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Regulation of Gonadotropin-Releasing Hormone Secretion by Cannabinoids

Departments of Psychiatry and Behavioral Sciences, Cell Biology, and Medicine (Endocrinology) (C.M.G., G.M.F., W.X., W.C.W.), Duke University Medical Center, Durham, North Carolina 27710; and Department of Biology (S.L.P.), Neuroscience and Behavior Program, and Center for Neuroendocrine Studies, University of Massachusetts, Amherst, Massachusetts 01003

Address all correspondence and requests for reprints to: William C. Wetsel, Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Box 3497, 028 Clinical and Research Laboratories Building, Durham, North Carolina 27710. E-mail: wetse001{at}mc.duke.edu.

Cannabinoids (CBs) exert untoward effects on reproduction by reducing LH secretion and suppressing gonadal function. Recent evidence suggests these effects are due primarily to hypothalamic dysfunction; however, the mechanism is obscure. Using immortalized hypothalamic GnRH neurons, we find these cells produce and secrete at least two different endocannabinoids. After release, 2-arachidonyl monoacylglycerol and anandamide are rapidly transported into GnRH neurons and are degraded to other lipids by fatty-acid amide hydrolase. The immortalized GnRH neurons also possess CB1 and CB2 receptors that are coupled to Gi/Go proteins whose activation leads to inhibition of GnRH secretion. In perifusion experiments, CBs block pulsatile release of GnRH. When a CB receptor agonist is delivered into the third ventricle of adult female mice, estrous cycles are prolonged by at least 2 d. Although in situ hybridization experiments suggest either that GnRH neurons in vivo do not possess CB1 receptors or that they are very low, transcripts are localized in close proximity to these neurons. Inasmuch as GnRH neurons in vivo possess G protein receptors that are coupled to phospholipase C and increased intracellular Ca²⁺, these same neurons should also be able to synthesize endocannabinoids. These lipids, in turn, could bind to CB receptors on neighboring cells, and perhaps GnRH neurons, to exert feedback control over GnRH function. This network could serve as a novel mechanism for regulating GnRH secretion where reproductive functions as diverse as the onset of puberty, timing of ovulation, duration of lactational infertility, and initiation/persistence of menopause may be affected.

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