5‐HT2C Receptor agonist anorectic efficacy potentiated by 5‐HT1B Receptor agonist co‐application; an effect mediated via augmented pro‐opiomelanocortin neuron activation

Abstract

A key component of the appetite‐regulating neural network is the 5‐HT2C receptor (5‐HT2CR); agonists of which suppress food intake and were recently approved for obesity treatment by the USFood and Drug Administration. Appetite is primarily mediated via activation of hypothalamic arcuate nucleus (ARC) pro‐opiomelanocortin (POMC) neurons which are disinhibited via a 5‐HT1BR mediated suppression of local inhibitory inputs. We investigated whether 5‐HT2CR agonist anorectic potency could be significantly enhanced by co‐administration of a 5‐HT1BR agonist and associated with augmented POMC neuron activation. The combined administration of subanorectic concentrations of 5‐HT2CR and 5‐HT1BR agonists produced a potent 45% reduction in food intake and significantly greater in vivo ARC neuron activation. The chemical phenotype of activated ARC neurons was assessed by calcium imaging in POMC‐EGFP brain slices, revealing that combined agonists activated significantly more POMC neurons (46%) compared to either drug alone (approximately 25% each). Single‐cell electrophysiological analysis demonstrated that 5‐HT2CR/5‐HT1BR agonist co‐administration did not significantly potentiate the firing frequency of individual ARC POMC‐EGFP cells compared to drugs alone. These data indicate a functional heterogeneity of ARC POMC neurons by revealing distinct subpopulations of POMC cells activated by 5‐HT2CRs and disinhibited by 5‐HT1BRs. Thus, co‐administration of a 5‐HT1BR agonist potentiates the anorectic efficacy of 5‐HT2CR compounds by increasing the number but not magnitude of activated ARC POMC neurons and is of therapeutic relevance to obesity treatment.