Cannabinoid signaling exerts profound influence over the hypothalamic control of homeostasis including but not limited to feeding. The hypothalamic feeding circuitry consists of several components. The stimulatory component of appetite includes the neuropeptide Y (NPY), orexin (hypocretin), ghrelin and melanin concentrating hormone (MCH) neurons. Inhibitory inputs are predominately from the proopiomelanocortin (POMC) neurons originating in the hypothalamic arcuate nucleus (ARC). POMC neurons synthesize and release anorexigenic peptides such as cocaine amphetamine related transcript (CART), α-melanocyte stimulating hormone (α-MSH), and β-endorphin. This study sought to determine whether cannabinoids modulate A-type K+ current (IA) in POMC neurons. To this end, whole-cell patch clamp recordings were performed in hypothalamic slices through the ARC prepared from castrated female and male guinea pigs. A robust IA that was blocked by high concentrations of K+ channel blocker 4-aminopyridine (3mM & 10mM) was found in 46% of male and 39% in female cells. We observed that the neuronal responsiveness to cannabinoids was sexually differentiated. In recordings of female neurons, bath application of the brain cannabinoid (CB1) receptor agonists WIN 55,212-2 (1μM) or arachidonyl-2′-chloroethylaminde (ACEA, 1μM) selectively induced a depolarizing rightward shift in the inactivation curve for the IA, significantly increasing the half-maximal voltage (V1/2) for inactivation. This effect was completely blocked by the CB1 receptor antagonist AM251 (1μM) and occurred without affecting the peak current magnitude (Imax). Post-hoc immunofluorescent labeling confirmed that these effects occurred in POMC cells. We observed no effect on the V1/2 or the Imax for the activation curve. In contrast, recordings from male neurons indicated no discernable effect of cannabinoids on the V1/2 or the Imax for either the inactivation or the activation of the IA. Collectively, these data reveal that POMC neurons express a prominent IA, and that cannabinoids positively modulate this current in a sex-specific way by altering the voltage dependence of its inactivation. The resultant inhibitory effect on this neuronal population may shed some insight into the mechanism(s) by which cannabinoids influence appetite.
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