Dopamine Acts as a Partial Agonist for a2A Adrenoceptor in Melanin-Concentrating Hormone Neurons

Abstract

Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide that promotes positive energy balance and anxiety. Since dopamine (DA) is also closely implicated in these functions, the present study investigated the effect of DA on MCH neurons. Using whole-cell patch-clamp recordings in rat brain slices, we found that DA hyperpolarizes MCH neurons by activating G-protein-activated inwardly rectifying K+ (GIRK) channels. Pharmacological study indicated that the effect was mediated by α2A adrenoceptors, not DA receptors. DA-induced outward current was also observed in the presence of tetrodotoxin or the dopamine β-hydroxylase inhibitor fusaric acid, suggesting thatDAdirectly binds toα2Areceptors onMCHneurons, rather than acting presynaptically or being transformed into norepinephrine (NE) in the slice preparation. The effects of NE and DA were concentration-dependent with EC50 of 5.9 and 23.7μM, respectively, and a maximal effect of 106.6 and 57.2 pA, respectively, suggesting that DA functions as a partial agonist. Prolonged (5 min) activation ofα2A receptors by eitherDAor NE attenuated the subsequent response toDAor NE, while 5 s applications were not sufficient to induce desensitization. Therefore, a history of α2A receptor activation by DA or NE can have a lasting inhibitory effect on the catecholaminergic transmission to MCH neurons. Our study suggests that α2A receptors expressed by MCH neurons may be one of the pathways by which DA and NE can interact and modulate mood and energy homeostasis, and this cross talk may have functional implications in mood disorders and obesity.