5-HT2C receptor agonist anorectic efficacy potentiated by 5-HT1B receptor agonist coapplication: an effect mediated via increased proportion of pro-opiomelanocortin neurons activated

• Published in: The Journal of neuroscience Vol. 33; no. 23; pp. 9800 - 9804
• Main Authors: Doslikova, Barbora, Garfield, Alastair S, Shaw, Jill, Evans, Mark L, Burdakov, Denis, Billups, Brian, Heisler, Lora K
• Format: Journal Article
• Language: English
• Published: United States Society for Neuroscience 05.06.2013
• Subjects: Animals; Appetite Depressants - administration & dosage; Brief Communications; Drug Synergism; Drug Therapy, Combination; Eating - drug effects; Eating - physiology; Feeding Behavior - drug effects; Feeding Behavior - physiology; Female; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurons - drug effects; Neurons - metabolism; Organ Culture Techniques; Pro-Opiomelanocortin - antagonists & inhibitors; Pro-Opiomelanocortin - metabolism; Serotonin 5-HT1 Receptor Agonists - administration & dosage; Serotonin 5-HT2 Receptor Agonists - administration & dosage; Treatment Outcome
• ISSN: 0270-6474; 1529-2401; 1529-2401
• DOI: 10.1523/JNEUROSCI.4326-12.2013

An essential component of the neural network regulating ingestive behavior is the brain 5-hydroxytryptamine2C receptor (5-HT2CR), agonists of which suppress food intake and were recently approved for obesity treatment by the US Food and Drug Administration. 5-HT2CR-regulated appetite is mediated primarily through activation of hypothalamic arcuate nucleus (ARC) pro-opiomelanocortin (POMC) neurons, which are also disinhibited through a 5-HT1BR-mediated suppression of local inhibitory inputs. Here we investigated whether 5-HT2CR agonist anorectic potency could be significantly enhanced by coadministration of a 5-HT1BR agonist and whether this was associated with augmented POMC neuron activation on the population and/or single-cell level. The combined administration of subanorectic concentrations of 5-HT2CR and 5-HT1BR agonists produced a 45% reduction in food intake and significantly greater in vivo ARC neuron activation in mice. The chemical phenotype of activated ARC neurons was assessed by monitoring agonist-induced cellular activity via calcium imaging in mouse POMC-EGFP brain slices, which revealed that combined agonists activated significantly more POMC neurons (46%) compared with either drug alone (∼25% each). Single-cell electrophysiological analysis demonstrated that 5-HT2CR/5-HT1BR agonist coadministration did not significantly potentiate the firing frequency of individual ARC POMC-EGFP cells compared with agonists 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. Therefore, coadministration of a 5-HT1BR agonist potentiates the anorectic efficacy of 5-HT2CR compounds by increasing the number, but not the magnitude, of activated ARC POMC neurons and is of therapeutic relevance to obesity treatment.