The inhibitory effect of anandamide on luteinizing hormone-releasing hormone secretion is reversed by estrogen

Abstract

Because ⌬-9-tetrahydrocannabinol (THC) inhibited luteinizing hormone-releasing hormone (LHRH) in male rats, we hypothesized that the endocannabinoid, anandamide (AEA), would act similarly. AEA microinjected intracerebroventricularly (i.c.v.) decreased plasma luteinizing hormone (LH) at 30 min in comparison to values in controls (P < 0.001). The cannabinoid receptor 1 (CB1-r)-specific antagonist, [N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide] (AM251), produced a significant elevation in plasma LH (P < 0.01). AEA (10 ؊9 M) decreased LHRH release from medial basal hypothalami incubated in vitro. These results support the concept that endogenous AEA inhibits LHRH followed by decreased LH release in male rats. In ovariectomized (OVX) female rats, AEA i.c.v. also inhibited LH release, but in this case AM251 had an even greater inhibitory effect than AEA. In vitro, AEA had no effect on LHRH in OVX rats. It seems that endogenous AEA inhibits LHRH followed by decreased LH release in OVX rats but that AM251 has an inhibitory action in this case. In striking contrast, in OVX, estrogen-primed (OVX-E) rats, AEA i.c.v. instead of decreasing LH, increased its release. This effect was completely blocked by previous injection of AM251. When medial basal hypothalami of OVX-E rats were incubated, AEA increased LHRH release. The synthesized AEA was higher in OVX-E rats than in OVX and males, indicating that estrogen modifies endocannabinoid levels and effects. The results are interpreted to mean that sex steroids have profound effects to modify the response to AEA. It inhibits LHRH and consequently diminishes LH release in males and OVX females, but stimulates LHRH followed by increased LH release in OVX-E-primed rats.AM251 ͉ CB1 receptor ͉ medial basal hypothalamus I t is well known that ⌬-9-tetrahydrocannabinol (THC), the active principle isolated from Cannabis sativa, alters many reproductive parameters in both male and female laboratory animals and humans (1). It has been reported that THC decreases secretion of hormones that control reproduction in male rats (2) but on the other hand stimulates sexual behavior in female rats (3). Also, a marked depression within 1 h in luteinizing hormone (LH) secretion after THC administration has been reported in male rats (2, 4). The molecular target for the action of this plant-derived cannabinol is the endocannabinoid system. This endogenous system consists of two types of GTP-binding protein-coupled receptors, cannabinoid receptors type 1 (CB1-r) and cannabinoid receptors type 2, and their endogenous ligands named anandamide (AEA) and 2-arachidonyl glycerol (5). This endocannabinoid system plays modulatory roles in many processes of the brain, such as the regulation of appetite, temperature, memory, and sexual and motor behavior (6). The activation of the endocannabinoid system acts in series with changes in the activity of several neurotransmitters including ␥-aminobutyric acid (GABA), dopamine, and glutamate (7).We had previously demon...

Marijuana, phytocannabinoids, the endocannabinoid system, and male fertility

“…For example, administration of AEA, which usually binds to postsynaptic CB1 receptors, decreased serum LH. This action could be prevented by a specific CB1 antagonist (SR141716) [56,57]. Farkas and coworkers furthermore demonstrated that endocannabinoid activates CB1 which, in turn, inhibits spontaneous gamma aminobutyric acid (GABA) release [58].…”

Endocannabinoids and Kisspeptins: Two Modulators in Fight for the Regulation of GnRH Activity

“…ECBs tone is certainly a key factor in ECBs activity. The inhibitory effect of AEA on GnRH-secreting neurons is reversed by estrogens (Scorticati et al, 2004), through the inhibition of astrocyte mGluR. Such a process inhibits prostaglandin mediated release of ECBs from GnRH secreting neurons (Glanowska & Moenter, 2011).…”

“…Current opinion postulates that ECB mediated LH, but not FSH, inhibition is the result of hypothalamic ECB activity. In fact, ECBs are well known inhibitors of GnRH release (Scorticati et al, 2004) and GnRH transcription (Chianese et al, 2011b;Meccariello et al, 2008). By contrast, direct or indirect action of ECBs upon GnRH secreting neurons is still controversial and under investigation.…”

“…ECBs are lipidic mediators capable to inhibit the release of hypothalamic GnRH (Scorticati et al, 2004), affecting, as a consequence, both steroroidogenesis and gonadal functions (Wang et al, 2004). While ECBs exert such a negative effect upon GnRH release, kisspeptins, the product of kiss gene, positively affect GnRH release.…”

Influence of metanandamide on steroidogenesis in rat adrenocorticocytes in vitro

“…Різний ефект метанандаміду, напев но, пов'язаний з неоднаковим характером метаболічних процесів в адренокортикальних клітинах самиць і самців. Припускаємо, що на рівні окремої адренокортикальної клітини має місце антагонізм між метанандамідом і естрогенами, оскільки такі взаємозв'язки було показано для гіпоталамуса [14]. Слід та кож зазначити існування статевої різниці щодо вмісту анандаміду в гіпофізі та гіпоталамусі щурів.…”