THE SEROTONIN (5-HT) ANTAGONIST METHYSERGIDE INCREASES NEUROPEPTIDE-Y(NPY) SYNTHESIS AND SECRETION IN THE HYPOTHALAMUS OF THE RAT

NPY is synthesized in neurons of the hypothalamic arcuate nucleus (ARC ) which project to the paraventricular nucleus (PVN), an important sit e of NPY release. Serotonin (5-HT) has been suggested to induce satiet y and 5-HT fibers contact NPY neurons in the ARC and PVN, suggesting t hat 5-HT could inhibit the ARC-PVN projection. Methysergide is a 5-HT antagonist which stimulates feeding in rats and increases NPY levels i n the hypothalamus. To clarify the effects of methysergide on NPY, we examined its effects on NPY synthesis and on NPY secretion in the PVN using push-pull sampling. Hypothalamic NPY mRNA levels were measured i n rats (n = 8/group) given either saline or methysergide (10 mg/kg) an d killed after 4 h or after 7 days. Food intake was increased by 33% i n the acute study and by 9% in the 7-day study (both P < 0.01). NPY mR NA levels were 80% higher in the 7-day study (P < 0.05) and unchanged in the acute study. NPY secretion was measured over a 3-h period after an i.p. injection of methysergide or saline (10 mg/kg, n = 12) with a flow rate of 15 mu l/min. Mean NPY secretion in the methysergide-inje cted rats was increased by 34% (P < 0.01). We conclude that methysergi de induced feeding is associated with increased activity of the NPY ne urons in the ARC-PVN projection. This is consistent with our previous findings suggesting that the NPYergic ARC-PVN projection may mediate, at least in part the effects of 5-HT on feeding and energy balance.