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Am J Physiol Regul Integr Comp Physiol 288: R1486 –R1491, 2005.
First published January 6, 2005; doi:10.1152/ajpregu.00779.2004.
CALL FOR PAPERS
Physiological Regulation of Appetite
The anorectic effect of fenfluramine is influenced by sex
and stage of the estrous cycle in rats
Lisa A. Eckel, Heidi M. Rivera, and Deann P. D. Atchley
Program in Neuroscience and Department of Psychology, Florida State University, Tallahassee, Florida
Submitted 16 November 2004; accepted in final form 5 January 2005
serotonin; satiety; estradiol; food intake; meal size
A GROWING LITERATURE SUGGESTS that the controls of food intake
are sexually dimorphic. For example, male rats typically consume more calories per day than female rats (8, 17, 24). This
sex difference in caloric intake is likely related to sex differences in gonadal hormone secretion, as testosterone and estradiol exert opposing effects on food intake. In the adult male rat,
testosterone increases food intake (22), and orchidectomy, in
the absence of testosterone replacement, induces weight loss
(13, 22). In the adult female rat, the preovulatory increase in
estradiol secretion induces a decrease in food intake that is
expressed throughout the nocturnal period of estrus (7, 16, 24),
and ovariectomy, in the absence of gonadal hormone replacement, increases food intake and weight gain (21, 23, 38). This
hyperphagia following ovariectomy is attributed to the decline
in circulating levels of estradiol, not progesterone, as estradiol
replacement alone normalizes food intake in the ovariectomized rat (21).
Address for reprint requests and other correspondence: Lisa A. Eckel,
Dept. of Psychology, Florida State Univ., Tallahassee FL 32306 –1270
([email protected]).
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Available data suggest that testosterone does not interact
with the neural circuits implicated in the control of food intake
(28). Rather, the orexigenic effect of testosterone appears to
arise from its ability to stimulate the development of lean tissue
mass, which functions to increase the male rat’s energy requirement (31). In contrast, considerable evidence suggests
that estradiol decreases food intake by selectively affecting the
neural controls of meal size. That is, the preovulatory increase
in estradiol secretion decreases the size but not the number of
meals consumed during estrus (reviewed in Ref. 14). This
action of estradiol is mediated, in part, by its ability to increase
the satiating effect of CCK, a gut peptide implicated in the
physiological control of meal size (35). For example, the
strength by which endogenous CCK inhibits meal size is
increased by estradiol treatment in the ovariectomized rat (2),
and during estrus in the cycling rat (15).
Like CCK, the serotonergic system has been implicated in
the physiological control of meal size (34). Because an interaction between estradiol and CCK alone cannot account for the
decrease in meal size in the estrous rat (14), our goal here was
to investigate whether estradiol interacts with the serotonergic
system to control meal size in the female rat. In particular, we
were interested in determining whether the feeding response
after an increase in serotonin (5-HT) neurotransmission was
influenced by sex and/or stage of the estrous cycle. To investigate this hypothesis, food intake was monitored in male,
diestrous female, and estrous female rats after acute administration of fenfluramine, a potent 5-HT releasing agent used
extensively to investigate the contribution of endogenous 5-HT
to food intake (34). Although the anorectic effect of fenfluramine is largely attributed to its ability to increase the strength
of negative-feedback satiety signals during a meal, there is
some evidence that fenfluramine may also decrease the
strength of meal-related positive-feedback signals, or induce an
aversive internal state that might promote early termination of
a meal (reviewed in Ref. 34). As such, we also examined
whether fenfluramine reduced the preference for a palatable
sucrose solution in male and female rats.
METHODS
Animals. Twenty-four male and 24 female Long-Evans rats
(Charles River Breeding Laboratories, Raleigh, NC; 45–55 days old at
study onset), were housed in a room maintained at 20 ⫾ 2°C under a
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Eckel, Lisa A., Heidi M. Rivera, and Deann P. D. Atchley.
The anorectic effect of fenfluramine is influenced by sex and stage
of the estrous cycle in rats. Am J Physiol Regul Integr Comp
Physiol 288: R1486 –R1491, 2005. First published January 6,
2005; doi:10.1152/ajpregu.00779.2004.—The controls of food intake differ in male and female rats. Daily food intake is typically
greater in male rats, relative to female rats, and a decrease in food
intake, coincident with the estrous stage of the ovarian reproductive
cycle, is well documented in female rats. This estrous-related decrease
in food intake has been attributed to a transient increase in the female
rat’s sensitivity to satiety signals generated during feeding bouts.
Here, we investigated whether sex or stage of the estrous cycle
modulate the satiety signal generated by fenfluramine, a potent serotonin (5-HT) releasing agent. To examine this hypothesis, food intake
was monitored in male, diestrous female, and estrous female rats after
intraperitoneal injections of 0, 0.25, and 1.0 mg/kg D-fenfluramine.
The lower dose of fenfluramine decreased food intake only in
diestrous and estrous females, suggesting that the minimally effective
anorectic dose of fenfluramine is lower in female rats, relative to male
rats. Although the larger dose of fenfluramine decreased food intake
in both sexes, the duration of anorexia was greater in diestrous and
estrous female rats, relative to male rats. Moreover, the magnitude of
the anorectic effect of the larger dose of fenfluramine was greatest in
estrous rats, intermediate in diestrous rats, and least in male rats. Thus
our findings indicate that the anorectic effect of fenfluramine is
modulated by gonadal hormone status.
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intervals: the first 2 h after drug treatment (i.e., from 1300 to 1500),
the subsequent 4-h period (i.e., from 1500 to 1900), and the subsequent 14 h period (i.e., from 1900 to 0900). These intervals were
chosen on the basis of the half-life of fenfluramine, which ranges from
2 to 4 h in the rat (10). The effects of injection day (diestrus and estrus
in females; day 1 and day 2 in males) and drug dose (0, 0.25, and 1.0
mg/kg fenfluramine) on food intake during each of these intervals was
analyzed using two-factor, repeated-measures ANOVAs in male and
female rats. In males, these analyses failed to reveal any main or
interactive effect of injection day (i.e., day 1 vs. day 2). Thus, to
simplify the illustration of food intake in male rats, only data taken
after the second injection of each drug dose are presented, and the
effects of drug dose on food intake during each interval were analyzed
using single-factor (drug dose), repeated-measures ANOVAs. The
anorectic effect of fenfluramine was further characterized by calculating the decrease in food intake (⫾0.1 g) after the largest dose of
fenfluramine, relative to saline vehicle, in male, diestrous female, and
estrous female rats. One-way ANOVAs were then used to determine
the influence of gonadal hormone status on the anorectic effect of
fenfluramine. Tukey’s honestly significant difference test was used to
investigate differences between means after significant main or interactive ANOVA effects.
In Experiment 2, preference for the sucrose solution was determined by the ratio of sucrose consumed to the total amount of fluid
consumed by each rat during the two-bottle preference test. In the
female group, an independent t-test was used to determine the influence of cycle stage on sucrose preference. Because this analysis
revealed no significant effect of cycle stage, data were collapsed
across cycle stage in female rats. In male and female rats, the effect of
fenfluramine treatment on sucrose preference was analyzed using
independent t-tests.
RESULTS
Experiment 1. In male rats, food intake was decreased only
during the first 2-h period after drug treatment [F(2,14) ⫽
10.83, P ⬍ 0.005] (Fig. 1, left). During this interval, the largest
dose of fenfluramine decreased food intake relative to the
lower dose of fenfluramine and saline (P ⬍ 0.05). No influence
of drug treatment was detected during the subsequent 4- or
14-h periods. In female rats, food intake during the first 2-h
period and the subsequent 4-h period was decreased by estrous
stage and drug treatment [F(2,14) ⫽ 16.34 ⫺ 44.08, P ⬍
0.005 ⫺ 0.0001] (Fig. 1, right). During these intervals, an
estrous-related decrease in food intake was detected, regardless
of drug treatment (P ⬍ 0.05). During the first 2-h period, both
doses of fenfluramine decreased food intake in diestrous and
estrous rats (P ⬍ 0.05). During the subsequent 4-h period, only
the largest dose of fenfluramine decreased food intake in
diestrous rats, whereas fenfluramine induced a dose-related
decrease in food intake in estrous rats (P ⬍ 0.05). No influence
of drug treatment was detected during the subsequent 14-h
period in either diestrous or estrous rats.
Fig. 2 depicts the influence of gonadal hormone status on the
magnitude of anorexia after treatment with the larger dose of
fenfluramine. At 2 h after drug treatment, the anorectic effect
of this dose of fenfluramine was similar across groups
[F(2,21) ⫽ 0.58, not significant (ns)] (Fig. 2A). That is,
fenfluramine treatment produced about a 2-g reduction in food
intake, relative to that consumed following saline vehicle
treatment, in male, diestrous female, and estrous female rats.
During the subsequent 4-h period, fenfluramine’s inhibitory
effect on food intake was influenced by gonadal hormone
status [F(2,21) ⫽ 4.87, P ⬍ 0.01] (Fig. 2B). At this time, the
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reverse 12:12-h light-dark cycle (dark phase ⫽ 1300 – 0100). Animal
usage and all procedures were approved by the Florida State University Institutional Animal Care and Use Committee and the guidelines
of the American Physiological Society (1).
Estrous cycles. Vaginal cytology samples were collected daily.
Stages of the estrous cycle (diestrus 1, diestrus 2, proestrus, and
estrus) were determined by examining the appearance and abundance
of cells within samples, as described previously (15, 16). Using this
strategy, proestrus included the light-phase peak in estradiol and
luteinizing hormone secretion (19), and estrus included the subsequent
dark phase when female rats ovulate and display increased sexual
receptivity (6). At study onset, all rats displayed regular, four-day
estrous cycles.
Experiment 1: effect of fenfluramine on food intake. Male and
female rats (n ⫽ 8 per sex) were housed in cages equipped with
feeding niches that provided access to spill-resistant food cups containing powdered chow (Purina 5001). Changes in food cup weights
were monitored via custom-designed software (ESP 500; R. Henderson; Florida State University) connected, via a computer interface, to
weight-sensitive load beams located below the food cups and infrared
beams positioned above the food cups. Additional software (Meal
Weight Analysis, R. Henderson, Florida State University) was used to
monitor food intake at specific intervals.
The computerized system monitoring food intake was stopped
daily at 0900 h. During the following 30 min, body weights were
recorded, vaginal cytology samples were collected, food cups and
water bottles were refilled, and the computer was then restarted. To
prevent rats from consuming a meal before dark onset, food access
was blocked during the last 4 h of the light phase (i.e., from 0900 to
1300). Rats were adapted to this restricted-feeding schedule before
drug testing. In female rats, a within-subject design was used to
examine the effects of varying doses of fenfluramine on food intake at
different stages of the estrous cycle. During three consecutive cycles
(i.e., 12 days), female rats received intraperitoneal injections of 0,
0.25, or 1.0 mg/kg D-fenfluramine (Sigma, St. Louis, MO), dissolved
in physiological saline vehicle. Injections were administered 60 min
before food access on diestrus 2, after a period of low estradiol
secretion, and on estrus, after a period of high estradiol secretion (19).
Injections were randomized with respect to drug dose and cycle phase.
In male rats, the same schedule of injections was administered at
2-day intervals over the 12-day test period. Although daily variation
in response to the same dose of fenfluramine was not expected in male
rats, this protocol ensured that male and female rats received equal
exposure to fenfluramine (i.e., two injections of each dose of fenfluramine).
Experiment 2: Effect of fenfluramine on preference for a 5%
sucrose solution. Male and female rats (n ⫽ 16 per sex) were housed
individually in custom-designed, polyethylene cages that provided
access to chow (Purina 5001) and two drip-resistant drinking bottles.
Rats were adapted to a 22-h water-deprivation schedule (daily water
access from 1100 to 1300) over a 7-day period. On the eighth day of
water deprivation, rats were given 2-h access to a novel 5% sucrose
solution instead of water. Immediately after sucrose access, half of the
male rats and half of the female rats received intraperitoneal injections
of 1 mg/kg fenfluramine. The remaining rats received intraperitoneal
injections of 1 ml/kg saline vehicle. In females, sucrose access and
injections of fenfluramine or saline were administered when rats were
either in diestrus 2 (n ⫽ 8) or estrus (n ⫽ 8). Preference for the
sucrose solution was assessed on the following day. From 1100 to
1300, rats were given 2-h access to one bottle containing water and
one bottle containing a 5% sucrose solution. To minimize the development of a drinking side preference, the position of the water and
sucrose bottles was reversed during the second h of the test. The
amount of 5% sucrose and water consumed was measured by weighing drinking bottles ( ⫾ 0.1 g) before and after the test.
Data analysis. In Experiment 1, the time course over which
fenfluramine modulated feeding behavior was examined at three
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Fig. 1. Time course of fenfluramine’s anorectic effect in male and female rats.
Data are means ⫾ SEs. After drug treatment, food intake was examined at
three intervals: the first 2-h period after drug treatment and the subsequent 4-h
and 14-h periods. In male rats (left), food intake was decreased for 2 h after
treatment with the larger dose of fenfluramine. The lower dose of fenfluramine
failed to modulate food intake in male rats. In female rats (right), the lower
dose of fenfluramine decreased food intake for 2 h in diestrous rats (D2) and
for 6 h in estrous rats (E). The larger dose of fenfluramine decreased food
intake for 6 h in both diestrous and estrous rats. *Less than 0 mg/kg
fenfluramine, P ⬍ 0.05. **Less than 0 and 0.25 mg/kg fenfluramine, P ⬍ 0.05).
⫹Less than diestrous rats, P ⬍ 0.05.
anorectic effect of fenfluramine was greater in diestrous and
estrous female rats, relative to male rats (P ⬍ 0.05). Among
female rats, the anorectic effect of fenfluramine was greater
during estrus, relative to diestrus (P ⬍ 0.01).
Experiment 2. Before fenfluramine treatment, all rats avidly
consumed the 5% sucrose solution on the conditioning day
(mean intake ⫽ 24.7 ⫾ 1.4 g/2 h). No estrous-related or sex
differences in the amount of sucrose consumed during the 2-h
access period were apparent. On the following day, all rats
displayed a strong preference for the sucrose solution during
the two-bottle sucrose preference test. Fenfluramine failed to
suppress this preference for sucrose in either male or female
rats [t(14) ⫽ 1.73 and 1.32, ns] (Fig. 3).
DISCUSSION
The major goal of the present study was to determine
whether the anorexia resulting from increased serotonergic
neurotransmission is influenced by sex or stage of the estrous
cycle. To investigate this hypothesis, food intake was monitored in male, diestrous female, and estrous female rats treated
with fenfluramine, a potent 5-HT agonist that increases extracellular concentration of 5-HT (32). In support of our hypothesis, the anorectic effect of fenfluramine was greater in female
rats, relative to male rats. Among females, we also found that
fenfluramine-induced anorexia was greater during estrus, relative to diestrus. It appears unlikely that the enhanced anorexia
in female rats was secondary to any nonspecific, aversive
effects of fenfluramine. Treatment with the larger dose of
fenfluramine did not alter the female rat’s preference for a 5%
sucrose solution.
Our data indicate that the anorectic effect of fenfluramine is
sexually dimorphic. First, the lower dose of fenfluramine tested
here decreased food intake in female rats, but failed to influence food intake in male rats. Thus the minimally effective
Fig. 3. Fenfluramine failed to reduce preference for a 5% sucrose solution in
either male or female rats. Data are means ⫾ SEs. In a single conditioning trial,
rats were given 2 h access to a novel 5% sucrose solution followed by injection
of 1 mg/kg fenfluramine or 1 ml/kg saline vehicle. The following day, rats
were given a 2 bottle (water vs. 5% sucrose solution) preference test. Preference for the sucrose solution was determined by the ratio of 5% sucrose intake
to total fluid intake. sal; saline, fen; fenfluramine.
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Fig. 2. Influence of gonadal hormone status on the anorectic effect of the
larger (1 mg/kg) dose of fenfluramine during the first 2-h period and the
subsequent 4-h period after drug treatment. Data are means ⫾ SEs. A:
anorectic effect of fenfluramine was similar in male, diestrous female, and
estrous female rats during the first 2-h period. B: during the subsequent 4-h
period, the anorectic effect of fenfluramine was greater in female rats, relative
to male rats. Among female rats, the anorectic effect of fenfluramine was
greater during estrus, relative to diestrus. *Greater than male rats, P ⬍ 0.05.
**Greater than diestrous and male rats, P ⬍ 0.05. FI; food intake.
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perphagia when the drug was administered during the diestrous
stage of the cycle (37). However, vehicle-treated rats failed to
display the typical, estrous-related decrease in food intake
during multiple feeding tests, suggesting that the effect of
8-OH-DPAT on food intake may have been conducted at a
time that was not optimal to detect an estrous-related change in
the efficacy of the drug. The discrepant findings between these
two studies may also be related to the fact that metergoline and
8-OH-DPAT reduce 5-HT activity via different mechanisms.
Metergoline-induced hyperphagia is mediated by antagonism
of postsynaptic 5-HT1/2/7 receptors, whereas 8-OH-DPATinduced hyperphagia is mediated by agonism of presynaptic
5-HT1A autoreceptors. Thus the hormonal changes that precede
estrus may modulate the expression or binding affinity of
postsynaptic, but not presynaptic, 5-HT receptors. Indeed,
previous research indicates that 5-HT2A receptor mRNA is
increased during estrus, relative to nonestrous phases (36).
Differences in gonadal hormone status were associated with
the changes in duration and magnitude of fenfluramine-induced
anorexia observed here. Specifically, the anorectic effect of
fenfluramine was greatest in estrous rats, intermediate in
diestrous rats, and least in male rats when assessed 6 h after
drug treatment. Our inability to detect a similar relationship
within the first 2 h of drug treatment may be the result of a floor
effect, as fenfluramine produced very large decreases in food
intake, particularly in estrous rats, which consumed very little
food (less than 0.5 g) at this time. Multiple mechanisms could
account for the estrous cycle- and sex-related changes in the
anorectic effect of fenfluramine. Because the duration of fenfluramine’s anorectic effect was greater in females, relative to
males, it is possible that drug clearance occurs more slowly in
the female rat. To test this hypothesis, hypothalamic concentrations of fenfluramine and its metabolite, norfenfluramine,
were measured in male and female rats at 2, 6, and 20 h after
acute injection of fenfluramine (29). At 2 h, hypothalamic
concentrations of fenfluramine and norfenfluramine were similar in male and female rats. However, at 6 and 20 h, the
concentration of fenfluramine was greater in female rats,
whereas the concentration of norfenfluramine was greater in
male rats. Importantly, the combined concentrations of fenfluramine and norfenfluramine, which are equipotent in their
ability to act as 5-HT releasing agents when assessed in terms
of brain concentration (9), were identical in male and female
rats at both time points (29). Thus, while the metabolism of
fenfluramine to norfenfluramine may be increased in the female rat, the clearance of fenfluramine and norfenfluramine,
assessed over a 20 h period, is similar in male and female rats,
at least within the hypothalamus. Alternative mechanisms that
could account for the estrous cycle and sex differences in the
anorectic effect of fenfluramine reported here include a greater
neuronal storage capacity for 5-HT, or reduced activity of
inhibitory presynaptic 5-HT receptors, in the female rat. In
support of these hypotheses, female rats were found to have
greater storage capacity for neuronal 5-HT and higher levels
of whole brain 5-HT than male rats (11). Additionally, the
preovulatory rise in estradiol secretion in female rats was
found to reduce the expression of somatodendritic 5-HT1A
receptors that function to decrease the firing rate of serotonergic neurons (26).
In addition to its anorectic effect, previous studies demonstrate that fenfluramine can induce an aversive internal state.
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anorectic dose of fenfluramine appears to be lower in the
female rat. Second, the duration of the anorectic effect of the
larger dose of fenfluramine was 6 h in diestrous and estrous
female rats and 2 h in male rats. Third, the magnitude of the
anorectic effect of the larger dose of fenfluramine was greater
in diestrous and estrous female rats, relative to male rats. In
males, the larger dose of fenfluramine reduced food intake by
⬃2 g. In females, the same dose of fenfluramine reduced food
intake by ⬃3.5 g during diestrus and by ⬃6.5 g during estrus.
Together, these results suggest that female rats are more
sensitive than male rats to the anorectic effect of fenfluramine.
Previous studies are consistent with our findings. Chronic
administration of fenfluramine induced a larger decrease in
daily food intake in female rats, relative to male rats (33), and
acute administration of sibutramine, a 5-HT reuptake inhibitor,
reduced consumption of a high-carbohydrate diet more in
female rats, than in male rats (25). Although it was noted that
the sex difference reported in the former study may have been
related to the greater body weight of their female rats (33),
such an explanation cannot account for the present findings. In
our study, male rats weighed more than female rats, and female
rats lost weight during estrus, relative to diestrus. In contrast to
the results found here and in previous studies (25, 33), Dagnault and colleagues (13) reported that chronic fenfluramine
treatment (6 –12 mg䡠kg⫺1 䡠day⫺1) produced similar reductions
in food intake in male and female rats. The lack of a sexually
dimorphic response in this study may be related to the fact that
the very high, sustained doses of fenfluramine produced large
decreases in food intake in both sexes such that a floor effect
may have limited their ability to detect a sex difference in the
anorectic effect of fenfluramine. Finally, our findings are consistent with other reports of sex differences in nonfeeding,
behavioral responses induced by other treatments that modulate 5-HT neurotransmission. For example, the collection of
responses that characterize the 5-HT behavioral syndrome (i.e.,
flattened body posture, resting tremor, forepaw treading, and
head weaving), induced by pargyline/L-tryptophan treatment, is
more pronounced in female rats than in male rats (11, 18).
Together, these studies suggest that females are more sensitive
than males to the behavioral responses elicited by direct manipulation of the 5-HT system by several different compounds
that increase 5-HT activity.
In the present study, the anorectic effect of fenfluramine was
also influenced by stage of the estrous cycle. First, the duration
of the anorectic response after administration of the lower dose
of fenfluramine was greater during estrus, relative to diestrus.
Second, the magnitude, but not the duration of the anorectic
response after administration of the larger dose of fenfluramine
was greater during estrus, relative to diestrus. We believe this
to be the first demonstration of an estrous cycle-related change
in the anorectic effect of any 5-HT agonist. There are, however, two previous reports of estrous cycle modulation of the
hyperphagia induced by drugs that reduce 5-HT activity. In one
study, posterior basolateral amygdala (pBLA) infusion of
metergoline, a 5HT1/2/7 receptor antagonist, induced a greater
increase in food intake in estrous rats, relative to diestrous rats
(30). Thus the estrous-related decrease in food intake may
involve activation of postsynaptic 5-HT receptors within the
pBLA. In another study, female rats treated with 8-OH-DPAT,
a drug that reduces 5-HT neurotransmission via activation of
presynaptic 5-HT1A autoreceptors, displayed increased hy-
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GRANTS
This work was supported by National Institute of Mental Health Grant
MH-63932 (L. A. Eckel), a National Institutes of Health Training Grant in the
Chemical Senses DC-000044 (H. M. Rivera), and an Individual National
Research Service Award MH-68973 (D. P. D. Atchley).
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For example, acute injection of fenfluramine increased aversive taste reactivity responses during intraoral infusions of a
2% sucrose solution (5) and supported the development of a
conditioned taste aversion to a novel tasting solution (12).
Fenfluramine may also reduce the palatability of novel-tasting
solutions. Fenfluramine treatment reduced the number of licks
generated by rats consuming a sucrose solution (3, 4), and
decreased sham intake of a sucrose solution in rats fitted with
open gastric fistulas (27). Although our rats were fed a familiar
chow diet that is usually resistant to conditioned taste aversion
learning, we wanted to rule out the possibility that the large
reductions in food intake observed in Experiment 1, particularly in female rats, were not partially mediated by the induction of an aversive internal state. Thus we examined whether
the largest dose of fenfluramine used here was sufficient to
induce a conditioned taste aversion to a novel, 5% sucrose
solution using a sensitive, two-bottle preference test. Neither
male nor female rats displayed any evidence of a conditioned
taste aversion. Rather, all rats displayed a strong preference for
the sucrose solution. Thus the fenfluramine-induced reductions
in food intake observed here appear to be behaviorally specific
and not secondary to an aversive effect of the largest dose of
fenfluramine tested here.
In summary, the present study demonstrated that the anorectic effect of fenfluramine is modulated by sex and stage of
the estrous cycle. Because fenfluramine’s anorectic effect is
largely attributed to its ability to increase serotonergic neurotransmission (32), our findings suggest that 5-HT plays a role
in the estrous-related decrease in food intake observed in
female rats, as well as the lower daily food intake of female
rats, relative to male rats. However, this interpretation is
limited somewhat by the fact that fenfluramine can also affect
the production or release of other neurotransmitters such as
acetylcholine and GABA. Although it remains to be determined whether alterations in such transmitter systems are
involved in fenfluramine’s ability to cause anorexia (21), and it
has been shown that some of these alterations are secondary to
fenfluramine’s action on serotonergic systems (20), additional
research involving more selective 5-HT receptor agonists and
antagonists is required to elucidate a definitive role for endogenous 5-HT in the differential control of food intake in male
and female rats. Because peripherally administered fenfluramine readily crosses the blood-brain barrier, our results could
have been mediated by a peripheral and/or central serotonergic
mechanism. Additional research involving site-specific infusions of 5-HT receptor agonists/antagonists into brain regions
implicated in the control of food intake, as well as peripheral
administration of 5-HT agonists/antagonists that fail to cross
the blood-brain barrier, will be useful in dissociating the
relative roles of peripheral and central serotonergic mechanisms in the control of food intake in male and female rats.
R1491
FENFLURAMINE ANOREXIA
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