Hypothalamic paraventricular 5-hydroxytryptamine inhibits the effects of ghrelin on eating and energy substrate...

Ghrelin microinjections into discrete regions of the hypothalamus, including the paraventricular nucleus (PVN), stimulate eating and promote carbohydrate oxidation, effects similar to PVN microinjection of neuropeptide Y (NPY). We have also reported that NPY's orexigenic and metabolic effects are antagonized by pretreatment with 5-hydroxytryptamine (5-HT) or 5-HT receptor agonists. In order to determine whether 5-HT also inhibits ghrelin's orexigenic and metabolic actions, the present study examined the effects of 5-HT pretreatment on ghrelin-induced alterations in eating and energy substrate utilization following direct injections into the hypothalamic PVN. Both 5-HT (5-20 nmol) and ghrelin (100 pmol) were administered at the onset of the dark cycle. Food intake was measured 2h postinjection. A separate group of rats (n=8) was injected with 5-HT paired with ghrelin and respiratory quotient (RQ; VCO(2)/VO(2)) was measured over 2h using an open circuit calorimeter. PVN injections of ghrelin increased food intake and increased RQ, reflecting a shift in energy substrate utilization in favor of carbohydrate oxidation. 5-HT effectively blocked the effects of ghrelin on both food intake and RQ. We then administered the 5-HT(2A/2C), receptor agonist, DOI, immediately prior to ghrelin. Similar to 5-HT, PVN DOI blocked ghrelin-induced eating and inhibited the peptide's effect on substrate utilization. These data are in agreement with other evidence suggesting that ghrelin functions as a gut-brain peptide in the control of food intake and energy metabolism, and indicate that 5-HT acts within the PVN to modulate ghrelin's orexigenic and metabolic signaling.