Inhibitory pathways and the inhibition of luteinizing hormone-releasing hormone release by alcohol

Abstract

In this research we examined the mechanisms by which ethanol (EtOH) inhibits luteinizing hormone-releasing hormone (LHRH) release from incubated medial basal hypothalamic explants. EtOH (100 mM) stimulated the release of two inhibitory neurotransmitters: ␥-aminobutyric acid (GABA) and ␤-endorphin. EtOH also inhibited NO production, indicative of a suppression of nitric oxide synthase (NOS) activity. This inhibition was reversed by naltroxone (10 ؊8 M), a -opioid receptor blocker, indicating that the inhibition of NOS by EtOH is mediated by ␤-endorphin. EtOH also blocked N-methyl-D-aspartic acid-induced LHRH release, but the blockade could not be reversed by either the GABA receptor blocker, bicuculline (10 ؊5 M), naltroxone (10 ؊8 M), or both inhibitors added together. However, increasing the concentration of naltrexone (10 ؊6 M) but not bicuculline (10 ؊4 M) reversed the inhibition. When we lowered the concentration of EtOH (50 mM), the EtOH-induced blockade of LHRH release could be reversed by either bicuculline (10 ؊5 M), naltroxone (10 ؊8 M), or the combination of the two blockers. Therefore, GABA is partially responsible for the blockade of N-methyl-D-aspartic acid-induced LHRH release. The block by GABA was exerted by inhibiting the activation of cyclooxygenase by NO, because it was reversed by prostaglandin E 2, the product of activation of cyclooxygenase. Because the inhibition caused by the higher concentration of EtOH could not be reduced by bicuculline (10 ؊4 M) but was blocked by naltroxone (10 ؊6 M), the action of alcohol can be accounted for by stimulation of ␤-endorphin neurons that inhibit LHRH release by inhibition of activation of NOS and stimulation of GABA release.nitric oxide synthase ͉ cyclooxygenase ͉ prostaglandin E2 ͉ naltrexone ͉ bicuculline E thanol (EtOH) can suppress reproductive function in humans, monkeys, and small rodents, such as the rat (1-4). In conscious animals, administration of EtOH via an indwelling gastric cannula in doses that produce mild intoxication inhibits pulsatile release of luteinizing hormone (LH), but not folliclestimulating hormone (4). In this situation, the responsiveness of the pituitary gland to acute injection of LH-releasing hormone (LHRH) is unaffected, which indicates that the mechanism of this effect is via suppression of pulsatile LHRH release into the hypophyseal portal vessels that triggers release of LH from gonadotropes of the adenohypophysis.Nitric oxide synthase (NOS)-containing neurons occur in various regions of the hypothalamus, including the median eminence-arcuate region (5). Previous research has indicated that NO stimulates the release of LHRH both in vivo and in vitro (6). On the basis of in vitro experiments using incubation of medial basal hypothalamus explants (MBH) in a static incubation system, it has been determined that norepinephrine (NE) activates constitutive NOS in this region (5-7). The NO released from these neurons diffuses to LHRH terminals, where it induces the release of LHRH. It has been shown that NO not only activat...

Alcohol inhibits luteinizing hormone-releasing hormone release by activating the endocannabinoid system

“…Previously, we demonstrated that EtOH increased GABA release and inhibited LHRH release (7). In the present work, we significantly reversed AEA and EtOH inhibition on LHRH release by the CB1-r antagonist, AM251, which indicates that both acted by means of CB1-r.…”

“…To understand the mechanism of action of AEA and EtOH by means of CB1-r, it is necessary to put the findings into the context of previous work (7). Those experiments indicated that EtOH inhibits the NMDA-stimulated release of LHRH by increasing the release of two neurotransmitters: ␤-endorphin and GABA.…”

“…The inhibition was reversed by naltrexone, a -opioid receptor antagonist, and by bicuculline, a GABA receptor antagonist, suggesting that at least two inhibitory pathways regulate the release of LHRH (7). Additionally, it has been shown that nitric oxide activates cyclooxygenase, which increases the release of prostanoids (8).…”

A Conceptualization of Integrated Actions of Ethanol Contributing to its GABAmimetic Profile: A Commentary

“…The reason for the return of neural activity over time is not presently known but may involve local circuits that invoke homeostatic control (unpublished data). Crowder et al, 2002;Lomniczi et al, 2000;Yang et al, 1996).…”

“…For example, Lomniczi et al (2000) reported that incubation of hypothalamic tissue with ethanol resulted in GABA releaseFa change proposed to relate to ethanolinduced release of endorphin. Crowder et al (2002) reported that ethanol concentrations as low as 20 mM inhibit kainate-induced inhibition of GABA A IPSCs from CA1 hippocampal neurons (see Weiner et al, 1999).…”