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APPETITE, OBESITY AND METABOLISM

Fluoxetine-induced changes in body weight and 5-HT_1A receptor-mediated hormone secretion in rats on a tryptophan-deficient diet

Center for Serotonin Disorders Research and Department of Pharmacology, Loyola University of Chicago, Stritch School of Medicine, Maywood, Illinois 60153

Submitted 19 June 2003 ; accepted in final form 31 October 2003

Tryptophan depleting protocols are commonly used to study the role of serotonin in mood disorders. The present study examined the impact of a tryptophan-deficient diet and fluoxetine on the serotonergic regulation of neuroendocrine function and body weight. We hypothesized that the regulation of postsynaptic 5-HT_1A receptors is dependent on the levels of 5-HT in the synapse. Rats on a control or a tryptophan-deficient diet received daily injections of saline or fluoxetine (5 or 10 mg·kg^-1·day^-1 ip) from day 7 to day 21. The tryptophan-deficient diet produced a 41% reduction in the level of 5-HT but no change in the density of [³H]paroxetine-labeled 5-HT transporters. Treatment with fluoxetine inhibited the gain in weight in rats maintained on the control diet. The tryptophan-deficient diet produced a significant loss in body weight that was not significantly altered by treatment with fluoxetine. Treatment with fluoxetine produced a dose-dependent desensitization of hormone responses to injection of the 5-HT_1A receptor agonist (±)8-hydroxy-2-(di-n-propylamino)tetralin ((±)8-OH-DPAT). The tryptophan-deficient diet produced an increase in the basal levels of corticosterone but did not alter the basal levels of ACTH or oxytocin. Also, this diet inhibited the magnitude of 8-OH-DPAT-induced increase in plasma levels of ACTH and oxytocin but did not impair the ability of fluoxetine to desensitize the 5-HT_1A receptor-mediated increase in plasma hormones. These data suggest that a reserve of 5-HT enables fluoxetine to desensitize postsynaptic 5-HT_1A receptors in the hypothalamus. In conclusion, the profound physiological changes induced by tryptophan depletion may complicate the interpretation of studies using this experimental approach.

selective serotonin reuptake inhibitors; oxytocin; adrenocorticotropic hormone; corticosterone