Impact of hypothalamic d-norfenfluramine and peripheral d-fenfluramine injection on macronutrient intake in the rat

Previous research with hypothalamic injection of serotonin (5-HT) has suggested that this monoamine may act within the medial hypothalamus to suppress carbohydrate intake in a selective, phasic and circadian-related fashion. To explore further the action of 5-HT in the brain, the present studies tested the serotonergic stimulants, d-norfenfluramine (DNF) and d-fenfluramine (DF), in freely feeding, brain-cannulated animals maintained on pure macronutrient diets (protein, carbohydrate and fat) and tested at different times of the diurnal cycle. The results show that administration of DNF into the paraventricular nucleus (PVN) potently influences appetite for a specific nutrient at a particular time of the light-dark cycle. Specifically, DNF injection at the onset of the nocturnal (active) period selectively and dose-dependently suppresses carbohydrate consumption, while leaving protein and fat intake unchanged. This drug, however, has no effect, even at high doses, on macronutrient intake in the middle and late h of the dark phase, strongly implicating a function for hypothalamic 5-HT in the control of carbohydrate ingestion at the beginning of the nocturnal cycle. The possibility that peripherally injected DF may act, in part, through this endogenous serotonergic system is supported by the additional finding that, at low doses of 0.06-0.5 mg/kg, DF preferentially modulates carbohydrate ingestion exclusively at the onset of the nocturnal period. However, at doses above 0.5 mg/kg, this compound produces a potent and general suppression of feeding of all macronutrients. In animals with brain cannulas aimed at different hypothalamic nuclei, the feeding-suppressive effect of DNF is found to be site specific; it is localized to the medial hypothalamic nuclei, including the ventromedial, suprachiasmatic and dorsomedial nuclei as well as the PVN. Serotonin in these nuclei may function to produce satiety specific for carbohydrate and, through the suprachiasmatic nucleus, control energy intake in a circadian-related manner.