D-Fenfluramine induces serotonin-mediated Fos expression in corticotropin-releasing factor and oxytocin neurons of the hypothalamus, and serotonin-independent Fos expression in enkephalin and neurotensin neurons of the amygdala

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The neurotransmitters expressed by neurons activated by d-fenfluramine (5 mg/kg, i.p.) were identified in the hypothalamus, amygdala and bed nucleus of the stria terminalis. Induction of Fos immunoreactivity following d-fenfluramine injection was used as an index of neuronal activation. To test whether d-fenfluramine activated neurons by releasing serotonin from the serotonergic nerve terminals, rats were pretreated with fluoxetine (10 mg/kg, i.p.), a serotonin reuptake inhibitor that prevents the release of serotonin stimulated by d-fenfluramine, 12 h before d-fenfluramine injection. The approximate percentages of peptidergic neurons that contained Fos immunoreactivity after d-fenfluramine administration were 94% of corticotropin-releasing factor and 22% of oxytocin cells in the paraventricular nucleus of the hypothalamus, 6% of oxytocin cells in the supraoptic nucleus of the hypothalamus, 36% of enkephalin and 15% of neurotensin cells in the central amygdaloid nucleus, and 19% of enkephalin and 9% of neurotensin cells in the bed nucleus of the stria terminalis. Fluoxetine pretreatment blocked Fos expression in corticotropin-releasing factor- and oxytocin-expressing cells in the hypothalamus, but not in enkephalin- and neurotensin-expressing cells located in the bed nucleus of the stria terminalis and central amygdaloid nucleus. d-Fenfluramine did not induce Fos immunoreactivity in vasopressin-, thyrotropin-releasing hormone-, somatostatin- and tyrosine hydroxylase-containing cells in the hypothalamus, and corticotropin-releasing factor-expressing cells in the central amygdaloid nucleus and bed nucleus of the stria terminalis. These results show that d-fenfluramine stimulates corticotropin-releasing factor- and oxytocin-expressing cells in the hypothalamus via serotonin release. The enkephalin- and neurotensin-expressing cells in the amygdala are activated by d-fenfluramine via non-serotonergic mechanisms. Induction of Fos expression by d-fenfluramine in restricted populations of cells suggests a selective activation of neuronal circuitry that is likely to be involved in the appetite suppressant effects of d-fenfluramine.