Among the modulatory functions of thyrotropin-releasing hormone (TRH), an anorectic behavior in rodents is observed when centrally injected. Hypothalamic PVN neurons receive serotonergic inputs from dorsal raphe nucleus and express serotonin (5HT) receptors such as 5HT1A, 5HT2A/2C, 5HT6, which are involved in 5HT-induced feeding regulation. Rats subjected to dehydration-induced anorexia (DIA) model show increased PVN TRH mRNA expression, associated with their decreased food intake. We analyzed whether 5HT input is implicated in the enhanced PVN TRH transcription that anorectic rats exhibit, given that 5HT increases TRH expression and release when studied in vitro By using mHypoA-2/30 hypothalamic cell cultures, we found that 5HT stimulated TRH mRNA, pCREB and pERK1/2 levels. By inhibiting basal PKA or PKC activities or those induced by 5HT, pCREB or pERK1/2 content did not increase suggesting involvement of both kinases in their phosphorylation. 5HT effect on TRH mRNA was not affected by PKA inhibition, but it diminished in the presence of PKCi suggesting involvement of PKC in 5HT-induced TRH increased transcription. This likely involves 5HT2A/2C and the activation of alternative transduction pathways than those studied here. In agreement with the in vitro data, we found that injecting 5HT2A/2C antagonists into the PVN of DIA rats reversed the increased TRH expression of anorectic animals, as well as their decreased food intake; also, the agonist reduced food intake of hungry restricted animals along with elevated PVN TRH mRNA levels. Our results support that the anorectic effects of serotonin are mediated by PVN TRH in this model.Significance statementInteraction between brain peptides and neurotransmitters' pathways regulates feeding behavior, but when altered it could lead to the development of eating disorders, such as anorexia. An abnormal increased TRH expression in hypothalamic PVN results in dehydration-induced anorectic rats, associated to their low food intake. The role of neurotransmitters in that alteration is unknown, and since serotonin inhibits feeding and has receptors in PVN, we analyzed its participation in increasing TRH expression and reducing feeding in anorectic rats. By antagonizing PVN serotonin receptors in anorectic rats, we identify decreased TRH expression and increased feeding, suggesting that the anorectic effects of serotonin are mediated by PVN TRH. Elucidating brain networks involved in feeding regulation would help to design therapies for eating disorders.
Keywords: PKC; PVN; Serotonin; TRH; anorexia.
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