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Sex Differences in the Cannabinoid Modulation of an A-Type K⁺ Current in Neurons of the Mammalian Hypothalamus

Department of Basic Medical Sciences, Western University of Health Sciences, Pomona, California

Submitted 17 November 2004; accepted in final form 13 May 2005

Cannabinoids regulate biological processes governed by the hypothalamus including, but not limited to, energy homeostasis and reproduction. The present study sought to determine whether cannabinoids modulate A-type K⁺ currents (I_A) in neurons of the hypothalamic arcuate nucleus (ARC). Whole cell patch-clamp recordings were performed in slices through the ARC prepared from castrated female and male guinea pigs. Forty percent of guinea pig ARC neurons exhibited a transient outward current that was antagonized by high (mM) concentrations of 4-aminopyridine and (100 nM) rHeteropodatoxin-2. Five of these neurons also were immunopositive for both -endorphin and the Kv4.2 channel subunit. Bath application of the CB1 receptor agonists WIN 55,212–2 (1 µM) or ACEA (1 µM) selectively induced a rightward shift in the inactivation curve for the I_A, significantly increasing the half-maximal voltage without affecting the peak current magnitude, in neurons from female but not male animals. The CB1 receptor antagonist AM251 (1 µM) reversed this action. Collectively, these data reveal that guinea pig ARC neurons, including proopiomelanocortin neurons, express a prominent I_A that is positively modulated by cannabinoids 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 hypothalamic function.

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