indeed, the results obtained with midazolam are not
supporting this hypothesis. Midazolam did not modify
binge eating in R+S rats, but increased HPF intake in the
other three groups of rats, as previously observed in
animals and humans (Cooper and Estall 1985). It may be
speculated that R+S rats exhibit a maximal food intake, and
midazolam cannot induce a further increase. Behavioral
evidence strongly indicates that a primary action of
benzodiazepines is to enhance the positive hedonic evalu-
ation (palatability) of tastes and foodstuffs. This generates
the increased food intake and instrumental responding for
food rewards (Cooper 2005). In our experimental condi-
tions in which rats were offered HPF and regular chow at
the same time, both vehicle-treated and midazolam-treated
rats avidly ingested HPF and took only a small amount of
regular chow. However, the hyperphagic effect of mid-
azolam can be observed also on regular chow; and
therapeutic applications have been proposed for benzodi-
azepine receptor ligands (Cooper 2005).
The other three drugs tested (topiramate, sibutramine,
and fluoxetine) have been reported to reduce binge eating
in humans (McElroy et al. 2004; McElroy et al. 2007; De
Bernardi et al. 2005; Appolinario et al. 2002; Appolinario
122 Psychopharmacology (2009) 204:113–125

Vehicle
Topiramate 30 mg/kg
Topiramate 60 mg/kg

160 NR + NS 160 NR + S

140 140
HPF Intake (kcal/kg)

HPF Intake (kcal/kg)

120 120
100 100
80 80
60 60

40 40
20 20
0 0
15 30 60 120 15 30 60 120
Time (min) Time (min)

160 R + NS 160 R+S

140 140
HPF Intake (kcal/kg)

HPF Intake (kcal/kg)

120 120

100 100
*
80 80
** **
*
60 60

40 40

20 20

0 0
15 30 60 120 15 30 60 120
Time (min) Time (min)

Fig. 8 Effect of topiramate (30 or 60 mg/kg) or its vehicle on HPF intake on the test day. *P<0.05, **P<0.01, statistical difference from vehicle-
treated rats in each of the four groups; where not indicated, the difference was not statistically significant

and McElroy 2004; Milano et al. 2005; Wilfley et al. 2008;
Leombruni et al. 2008; Shapiro et al. 2007; Arnold et al.
2002; Carter et al. 2003; National Institute for Clinical
Excellence 2004), even though only fluoxetine has been
accepted by the FDA to treat the symptomatology in
bulimia nervosa. Therefore, the three drugs were tested to
assess the predictive validity of the experimental model.
Interestingly, the results obtained showed that the three
drugs reduced binge eating in our model.
Sibutramine reduced HPF intake in all the experimental
groups, suggesting that its effect is a general effect on
appetite and/or satiety and is not selective on the binge-type
behavior observed in the R+S group. Sibutramine induced
the most pronounced reduction in HPF intake in compar-
ison to the other drugs tested. In comparison to the SSRI
inhibitor fluoxetine, the higher intensity of the effect of
sibutramine may be related to its property to block both
serotonin and noradrenaline reuptake (Jackson et al. 1997).
In addition, it has been reported that sibutramine inhibits
mainly carbohydrate and fat intake (LeBlanc and Thibault
2003), and the HPF offered is rich in these macronutrients.
The effect of fluoxetine, at the dose of 10 mg/kg,
was statistically significant in the following three
groups: NR+NS, NR+S, and R+S; at the dose of
3 mg/kg, fluoxetine significantly reduced HPF intake
only in the R+S group, although a trend to reduce HPF
intake was recorded also in the NR+S group. Thus, at
this dose, the effect of fluoxetine shows some selectivity
Psychopharmacology (2009) 204:113–125 123

Vehicle
Midazolam 5 mg/kg
Midazolam 10 mg/kg

240
** **
NR + NS 240 NR + S
220 220
**
200 200
HPF Intake (kcal/kg)

**

HPF Intake (kcal/kg)

180 180 **
** ** ** *
160 160
140 ** ** 140 * *
120 ** 120
100
*
100
80 80
60 60
40 40
20 20
0 0
15 30 60 120 15 30 60 120
Time (min) Time (min)

240 240 R+S

220 ** 220
200 200
HPF Intake (kcal/kg)

**
HPF Intake (kcal/kg)

180 ** 180
160 ** 160
** **
140 ** 140
120 ** 120
100 100
80 80
60 60
40 40
20 20
0 0
15 30 60 120 15 30 60 120
Time (min) Time (min)
Fig. 9 Effect of midazolam (5 or 10 mg/kg) or its vehicle on HPF intake on the test day. *P<0.05, **P<0.01, statistical difference from vehicle-
treated rats in each of the four groups; where not indicated, the difference was not statistically significant

for stress-induced overeating, although, as observed in
the clinic, no specific effect could be observed.
On the other hand, topiramate selectively reduced HPF
intake in R+S rats and did not modify HPF intake in control
animals (NR+NS) or in animals that experienced food
restriction or stress separately (R+NS or NR+S). Thus, the
effect of topiramate was evident only in conditions in which
binge-type eating occurred. Accordingly, several clinical
reports have shown that topiramate significantly reduces
binge eating episodes, reduces weight gain associated with
binge eating disorders, and improves the severity and
compulsive features of binge eating disorders (McElroy et
al. 2004; McElroy et al. 2007; De Bernardi et al. 2005).
Further studies are needed to evaluate the mechanism of
action of topiramate on binge eating. However, since its
effect is evident only in conditions in which binge eating is
evoked, it may be hypothesized that topiramate acts by
reducing craving for HPF, as it does for alcohol, cocaine,
and nicotine (Johnson et al. 2003; Kampman et al. 2004;
Resis et al. 2008; Reid et al. 2007), or by reducing
impulsive behavior associated with binge eating episodes
(Dolengevich et al. 2006). Topiramate is an antiepileptic
drug with a complex pharmacological profile, inhibiting
sodium channels, modulating calcium and potassium
channels, potentiating or directly activating GABA-A
receptors containing beta2 or beta3 subunits, inhibiting
AMPA/kainate glutamate receptors, and inhibiting carbonic
anhydrase (Schneiderman 1998; Simeone et al. 2006;
Johannessen Landmark 2007; White et al. 2007). Since
the balance between the inhibitory GABAergic and the
124
excitatory glutamatergic neurotransmission is thought to be
associated with craving for food (Han et al. 2008), the
effect of topiramate on GABA and glutamate receptors may
mediate its anticraving effect.
With regard to the preclinical model of binge eating
under evaluation, the effect observed for fluoxetine, sibutr-
amine, and topiramate provides clear-cut support of the
predictive validity of the model.
In conclusion, the present study confirms that cyclic
caloric restriction and acute environmental stress in young
female rats interact to produce robust compulsive HPF
intake. In addition, the experimental procedure to elicit the
acute stress episode, compared to the electric foot shock,
offers not only the advantage of generating pronounced and
highly reproducible binge eating for HPF in young female
rats, but increases also the face validity of the approach.
Even though the stress is milder than that evoked by
electric foot shock, nevertheless, it is sufficient to induce
neuroendocrine changes clearly consistent with a stress
response. Finally, the peculiar pharmacological profile of
the drugs tested suggests that the model, in addition to
construct and face validity as an isomorphic model of binge
eating, is apparently endowed with good predictive validity
(Corwin and Buda-Levin 2004; Smith 1989; Willner 1991).
Thus, the present model may be useful to evaluate new
pharmacological strategies for the treatment of bingeing-
related eating disorders.
Acknowledgements This study was supported by the MURST,
Rome, Italy (PRIN 2006 to M. Massi).
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