Absence of fenfluramine-induced anorexia and reduced c-Fos induction in the hypothalamus and central amygdaloid complex of serotonin 1B receptor knock-out mice.
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.
Lucas
J J
JJ
Center for Neurobiology and Behavior, Columbia University, New York, New York 10032, USA.
Yamamoto
A
A
Scearce-Levie
K
K
Saudou
F
F
Hen
R
R
D000679:Amygdala / Q000187:drug effects; D000818:Animals; D000855:Anorexia / Q000139:chemically induced; D001067:Appetite Depressants / Q000378:metabolism / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D005247:Feeding Behavior / Q000187:drug effects; D005277:Fenfluramine / Q000378:metabolism / Q000627:therapeutic use*; D007031:Hypothalamus / Q000187:drug effects; D008032:Limbic System / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis; D011985:Receptors, Serotonin / Q000235:genetics*; D017367:Selective Serotonin Reuptake Inhibitors / Q000378:metabolism / Q000627:therapeutic use*
D001067:Appetite Depressants; D005277:Fenfluramine; D009419:Nerve Tissue Proteins; D016760:Proto-Oncogene Proteins c-fos; D011985:Receptors, Serotonin; D017367:Selective Serotonin Reuptake Inhibitors