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 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.
Javed
A
A
Neuroscience program, Loyola University of Chicago School of Medicine, Maywood, IL 60153, USA.
Kamradt
M C
MC
Van de Kar
L D
LD
Gray
T S
TS
D000679:Amygdala / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D004745:Enkephalins / Q000378:metabolism; D005277:Fenfluramine / Q000494:pharmacology*; D007031:Hypothalamus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009496:Neurotensin / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010121:Oxytocin / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000502:physiology*; D018490:Serotonin Agents / Q000494:pharmacology*
D004745:Enkephalins; D018377:Neurotransmitter Agents; D016760:Proto-Oncogene Proteins c-fos; D018490:Serotonin Agents; D005277:Fenfluramine; D012701:Serotonin; D009496:Neurotensin; D010121:Oxytocin; D003346:Corticotropin-Releasing Hormone