Modulation of GABA release by 5-HT receptors: An interplay with AMPA-receptors and voltage-gated Ca channels.

Obesity has become a worldwide health challenge and commonly results from the intake of more calories than the body requires. The brain represents the master controller of food intake and as such has been the target of obesity medications. However, key mechanisms of druggable targets remain to be defined. Neurons within the arcuate nucleus of the hypothalamus co-expressing neuropeptide Y (NPY), agouti-related protein (AgRP) and GABA (NAG) are fundamental stimulators of hunger and food intake. NAG neurons also inhibit local satiety-promoting pro-opiomelanocortin (POMC) neurons. Agonists of the 1B subtype of metabotropic serotonin receptor (5-HTR) reduce food intake in part through the inhibition of hunger-promoting NAG neurons. We first confirmed that 5-HTR activation suppressed intake of a palatable Western diet in a mouse model of common dietary-induced obesity and genetically prone obesity. Next, we combined several electrophysiological approaches to analyse the effect of 5-HTRs in NAG neuron cell activity and GABA release. 5-HTR activation reduced NAG neuron action potential frequency and neurotransmitter release. We found that 5-HTR impact on GABA release from NAG neurons is mediated through voltage-gated Ca channels with a critical input from glutamate receptors of AMPA subtype (AMPARs). As a fundamental outcome, this type of interplay provides an uncommon example of metabotropic action of AMPARs which regulates inhibitory signalling due to modulation of GABA release. As a translational outcome, our results provide a key mechanism through which 5-HTR drugs inhibit appetite-stimulating neurons within the brain to suppress food intake. This article is part of the Special Issue on "Ukrainian Neuroscience".