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Reduction of Food Intake by Manipulation of Central Serotonin Current Experimental Results

Published online by Cambridge University Press:  06 August 2018

S. Garattini*
Affiliation:
Mario Negri Institute for Pharmacological Research, Milan
T. Mennini
Affiliation:
Mario Negri Institute for Pharmacological Research, Milan
R. Samanin
Affiliation:
Mario Negri Institute for Pharmacological Research, Milan
*
Correspondence

Extract

Serotonergic anorectics are correctly defined only if they enhance 5-HT transmission and have their anorectic effects inhibited by drugs that block 5-HT receptors. Fenfluramine, the prototype indirect 5-HT agonist, and its metabolite, norfenfluramine, act as 5-HT releasers and uptake inhibitors and are both more effective in the dextro form. They lack the stimulant activity and do not cause hyperthermia or stereotypical behaviour as is characteristic of amphetamines. The anorectic effect of those drugs is attenuated by metergoline, a 5-HT receptor antagonist, in animals and man; 5-HT uptake inhibitors such as fluoxetine, zimelidine, SL 810385, and sertraline also cause anorexia, but only sertraline antagonism by metergoline has been reported. The effect of serotonergic anorectics on 5-HT release has been poorly investigated. Quipazine and RU-24969 cause anorexia by acting directly on 5-HT post-synaptic receptors. Serotonergic nerve terminals take up [3H]-D-fenfluramine and bind with high affinity in rat brain; uptake, an active process, appears to occur at a different site than binding, which is not affected by ouabain or low temperature. Anorexia is probably induced by interaction with 5-HT1B receptors in the rat; the human equivalent of this receptor is not known, but the 5-HT1D type is a likely candidate.

Type
Research Article
Copyright
Copyright © Royal College of Psychiatrists, 1989 

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References

Angel, I., Taranger, M.-A., Claustre, Y., et al (1988) Anorectic activities of serotonin uptake inhibitors: correlation with their potencies at inhibiting serotonin uptake in vivo and 3H-mazindol binding in vitro. Life Sciences, 43, 651658.Google ScholarPubMed
Antelman, S. A., Caggiula, A. R., Eichler, A. J., et al (1979) The importance of stress in assessing the effects of anorectic drugs. Current Medical Research and Opinion, 6 (Suppl. 1), 7382.Google Scholar
Bendotti, C. & Samanin, R. (1986) 8-Hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) elicits eating in free-feeding rats by acting on central serotonin neurons. European Journal of Pharmacology, 121, 147150.Google Scholar
Bendotti, C. & Samanin, R. (1987) The role of putative 5-HT1A and 5-HT1B receptors in the control of feeding in rats. Life Sciences, 41, 635642.Google Scholar
Bendotti, C., Garattini, S. & Samanin, R. (1987) Eating caused by neuropeptide-Y injection in the paraventricular hypothalamus: response to (+)-fenfluramine and (+)-amphetamine in rats. Journal of Pharmacy and Pharmacology, 39, 900903.Google Scholar
Bettini, E., Ceci, A., Spinelli, R., et al (1987) Neuroleptic-like effects of the l-isomer of fenfluramine on striatal dopamine release in freely moving rats. Biochemical Pharmacology, 36, 23872391.Google Scholar
Blundell, J. E. (1984) Serotonin and appetite. Neuropharmacology, 23, 15371551.Google Scholar
Borroni, E., Ceci, A., Garattini, S., et al (1983) Differences between d-fenfluramine and d-norfenfluramine in serotonin presynaptic mechanisms. Journal of Neurochemistry, 40, 891893.Google ScholarPubMed
Borsini, F., Bendotti, C., Aleotti, A., et al (1982) d-Fenfluramine and d-norfenfluramine reduce food intake by acting on different serotonin mechanisms in the rat brain. Pharmacological Research Communications, 14, 671678.Google Scholar
Borsini, F., Bendotti, C., Przewlocka, B., et al (1983) Monoamine involvement in the overeating caused by muscimol injection in the rat nucleus raphe dorsalis and the effects of d-fenfluramine and d-amphetamine. European Journal of Pharmacology, 94, 109115.Google Scholar
Borsini, F., Bendotti, C., & Samanin, R. (1985) Salbutamol, d-amphetamine and d-fenfluramine reduce sucrose intake in freely fed rats by acting on different neurochemical mechanisms. International Journal of Obesity, 9, 277283.Google Scholar
Bradley, P. B., Engel, G., Fenuik, W., et al (1986) Proposals for the classification and nomenclature of functional receptors for 5-hydroxytryptamine. Neuropharmacology, 25, 563576.Google Scholar
Briley, M. & Langer, S. Z. (1981) Sodium dependency of [3H]imipramine binding in rat cerebral cortex. European Journal of Pharmacology, 72, 377380.Google Scholar
Carruba, M. O., Ricciardi, S., Spano, P., et al (1985) Dopaminergic and serotoninergic anorectics differentially antagonize insulin- and 2-DG-induced hyperphagia. Life Sciences, 36, 17391749.Google Scholar
Clineschmidt, B. V., Zacchei, A. G., Totaro, J. A., et al (1978) Fenfluramine and brain serotonin. Annals of the New York Academy of Sciences, 305, 222241.Google Scholar
De Blasi, A. & Mennini, T. (1983) The affinity of metergoline for 3H-serotonin (5HT) binding sites is regulated by guanine nucleotide. Life Sciences, 32, 25852588.CrossRefGoogle ScholarPubMed
De Simoni, M. G., Juraszczyk, Z., Fodritto, F., et al (1988) Different effects of fenfluramine isomers and metabolites on extracellular 5-HIAA in nucleus accumbens and hippocampus of freely moving rats. European Journal of Pharmacology, 153, 295299.Google Scholar
Dourish, C. T., Hutson, P. H. & Curzon, G. (1985a) Characteristics of feeding induced by the serotonin agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT). Brain Research Bulletin, 15, 377384.Google ScholarPubMed
Dourish, C. T., Hutson, P. H. & Curzon, G. (1985b) Low doses of the putative serotonin agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) elicit feeding in the rat. Psychopharmacology, 86, 197204.Google Scholar
Dourish, C. T., Hutson, P. H., Kennett, G. A., et al (1986) 8-OH-DPAT-induced hyperphagia: its neural basis and possible therapeutic relevance. Appetite, 7 (Suppl.), 127140.CrossRefGoogle ScholarPubMed
Freeman, C. P. L. (1988) Drug treatment for bulimia and bulimia nervosa. Psychopharmacology, 96 (Suppl.), 124.Google Scholar
Fuller, R. W., Snoddy, H. D. & Hemrick, S. K. (1978) Effects of fenfluramine and norfenfluramine on brain serotonin metabolism in rats (40021). Proceedings of the Society for Experimental Biology and Medicine, 157, 202205.Google Scholar
Garattini, S. (1981) Central mechanisms of fenfluramine and related anorectic drugs. Japanese Journal of Pharmacology, 31, 29P35P.Google Scholar
Garattini, S. (1987) Mechanisms of the anorectic activity of dextrofenfluramine. In Body Weight Control. The Physiology, Clinical Treatment and Prevention of Obesity (eds Bender, A. E. & Brookes, L. J.). Edinburgh: Churchill Livingstone.Google Scholar
Garattini, S. & Samanin, R. (1976) Anorectic drugs and brain neurotransmitters. In Appetite and Food Intake, Dahlem Workshop on Appetite and Food Intake, December 8–12, 1975 (ed T. Silverstone), pp. 83108.Google Scholar
Garattini, S., Borroni, E., Mennini, T., et al (1978) Differences and similarities among anorectic agents. In Central Mechanisms of Anorectic Drugs (eds Garattini, S. & Samanin, R.). New York: Raven Press.Google Scholar
Garattini, S., Caccia, S., Mennini, T., et al (1979) Biochemical pharmacology of the anorectic drug fenfluramine: a review. Current Medical Research and Opinion, 6 (Suppl. 1), 1527.CrossRefGoogle Scholar
Garattini, S., Mennini, T., Bendotti, C., et al (1986) Neurochemical mechanism of action of drugs which modify feeding via the serotoninergic system. Appetite, 7 (Suppl.), 1538.Google Scholar
Garattini, S., Mennini, T., Samanin, R. (1987) From fenfluramine racemate to d-fenfluramine: Specificity and potency of the effects on the serotoninergic system and food intake. Annals of the New York Academy of Sciences, 409, 156166.Google Scholar
Garattini, S., Bizzi, A., Caccia, S., et al (1988) Progress in assessing the role of serotonin in the control of food intake. Clinical Neuropharmacology, 11 (Suppl. 1), S8–32.Google ScholarPubMed
Ghezzi, D., Samanin, R., Bernasconi, S., et al (1973) Effect of thymoleptics on fenfluramine-induced depletion of brain serotonin in rats. European Journal of Pharmacology, 24, 205210.Google Scholar
Gobbi, M., Taddei, C. & Mennini, T. (1988) Different components of 3H-imipramine binding in rat brain membranes: relation to serotonin uptake sites. Life Sciences, 42, 575583.CrossRefGoogle ScholarPubMed
Goodall, E. & Silverstone, T. (1987) The effect of the 5-HT releasing drug d-fenfluramine and 5-HT receptor blocker, metergoline, on food intake in human subjects. Annals of the New York Academy of Sciences, 499, 321323.Google Scholar
Habert, E., Graham, D., Tahraoui, L., et al (1985) Characterization of [3H]paroxetine binding to rat cortical membranes. European Journal of Pharmacology, 118, 107114.Google Scholar
Hewson, G., Leighton, G. E., Hill, R. G., et al (1988) Ketanserin antagonises the anorectic effect of DL-fenfluramine in the rat. European Journal of Pharmacology, 145, 227230.CrossRefGoogle ScholarPubMed
Heym, J. & Koe, B. K. (1988) Pharmacology of sertraline: a review. Journal of Clinical Psychiatry, 49 (Suppl.), 4045.Google ScholarPubMed
Hoyer, D., Engel, G. & Kalkman, H. O. (1985) Molecular pharmacology of 5-HT1 and 5-HT2 recognition sites in rat and pig brain membranes: radioligand binding studies with [3H]5-HT, [3H]8-OH-DPAT, (–)[125T]iodocyanopindolol, [3H]mesulergine and [3H]ketanserin. European Journal of Pharmacology, 118, 1323.Google Scholar
Hoyer, D., Pazos, A., Probst, A., et al (1986) Serotonin receptors in the human brain. I. Characterization and autoradiographic localization of 5-HT1A recognition sites. Apparent absence of 5-HT1B recognition sites. Brain Research, 376, 8596.CrossRefGoogle Scholar
Hutson, P. H., Dourish, C. T. & Curzon, G. (1986) Neurochemical and behavioural evidence for mediation of the hyperphagic action of 8-OH-DPAT by 5-HT cell body autoreceptors. European Journal of Pharmacology, 129, 347352.CrossRefGoogle ScholarPubMed
Invernizzi, R., Kmieciak-Kolada, K. & Samanin, R. (1982) Is receptor activation involved in the mechanism by which (+)-fenfluramine and (+)-norfenfluramine deplete 5-hydroxytryptamine in the rat brain? British Journal of Pharmacology, 75, 525530.Google Scholar
Invernizzi, R., Berettera, C., Garattini, S., et al (1986) d- and l-Isomers of fenfluramine differ markedly in their interaction with brain serotonin and catecholamines in the rat. European Journal of Pharmacology, 120, 915.Google ScholarPubMed
Kilpatrick, G. J., Jones, B. J. & Tyers, M. B. (1987) Identification and distribution of 5-HT3 receptors in rat brain using radioligand binding. Nature, 330, 746748.Google Scholar
Koe, B. K., Weissman, A., Welch, W. M., et al (1983) Sertraline, 1S, 4S-N-methyl-4-(3,4-diclorophenyl)-1,2,3,4-tetrahydro-1-naphthylamine, a new uptake inhibitor with selectivity for serotonin. Journal of Pharmacology and Experimental Therapeutics, 226, 686700.Google Scholar
Leysen, J. E., Gommeren, W., Van Gompel, P., et al (1985) Receptor-binding properties in vitro and in vivo of ritanserin: a very potent and long acting serotonin-S2 antagonist. Molecular Pharmacology, 27, 600611.Google ScholarPubMed
Lucki, I. (1988) Rapid discrimination of the stimulus properties of 5-hydroxytryptamine agonists using conditioned taste aversion. Journal of Pharmacology and Experimental Therapeutics, 247, 11201127.Google ScholarPubMed
Massi, M., & Marini, S. (1987) Effect of the 5HT2 antagonist ritanserin on food intake and on 5HT-induced anorexia in the rat. Pharmacology, Biochemistry and Behavior, 26, 333340.CrossRefGoogle ScholarPubMed
Mennini, T., Borroni, E., Samanin, R., et al (1981) Evidence of the existence of two different intraneuronal pools from which pharmacological agents can release serotonin. Neurochemistry International, 3, 289294.CrossRefGoogle ScholarPubMed
Mennini, T., Garattini, S. & Caccia, S. (1985) Anorectic effect of fenfluramine isomers and metabolites: relationship between brain levels and in vitro potencies on serotonergic mechanisms. Psychopharmacology, 85, 111114.Google Scholar
Mennini, T., Mocaer, E. & Garattini, S. (1987) Tianeptine, a selective enhancer of serotonin uptake in rat brain. Naunyn-Schmiedeberg's Archives of Pharmacology, 336, 478482.Google Scholar
Mennini, T., Gobbi, M., Taddei, C., et al (1988) Characterization of high affinity and stereospecific [3H]d-fenfluramine binding to rat brain. Neurochemistry International, 13, 345351.CrossRefGoogle ScholarPubMed
Miranda, G. F., Poggesi, E., Bianchetti, A., et al (1988) Reduction of normal food intake in rats and dogs and inhibition of experimentally induced hyperphagia in rats by CM 57373 and fenfluramine. European Journal of Pharmacology, 150, 155161.Google Scholar
Nathan, C. & Rolland, Y. (1987) Pharmacological treatments that affect CNS activity: serotonin. Annals of the New York Academy of Sciences, 499, 277296.CrossRefGoogle ScholarPubMed
Peroutka, S. J. (1988) Serotonin receptor subtypes. ISI Atlas of Science: Pharmacology, 2, 14.Google Scholar
Pinder, R. M., Brogden, R. N., Sawyer, P. R., et al (1975) Fenfluramine: a review of its pharmacological properties and therapeutic efficacy in obesity. Drugs, 10, 241323.Google Scholar
Pollock, J. D. & Rowland, N. (1981) Peripherally administered serotonin decreases food intake in rats. Pharmacology, Biochemistry and Behavior, 15, 179183.Google Scholar
Richardson, B. P., Engel, G., Donatsch, P. & Stadler, P. A. (1985) Identification of serotonin M-receptor subtypes and their specific blockade by a new class of drugs. Nature, 316, 126131.Google Scholar
Samanin, R. (1983) Drugs affecting serotonin and feeding. In Biochemical Pharmacology of Obesity (ed Curtis-Prior, P. B.). Amsterdam: Elsevier.Google Scholar
Samanin, R. & Garattini, S. (1982) Neuropharmacology of feeding. in Drugs and Appetite (ed Silverstone, T.). London: Academic Press.Google Scholar
Samanin, R., Bendotti, C., Candelaresi, G., et al (1977) Specificity of serotoninergic involvement in the decrease of food intake induced by quipazine in the rat. Life Sciences, 21, 12591265.Google Scholar
Samanin, R., Mennini, T., Ferraris, A., et al (1979) m-Chlorophenylpiperazine: a central serotonin agonist causing powerful anorexia in rats. Naunyn-Schmiedeberg's Archives of Pharmacology, 308, 159163.Google Scholar
Samanin, R., Mennini, T., & Garattini, S. (1980a) Evidence that it is possible to cause anorexia by increasing release and/or directly stimulating postsynaptic serotonin receptors in the brain. Progress in Neuro-Psychopharmacology, 4 363369.Google Scholar
Samanin, R., Mennini, T., Ferraris, A., et al (1980b) Repeated treatment with d-fenfluramine or metergoline alters cortex binding of 3H-serotonin and serotonergic sensitivity in rats. European Journal of Pharmacology, 61, 203206.CrossRefGoogle ScholarPubMed
Samanin, R., Caccia, S., Bendotti, C., et al (1980c) Further studies on the mechanism of serotonin-dependent anorexia in rats. Psychopharmacology, 68, 99104.Google Scholar
Samanin, R., Mennini, T., Bendotti, C., et al (1989) Evidence that central 5-HT2 receptors do not play an important role in the anorectic activity of d-fenfluramine in the rat. Neuropharmacology, 28, 465469.Google Scholar
Schechter, L.E. & Simansky, K.J. (1988) 1-(2,5-Dimethoxy-4-iodophenyl)-2-aminopropane (DOI) exerts an anorexic action that is blocked by 5-HT2 antagonists in rats. Psychopharmacology, 94, 342346.Google Scholar
Schwartz, D., Hernandez, L. & Hoebel, B.G. (1989) Fenfluramine administered systemically or locally increases extracellular serotonin in the lateral hypothalamus as measured by microdialysis. Brain Research, 482, 261270.Google Scholar
Silverston, T. & Goodall, E. (1987) Recent studies on the clinical pharmacology of anorectic drugs. In 5th International Congress on Obesity (eds Berry, E.M., Blondheim, S.H., Eliahou, H.E., et al). Westport: Food and Nutrition Press.Google Scholar
Thurlby, P.L., Garattini, S. & Samanin, R. (1985) Effects of serotonin antagonists on the performance of a simple food acquisition task in rats treated with fenfluramine isomers. Pharmacological Research Communications, 17, 11291138.Google Scholar
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