d-Fenfluramine- and d-norfenfluramine-induced hypophagia: differential mechanisms and involvement of postsynaptic 5-HT receptors

doi:10.1016/0014-2999(93)90013-8

European Journal of Pharmacology

Volume 242, Issue 1, 21 September 1993, Pages 83-90

https://doi.org/10.1016/0014-2999(93)90013-8 Get rights and content

Abstract

Severe depletion of 5-hydroxytryptamine (5-HT) by para-chlorophenylalanine (pCPA, 150 mg/kg per day × 3) did not alter the hypophagic effect of d-fenfluramine (1–3 mg/kg i.p.) 1 h after food presentation in 24-h food-deprived rats, and moderately and comparably increased the hypophagic effects of its metabolite, d-norfenfluramine (0.35–1.0 mg/kg i.p.), and of the 5-HT_1C receptor agonist, 1-(3-chlorophenyl)piperazine (mCPP; 1.5, 2.0 mg/kg i.p.). Chronic treatment with mCPP (2.5 mg/kg i.p. × 14) attenuated the hypophagia induced by d-norfenfluramine (1, 1.5 mg/kg) but not d-fenfluramine (1, 3 mg/kg). 1-(1-Naphthyl)piperazine (3, 8 μmol/kg s.c.), which has greater affinity for 5-HT_1C than for 5-HT₂ receptors, had no effect on the hypophagia induced by d-fenfluramine (1.25, 2.0 mg/kg), but 1.3 and 3 μmol/kg 1-(1-naphthyl)piperazine largely and comparably attenuated the substantial hypophagic effect of d-norfenfluramine (0.75 mg/kg). The essentially complete hypophagic action of d-norfenfluramine (1.25 mg/kg) was inhibited by 1-(1-naphthyl)piperazine with ID₅₀=2.13 μmol/kg. Ketanserin, which binds more weakly than 1-(1-naphthyl)piperazine to 5-HT_1C receptors and more strongly to 5-HT₂ receptors, attenuated weaker but not stronger hypophagic effects of d-fenfluramine (1.25, 2.0 mg/kg) when given at high dosage (8, 16 μmol/kg s.c.). Ketanserin (16 μmol/kg) also weakly attenuated the hypophagia due to d-norfenfluramine (0.75 mg/kg), but not the essentially complete hypophagia due to d-norfenfluramine (1.25 mg/kg). The results support direct activation of postsynaptic 5-HT_1C receptors as a major mechanism of d-norfenfluramine- but not d-fenfluramine-induced hypophagia in hungry rats, and suggest that increased release (or decreased reuptake) of 5-HT may not be required for the hypophagic effects of either drug.

References (54)

B.J. Baker et al.
Effects of dl-fenfluramine and xylamidine on gastric emptying of maintenance diet in freely feeding rats
Eur. J. Pharmacol.
(1988)
H.H.G. Berendsen et al.
Depletion of brain serotonin differently effects behaviours induced by 5-HT_1A, 5-HT_1C and 5-HT₂ receptor activation in rats
Behav. Neurol. Biol.
(1991)
D.A. Booth et al.
Gastromotor mechanism of fenfluramine anorexia
Appetite
(1986)
F. Borsini et al.
d-Fenfluramine and d-norfenfluramine reduce food intake by acting on different seretonin mechanisms in the rat brain
Pharmacol. Res. Commun.
(1982)
B.V. Clineschmidt
5,6-Dihydroxytryptamine: suppression of the anorexigenic action of fenfluramine
Eur. J. Pharmacol.
(1973)
B.V. Clineschmidt et al.
Role of monoamines in the anorexigenic actions of fenfluramine, amphetamine and p-chloromethamphetamine
Eur. J. Pharmacol.
(1974)
P.J. Conn et al.
Denervation supersensitivity of 5-HT_1C receptors in rat choroid plexus
Brain Res.
(1987)
R.F. Davies et al.
Fenfluramine anorexia: a peripheral locus of action
Physiol. Behav.
(1983)
P.J. Fletcher et al.
A comparison of the effects of tryptamine and 5-hydroxytryptamine on feeding following injection into the paraventricular nucleus of the hypothalamus
Pharmacol. Biochem. Behav.
(1989)
G. Grignaschi et al.
Role of 5-HT receptors in the effect of d-fenfluramine on feeding patterns in the rat
Eur. J. Pharmacol.
(1992)

A.S. Hollister et al.

The roles of monoamine neural systems in the anorexia induced by (+)-amphetamine and related compounds

Neuropharmacology

(1975)

P.H. Hutson et al.

Hypothermia induced by putative 5-HT_1A agonists LY165 163 and 8-OH-DPAT is not prevented by 5-HT depletion

Eur. J. Pharmacol.

(1987)

G.A. Kennett et al.

5-HT_1B agonists induce anorexia at a postsynaptic site

Eur. J. Pharmacol.

(1987)

S.F. Leibowitz et al.

Medial hypothalamic nuclei mediate serotonin's inhibitory effect on feeding behavior

Pharmacol. Biochem. Behav.

(1990)

T. Mennini et al.

Characterization of high affinity and stereospecific [³H]-d-fenfluramine binding to rat brain

Neurochem. Int.

(1988)

N.E. Rowland et al.

Neurobiology of an anorectic drug: fenfluramine

Prog. Neurobiol.

(1986)

R. Samanin et al.

The effects of selective lesioning of brain serotonin or catecholamine containing neurones on the anorectic activity of fenfluramine and amphetamine

Eur. J. Pharmacol.

(1972)

R. Samanin et al.

Evidence that central 5-HT₂ receptors do not play an important role in the anorectic activity of d-fenfluramine in the rat

Neuropharmacology

(1989)

G. Shor-Posner et al.

Hypothalamic serotonin in the control of meal patterns and macronutrient selection

Brain Res. Bull.

(1986)

M.A. Sills et al.

Development of selective tolerance to the serotonin behavioral syndrome and suppression of locomotor activity after repeated administration of either 5-MeODMT or mCPP

Life Sci.

(1985)

L.H. Storlien et al.

D-fenfluramine effects on hypothalamic monoamine activities and their hormonal correlates

Brain Res.

(1992)

I. Tohyama et al.

Quantitative morphometric analysis of two types of serotonin-immunoreactive nerve fibres differentially responding to p-chlorophenylalanine treatment in the rat brain

Neuroscience

(1988)

G.F. Weiss et al.

Medial hypothalamic serotonin: effects of deprivation- and norepinephrine-induced eating

Pharmacol. Biochem. Behav.

(1986)

G.F. Weiss et al.

Impact of hypothalamic d-norfenfluramine and peripheral d-fenfluramine injection on macronutrient intake in the rat

Brain Res. Bull.

(1990)

S. Caccia et al.

Pharmacokinetics of fenfluramine enantiomers in man

Eur. J. Drug Metab. Pharmacokinet.

(1979)

S. Caccia et al.

Kinetics of fenfluramine isomers in the rat

Eur. J. Drug Metab. Pharmacokinet.

(1981)

S. Caccia et al.

Species differences in the kinetics and metabolism of fenfluramine isomers

Arch. Int. Pharmacodyn.

(1982)

Cited by (84)

Role of the serotonergic system in appetite and ingestion control
2020, Handbook of Behavioral Neuroscience
Early human and rodent studies, many using fenfluramine, suggested that serotonin modulates satiation and satiety. The more recent characterization of serotonin receptor subtypes and the use of genetically manipulated mice have identified specific roles for the 5-HT_2C, 5-HT_1B, 5-HT₃, and 5-HT₆ receptor subtypes in feeding behavior and has also contributed to the development of 5-HT_2C receptor agonists as a treatment for obesity. It has also become clear that serotonin modulates several reward-related aspects of feeding in addition to satiety.
Serotonin acts at multiple brain sites to modulate feeding behavior, including several nuclei in the brainstem, hypothalamic subregions such as the arcuate and paraventricular nuclei, and the mesocorticolimbic dopamine system. There are important interactions between serotonin and hypothalamic peptide containing cells, and with cholecystokinin and other peptides. Serotonin has multiple influences at the behavioral level, which range from the mediation of short-term satiation and satiety in response to gastric distension and the presence of gut nutrients to modulation of reward and the behavioral responses evoked by conditioned cues that lead to the initiation of feeding.
Prelimbic cortex 5-HT1A and 5-HT2C receptors are involved in the hypophagic effects caused by fluoxetine in fasted rats
2015, Pharmacology Biochemistry and Behavior
Citation Excerpt :
Corroborating our results, it has been demonstrated that administration of d-fenfluramine, a SSRI, provided evidence that 5-HT2C receptors play a critical role in mediating the inhibitory action of serotonin on feeding behavior. D-norfenfluramine, a major metabolite of d-fenfluramine, is an agonist of 5-HT2C receptors (Gibson et al., 1993). Thus, rats that were pretreated with the selective 5-HT2C receptor antagonist SB-242084 did not present the hypophagic response evoked by either d-fenfluramine or d-norfenfluramine (Vickers et al., 2001).
The regulation of food intake involves a complex interplay between the central nervous system and the activity of organs involved in energy homeostasis. Besides the hypothalamus, recognized as the center of this regulation, other structures are involved, especially limbic regions such as the ventral medial prefrontal cortex (vMPFC). Monoamines, such as serotonin (5-HT), play an important role in appetite regulation. However, the effect in the vMPFC of the selective serotonin reuptake inhibitor (SSRI), fluoxetine, on food intake has not been studied. The aim of the present study was to study the effects on food intake of fed and fasted rats evoked by fluoxetine injection into the prelimbic cortex (PL), a sub-region of the vMPFC, or given systemically, and which 5-HT receptors in the PL are involved in fluoxetine responses. Fluoxetine was injected into the PL or given systemically in male Wistar rats. Independent groups of rats were pretreated with intra-PL antagonists of 5-HT receptors: 5-HT1A (WAY100635), 5-HT2C (SB242084) or 5-HT1B (SB216641). Fluoxetine (0.1; 1; 3; 10 nmol/200 nL) injected into the PL induced a dose-dependent hypophagic effect in fasted rats. This effect was reversed by prior local treatment with WAY100635 (1; 10 nmol) or SB242084 (1; 10 nmol), but not with SB216641 (0.2; 2.5; 10 nmol). Systemic fluoxetine induced a hypophagic effect, which was blocked by intra-PL 5-HT2C antagonist (10 nmol) administration. Our findings suggest that PL 5-HT neurotransmission modulates the central control of food intake and 5-HT1A and 5-HT2C receptors in the PL could be potential targets for the action of fluoxetine.
Serotonin controlling feeding and satiety
2015, Behavioural Brain Research
Citation Excerpt :
As the effect of d-fenfluramine was thought to be based on the increased availability of postsynaptic 5-HT, it was initially a surprising finding that inhibition of brain 5-HT synthesis with pCPA did not interfere with the hypophagic action of d-fenfluramine. Furthermore, low doses of fenfluramine do not impact on 5-HT release but already induce hypophagia [29,64]. In addition, d-fenfluramine maintains its hypophagic efficacy even following inhibition of 5-HT release [65].
Serotonin has been implicated in the control of satiety for almost four decades. Historically, the insight that the appetite suppressant effect of fenfluramine is linked to serotonin has stimulated interest in and research into the role of this neurotransmitter in satiety. Various rodent models, including transgenic models, have been developed to identify the involved 5-HT receptor subtypes. This approach also required the availability of receptor ligands of different selectivity, and behavioural techniques had to be developed simultaneously which allow differentiating between unspecific pharmacological effects of these ligands and ‘true’ satiation and satiety. Currently, 5-HT1B, 5-HT2C and 5-HT6 receptors have been identified to mediate serotonergic satiety in different ways. The recently approved anti-obesity drug lorcaserin is a 5-HT2C receptor agonist. In brain, both hypothalamic (arcuate nucleus, paraventricular nucleus) and extrahypothalamic sites (parabrachial nucleus, nucleus of the solitary tract) have been identified to mediate the serotonergic control of satiety. Serotonin interacts within the hypothalamus with endogenous orexigenic (Neuropeptide Y/Agouti related protein) and anorectic (α-melanocyte stimulating hormone) peptides. In the nucleus of the solitary tract serotonin integrates peripheral satiety signals. Here, the 5-HT3, but possibly also the 5-HT2C receptor play a role. It has been found that 5-HT acts in concert with such peripheral signals as cholecystokinin and leptin. Despite the recent advances of our knowledge, many of the complex interactions between 5-HT and other satiety factors are not fully understood yet. Further progress in research will also advance the development of new serotonergic anti-obesity drugs.
Medial amygdaloid nucleus 5-HT<inf>2C</inf> receptors are involved in the hypophagic effect caused by zimelidine in rats
2012, Neuropharmacology
Citation Excerpt :
Administration of d-fenﬂuramine, a serotonin releaser, provided the first evidence that 5-HT2C receptors play a critical role in mediating the inhibitory action of serotonin on feeding. The major metabolite of d-fenﬂuramine, d-norfenﬂuramine, is an agonist of 5-HT2C receptors (Gibson et al., 1993). Rats that were pretreated with the selective 5-HT2C receptor antagonist SB-242084 did not show a hypophagic response evoked by either d-fenﬂuramine or d-norfenﬂuramine (Vickers et al., 2001).
The medial amygdaloid nucleus (MeA) is a sub-region of the amygdaloid complex that has been described as participating in food intake regulation. Serotonin has been known to play an important role in appetite and food intake regulation. Moreover, serotonin 5-HT_2C and 5-HT_1A receptors appear to be critical in food intake regulation. We investigated the role of the serotoninergic system in the MeA on feeding behavior regulation in rats.
The current study examined the effects on feeding behavior regulation of the serotonin reuptake inhibitor, zimelidine, administered directly into the MeA or given systemically, and the serotoninergic receptors mediating its effect. Our results showed that microinjection of zimelidine (0.2, 2 and 20 nmol/100 nL) into the MeA evoked dose dependent hypophagic effects in fasted rats. The selective 5-HT_1A receptor antagonist WAY-100635 (18.5 nmol/100 nL) or the 5-HT_1B receptor antagonist SB-216641 microinjected bilaterally into the MeA did not change the hypophagic effect evoked by local MeA zimelidine treatment. However, microinjection of the selective 5-HT_2C receptor antagonist SB-242084 (10 nmol/100 nL) was able to block the hypophagic effect of zimelidine. Moreover, microinjection of the 5-HT_2C receptor antagonist SB-242084 into the MeA also blocked the hypophagic effect caused by zimelidine administered systemically.
These results suggest that MeA 5-HT_2C receptors modulate the hypophagic effect caused by local MeA administration as well as by systemic zimelidine administration. Furthermore, 5-HT_2C into the MeA could be a potential target for systemic administration of zimelidine.
Estradiol increases the anorexia associated with increased 5-HT <inf>2C</inf> receptor activation in ovariectomized rats
2012, Physiology and Behavior
Citation Excerpt :
Although FEN increases 5-HT neurotransmission via multiple mechanisms, its anorexigenic effect appears to be mediated primarily by its postsynaptic action. This view is supported by studies showing that FEN's anorexigenic effect is attenuated by selective blockade or targeted deletion of 5-HT2C receptors [21,22], but is unaffected by drugs that decrease 5-HT synthesis, deplete 5-HT storage, or block 5-HT reuptake [23–25]. Thus, the most parsimonious interpretation of our findings is that estradiol increases FEN's anorexigenic effect by augmenting its postsynaptic action at 5-HT2C receptors.
Estradiol's inhibitory effect on food intake is mediated, in part, by its ability to increase the activity of meal-related signals, including serotonin (5-HT), which hastens satiation. The important role that postsynaptic 5-HT_2C receptors play in mediating 5-HT's anorexigenic effect prompted us to investigate whether a regimen of acute estradiol treatment increases the anorexia associated with increased 5-HT_2C receptor activation in ovariectomized (OVX) rats. We demonstrated that intraperitoneal and intracerebroventricular (i.c.v.) administration of low doses of the 5-HT_2C receptor agonist meta-chlorophenylpiperazine (mCPP) decreased 1-h dark-phase food intake in estradiol-treated, but not oil-treated, OVX rats. During a longer feeding test, we demonstrated that i.c.v. administration of mCPP decreased 22-h food intake in oil-treated and, to a greater extent, estradiol-treated OVX rats. In a second study, we demonstrated that estradiol increased 5-HT_2C receptor protein content in the caudal brainstem, but not hypothalamus, of OVX rats. We conclude that a physiologically-relevant regimen of acute estradiol treatment increases sensitivity to mCPP's anorexigenic effect. Our demonstration that this same regimen of estradiol treatment increases 5-HT_2C receptor protein content in the caudal hindbrain of OVX rats provides a possible mechanism to explain our behavioral findings.
A role for serotonin in the antidepressant activity of N<sup>G</sup>-Nitro-L-arginine, in the rat forced swimming test
2010, Pharmacology Biochemistry and Behavior
The present study determined regional serotonin (5-HT) synthesis and metabolism changes associated with the nitric oxide synthase (NOS) inhibitor N^G-nitro-L-arginine (L-NA) and the influence of 5-HT receptor blockade in the antidepressant-like actions of L-NA in the forced swimming test (FST). Regional effects of L-NA (5,10 and 20 mg/kg i.p.) on tryptophan hydroxylase (TPH) activity, the rate limiting enzyme for 5-HT synthesis, were determined by measuring accumulation of the transient intermediate 5-hydoxytryptophan (5-HTP) following in vivo administration of the amino acid decarboxylase inhibitor, NSD 1015 (100 mg/kg). L-NA (5–20 mg/kg) dose dependently increased 5-HTP accumulation, particularly in the amygdaloid cortex, following exposure to the FST. L-NA also provoked an increase in regional brain 5-HIAA concentrations and in the 5-HIAA:5-HT metabolism ratio. Co-treatment with NSD-1015 failed to consistently modify the antidepressant-like effects of L-NA in the FST. Sub-active doses of L-NA (1 mg/kg) and the 5-HT re-uptake inhibitor fluoxetine (2.5 mg/kg) acted synergistically to increase swimming in the test. Co-treatment with the non-selective 5-HT receptor antagonist metergoline (1, 2 and 4 mg/kg), attenuated the L-NA (20 mg/kg)-induced reduction in immobility and increase in swimming behaviours. Metergoline alone however provoked an increase in immobility and reduction in swimming behaviours in the test. A similar response was obtained following co-treatment with the preferential 5-HT_2A receptor antagonist ketanserin (5 mg/kg) and the 5-HT_2C receptor antagonist RO-430440 (5 mg/kg). Co-treatment with the 5-HT_1A receptor antagonist WAY 100635 (0.3 mg/kg) or the 5-HT_1B receptor antagonist GR 127935 (4 mg/kg) failed to influence the antidepressant-like activity of L-NA. Taken together these data provide further support for a role for 5-HT in the antidepressant-like properties of NOS inhibitors.

View all citing articles on Scopus

View full text

d-Fenfluramine- and d-norfenfluramine-induced hypophagia: differential mechanisms and involvement of postsynaptic 5-HT receptors

Abstract

Eur. J. Pharmacol.

Behav. Neurol. Biol.

Appetite

Pharmacol. Res. Commun.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Brain Res.

Physiol. Behav.

Pharmacol. Biochem. Behav.

Eur. J. Pharmacol.

Neuropharmacology

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Pharmacol. Biochem. Behav.

Neurochem. Int.

Prog. Neurobiol.

Eur. J. Pharmacol.

Neuropharmacology

Brain Res. Bull.

Life Sci.

Brain Res.

Neuroscience

Pharmacol. Biochem. Behav.

Brain Res. Bull.

Pharmacokinetics of fenfluramine enantiomers in man

Eur. J. Drug Metab. Pharmacokinet.

Kinetics of fenfluramine isomers in the rat

Eur. J. Drug Metab. Pharmacokinet.

Species differences in the kinetics and metabolism of fenfluramine isomers

Arch. Int. Pharmacodyn.