Regulation of gonadotropin-releasing hormone secretion by cannabinoids.

Abstract:

: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.

journal_name

Endocrinology

journal_title

Endocrinology

authors

Gammon CM,Freeman GM Jr,Xie W,Petersen SL,Wetsel WC

doi

10.1210/en.2004-1672

subject

Has Abstract

pub_date

2005-10-01 00:00:00

pages

4491-9

issue

10

eissn

0013-7227

issn

1945-7170

pii

en.2004-1672

journal_volume

146

pub_type

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