JAOA • Vol 105 • No 1 • January 2005 • 26-27
Gender Differences in the Cannabinoid Modulation of an A-type K1 Current in Neurons of the Mammalian Hypothalamus
Stephanie L. Tang;
Edward J. Wagner
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),
-melanocyte stimulating hormone (-MSH), and
ß-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 AND 10mM)
was found in 46% of male and 39% of 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 (1 µM) or arachidonyl-2'-chloroethylaminde
(ACEA, 1 µM) 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 (1 µM) 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
discernible 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.
Western University of Health Sciences College of Osteopathic Medicine,
Pomona, Calif
