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

The neurotransmitters expressed by neurons activated by D-fenfluramine (5 m g/kg, i.p.) were identified in the hypothalamus, amygdala and bed nucleus o f the stria terminalis. Induction of Fos immunoreactivity following D-fenfl uramine injection was used as an index of neuronal activation. To test whet her D-fenfluramine activated neurons by releasing serotonin from the seroto nergic nerve terminals, rats were pretreated with fluoxetine (10 mg/kg, i.p .), a serotonin reuptake inhibitor that prevents the release of serotonin s timulated by D-fenfluramine, 12 h before D-fenfluramine injection. The appr oximate percentages of peptidergic neurons that contained Fos immunoreactiv ity after D-fenfluramine administration were 94% of corticotropin-releasing factor and 22% of oxytocin cells in the paraventricular nucleus of the hyp othalamus, 6% of oxytocin cells in the supraoptic nucleus of the hypothalam us, 36% of enkephalin and 15% of neurotensin cells in the central amygdaloi d nucleus, and 19% of enkephalin and 9% of neurotensin cells in the bed nuc leus of the stria terminalis. Fluoxetine pretreatment blocked Fos expressio n in corticotropin-releasing factor- and oxytocin-expressing cells in the h ypothalamus, but not in enkephalin- and neurotensin-expressing cells locate d in the bed nucleus of the stria terminalis and central amygdaloid nucleus . D-Fenfluramine did not induce Fos immunoreactivity in vasopressin-, thyro tropin-releasing hormone-, somatostatin- and tyrosine hydroxylase-containin g cells in the hypothalamus, and corticotropin-releasing factor-expressing cells in the central amygdaloid nucleus and bed nucleus of the stria termin alis. These results show that D-fenfluramine stimulates corticotropin-releasing f actor- and oxytocin-expressing cells in the hypothalamus via serotonin rele ase. The enkephalin- and neurotensin-expressing cells in the amygdala are a ctivated by D-fenfluramine via non-serotonergic mechanisms. Induction of Fo s 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. (C) 1999 IBRO. Publi shed by Elsevier Science Ltd.