Hypothalamic paraventricular 5-hydroxytryptamine: Receptor-specific inhibition of NPY-stimulated eating and energy metabolism

Abstract

The feeding effects of 5-hydroxytryptamine (5-HT) 1 and 5-HT 2 receptor agonists injected into the hypothalamic paraventricular nucleus (PVN) immediately prior to PVN administration of neuropeptide Y (NPY) were examined. The impact of these same compounds on NPY-induced alterations in energy metabolism was also assessed in an attempt to characterize further the potential interactive relationship of PVN NPY and 5-HT on feeding and whole body calorimetry. Specifically, several experiments examined the effect of various 5-HT receptor agonists on NPY-stimulated eating and alterations in energy substrate utilization [respiratory quotient (RQ)]. This included the 5-HT 1A receptor agonist 8-OH-DPAT, the 5-HT 1B/1A agonist RU 24969, the 5-HT 1D agonist L-694,247, the 5-HT 2A/2C agonist DOI, the 5-HT 2B agonist BW 723C86 and the 5-HT 2C agonist mCPP. In feeding tests conducted at the onset of the dark cycle, drugs were administered 5 min prior to PVN injection of NPY and food intake was measured 2 h postinjection. The metabolic effects of NPY following a similar pretreatment were monitored using an open-circuit calorimeter measuring the volume of oxygen consumed (VO 2), carbon dioxide produced (VCO 2) and RQ (VCO 2/VO 2). PVN injection of NPY (100 pmol) potentiated feeding and evoked reliable increases in RQ. Only DOI (2.5–5 nmol) pretreatment antagonized NPY-induced eating and blocked the peptide's effect on energy substrate utilization. Direct PVN pretreatment with spiperone (SPRN), a 5-HT 2A receptor antagonist, and ketanserin (KTSN), a 5-HT 2A/2C antagonist, but not SDZ SER 082, a 5-HT 2B/2C antagonist, or the 5-HT 2C antagonist RS 102221, blocked the effect of DOI in both feeding and metabolic tests providing additional evidence that activation of PVN 5-HT 2A receptors inhibits NPY's action on feeding and substrate utilization.