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The Journal of Neuroscience, July 15, 1998, 18(14):5537-5544
Absence of Fenfluramine-Induced Anorexia and Reduced c-fos Induction in the Hypothalamus and Central Amygdaloid Complex of Serotonin 1B Receptor Knock-Out Mice
José J. Lucas1, Ai Yamamoto1, Kimberly Scearce-Levie1, Frédéric Saudou2, and René Hen1 1 Center for Neurobiology and Behavior, Columbia University, New York, New York 10032, and 2 Division of Neuroscience, Children's Hospital, Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115
Fenfluramine, a serotonin releaser and uptake inhibitor, has been widely prescribed as an appetite suppressant. Despite its popular clinical use, however, the precise neural pathways and specific 5-HT receptors that account for its anorectic effect have yet to be elucidated. To test the hypothesis that stimulation of 5-HT1B receptors is required for the anorectic effect of fenfluramine, we assessed food intake in wild-type and 5-HT1B knock-out mice. Next, to determine possible brain structures and pathways that may contribute to the 5-HT1B-mediated effects of fenfluramine, we studied by immunohistochemistry the induction of the immediate early gene c-fos. Although the effect of fenfluramine on locomotion was indistinguishable between both wild-type and 5-HT1B knock-out mice, the anorectic effect of the drug was absent in only the knock-out mice. Furthermore, the induction of c-Fos immunoreactivity found in the paraventricular nucleus of the hypothalamus (PVN) of wild-type mice was substantially reduced in the knock-outs. Induction in the central amygdaloid nucleus (CeA) and in the bed nucleus of the stria terminalis (BNST), although robust in wild-type animals, was completely absent in knock-out animals. The mixed 5-HT1A/1B agonist RU24969 was able to mimic both the hypophagia and c-fos induction elicited by fenfluramine in wild-type mice, but not in the 5-HT1B knock-out mice. Our results thus demonstrate that stimulation of 5-HT1B receptors is required for fenfluramine-induced anorexia and suggest a role for the PVN, CeA, and BNST in mediating this effect.
Key words: fenfluramine; feeding; serotonin 1B receptor; knock-out mice; RU24969; Fos; paraventricular nucleus of the hypothalamus; central amygdaloid nucleus; bed nucleus of the stria terminalis
Copyright © 1998 Society for Neuroscience 0270-6474/98/18145537-08$05.00/0
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