Anorectic activities of serotonin uptake inhibitors: Correlation with their potencies at inhibiting serotonin uptake in vivo and 3H-mazindol binding in vitro

doi:10.1016/0024-3205(88)90135-X

Life Sciences

Volume 43, Issue 8, 1988, Pages 651-658

https://doi.org/10.1016/0024-3205(88)90135-X Get rights and content

Abstract

The mechanism of anorectic action of several serotonin uptake inhibitors was investigated by comparing their anorectic potencies with several biochemical and pharmacological properties and in reference to the novel compound SL 81. 0385. The anorectic effect of the potent serotonin uptake inhibitor SL 81.0385 (ED₅₀ = 4 mg/kg, i.p.) was potentiated by pretreatment with 5-hydroxytryptophan and blocked by the serotonin receptor antagonist metergoline. A good correlation (r = 0.98, p < 0.01) was obtained between the ED₅₀ values of anorectic action and the ED₅₀ values of serotonin uptake inhibition $in vivo$ (but not $in vitro$ ) for several specific serotonin uptake inhibitors. Most of the drugs tested displaced [³H]-mazindol from its binding to the anorectic recognition site in the hypothalamus, except the pro-drug zimelidine which was inactive (IC₅₀ > 100 μM). Excluding zimelidine, a good correlation (r = 0.835, p < 0.01) was obtained between the affinities of these drugs for [³H]-mazindol binding and their anorectic action indicating that their anorectic activity may be associated with an effect mediated through this site. Taken together these results suggest that the anorectic action of serotonin uptake inhibitors is directly associated to their ability to inhibit serotonin uptake and thus increasing the synaptic levels of serotonin. The interactions of these drugs with the anorectic recognition site labelled with [³H]-mazindol is discussed in connection with the serotonergic regulation of carbohydrate intake.

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The increased synaptic availability of serotonin in the CNS promoted by fluoxetine cause weight loss in rodents as a consequence of its inverse relationship with energy consumption, as it promotes a reduction in food intake by stimulating satiety in rats [15]. Inhibition of serotonin reuptake is related to hypophagia [24]. This effect is observed in mature organisms, however, little is known about how serotonin acts on energy balance regulation during growth and development.
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Because much evidence implicates the dopamine transporter in the reinforcing effects of cocaine, development of potential medications for cocaine dependence has included the dopamine transporter as a target. The present overview covers progress in the drug development area regarding several classes of dopamine uptake inhibitors, with an emphasis on structure–activity relationships that enhance potency and selectivity at transporters for dopamine compared with those for serotonin or norepinephrine. The following categories of compounds are covered: tropane, benztropine, 1-[2-[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine (GBR), methylphenidate, mazindol, and phencyclidine analogs. Activity at transporters as well as on behavior is highlighted.
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Clinical studies indicate that selective serotonin-reuptake inhibitors (SSRIs) may decrease alcohol intake and craving in particular subgroups of alcoholics. The aim of the present study was to compare the behavioral profile of various SSRIs in alcohol-preferring cAA rats, a genetic model of alcoholism. The effects of acute IP administration of fluoxetine (doses in mg/kg 1–10), citalopram (3–30), fluvoxamine (3–30) and paroxetine (1–10) on ethanol (EtOH) intake and preference, as well as food and total fluid intake, were determined in a 12-h access, water vs. 10% v/v EtOH two-bottle choice paradigm. Each compound reduced EtOH intake [Minimal Effective Doses (MEDs) 5, 10, 30 and 1 mg/kg for fluoxetine, citalopram, fluvoxamine, and paroxetine, respectively]. The degree of selectivity, that is, the extent to which reductions in EtOH intake could be separated from reductions in food and/or total fluid intake varied across the compounds. Thus, whereas EtOH intake was more markedly affected than food intake by fluoxetine, both parameters were equally affected by citalopram, and food intake was more markedly affected than EtOH intake by fluvoxamine and paroxetine. The anti-alcohol effect also differed with respect to specificity, that is, the degree to which effects on EtOH intake coincided with effects on EtOH preference. Whereas fluoxetine showed the highest level of specificity, followed by citalopram and fluvoxamine, the effect of paroxetine was nonspecific. The observed variation in the degree of selectivity and specificity of the anti-alcohol effect of SSRIs suggests that reductions in EtOH intake are not merely a consequence of a general suppressive effect on consummatory behavior. It is hypothesized that differences between the behavioral profiles of these compounds reflect a differential involvement of 5-HT receptor subtypes.
Neurobiological and psychopharmacological basis in the therapy of bulimia and anorexia
1996, Progress in Neuro-Psychopharmacology and Biological Psychiatry
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  1. Eating disorders can be found in several psychiatric pathologies: schizophrenia, delusional disorder (somatic type), bipolar disorders, major depressive disorder, borderline personality disorder, generalized anxiety disorder, body dysmorphic disorder, somatization disorder and conversion disorder.
- 2.
  2. Although their clinical features have been defined, relatively little is known about the role of neurobiological patterns in the pathogenesis of these disorders. Several CNS neurotransmitters and neuromodulators are involved in the regulation of eating behavior in animals and have been implicated in symptoms such as depression and anxiety often observed in patients with eating disorders. The authors will review some studies on NA, DA, 5-HT, beta-endorphines, CRH, VP, OT, CCK, NPY and PYY envolved in eating disorders. Furthermore, we will highlight some of the studies on drug therapy of eating disorders taking into account the effects of these agents on neurotransmitters and neuromodulators.
- 3.
  3. Antidepressant drugs have long been used for anorexia nervosa and bulimia, these disorders been claimed to be affective equivalent. Antidepressant agents seem to be effective in reducing the frequency of binge-eating episodes, purging behavior and depressive symptomatology. It is notable that antidepressant agents have been proved to be effective in patients with chronic bulimic symptoms, even in cases persisting for many years and in patients who had repeatedly failed courses of alternative therapeutic approaches. In all of the positive studies, antidepressant agents appeared effective even in bulimic subjects who did not display concomitant depression.
- 4.
  4. Few controlled studies on use of medications for anorexia nervosa have been published. Central serotonergic receptor-blocking compounds such as cyproheptadine cause marked increase in appetite and body weight. Zinc supplementation or cisapride could be a therapeutic option in addition to psychological and other approaches in anorexia nervosa.
- 5.
  5. There is no therapy as yet which is fully effective in alimentary disorders. Psychotropic drugs give some relief from symptoms, but they cannot cure the disorders. An integrated approach, either pharmacological or psychological, is still recommendable.
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Studies in which serotonergic drugs were administered either systemically or directly into central sites have implicated 5-HT in the inhibitory control of feeding in mammals. In animal models and in humans, 5-HT agonists such as fenfluramine, fluoxetine and sertraline reduced the rate of eating and the size of meals in a manner suggesting that increasing serotonergic neurotransmission specifically enhanced satiation. In rodents, directly acting agonists at 5-HT_1B, 5-HT_2C or 5-HT_2A receptors decreased food intake but by different behavioral mechanisms. Stimulation of the 1B and 2C subtypes may probe physiological roles in feeding and satiety. The former receptors may be involved primarily in regulating meal size and the latter more in controlling eating rate. Activation of both may be required for complete expression of behavioral satiety. By contrast, stimulating 2A sites may simply disrupt the continuity of feeding. Drugs that stimulate 5-HT_1A autoreceptors increase food intake, presumably by acutely reducing the firing of serotonergic neurons in the brain. The hypothalamic paraventricular nucleus (PVN) has been proposed as an important terminal field in the forebrain that is involved in 5-HT's satiety role although recent studies implicate extra-PVN regions in this function. Peripherally administered 5-HT also decreases food intake in rats in a behaviorally specific manner. Studies with antagonists and with structural analogs of 5-HT revealed that 5-HT's peripheral satiety action involves 5-HT₁-like and 5-HT₂-like mechanisms. Thus, within and outside the brain, multiple pharmacological and behavioral mechanisms contribute to serotonergic functions in ingestion. The rich body of data from preclinical investigation in animals provides the foundation for therapeutic development in humans.
Effect of mefenorex on 5-HT release: Studies in vitro on rat hypothalamic slices and in vivo by microdialysis
1995, Pharmacology, Biochemistry and Behavior
Mefenorex, used for 20 years as an anorexic drug, has not been studied so far with regard to its central mechanism of action, although its chemical structure suggests a serotonergic mechanism. In the present study, the effect of mefenorex on serotonin (5-HT) release was investigated both in vitro, on rat hypothalamic slices and in vivo, using microdialysis in the paraventricular (PVN)-ventromedian (VMM) hypothalamic area while mefenorex was applied locally by means of counterdialysis. In vitro, mefenorex increased the spontaneous release of ³H 5-HT from hypothalamic slices but not the electrically evoked release. This suggests a 5-HT releasing action of mefenorex not mediated through the terminal autoreceptor. The in vivo study confirmed the enhanced release and provided additional information. The delayed and modest increase of the 5-HT intracellular metabolite 5-HIAA may be indicative of an inhibition of reuptake. The dopaminergic system was also, but more modestly, activated by mefenorex. The increase in 5-HT release together with the inhibition of its reuptake may represent the main mechanism of action of mefenorex, and the secondary activation of the dopaminergic system may contribute in its anorexigenic effect at the level of the PVN-VMH area.

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Anorectic activities of serotonin uptake inhibitors: Correlation with their potencies at inhibiting serotonin uptake in vivo and 3H-mazindol binding in vitro

Abstract

Neuropharmacology

Prog. Neuro-Psychopharmacol.

Prog. Neuro-Psychopharmacol

Eur. J. Pharmacol.

Life Sci.

Eur. J. Pharmacol.

Brain Res. Bull.

Pharmacol. Biochem. Behav.

Biochem. Pharmacol.

Appetite

Anorectic activities of serotonin uptake inhibitors: Correlation with their potencies at inhibiting serotonin uptake $in vivo$ and ³H-mazindol binding $in vitro$