Effects of cannabinoids on prolactin and gonadotrophin secretion: involvement of changes in hypothalamic γ-aminobutyric acid (GABA) inputs

Miguel, Rosario de; Romero, J. C.; Muñoz, Riansares; Garcı́a-Gil, Lucı́a; González, Sara; Villanúa, María Ángeles; Makriyannis, Alexandros; Ramos, J.A.; Fernández‐Ruiz, Javier

doi:10.1016/s0006-2952(98)00185-3

Cited by 53 publications

(27 citation statements)

References 36 publications

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“…In fact, AEA did not affect ␤-endorphin release. In vitro studies demonstrated that EtOH and THC increased GABA content in MBH (21,22). In a previous work (7), we demonstrated that EtOH increased GABA release, and in the present work we demonstrated that there was a bell-shaped curve of AEAstimulated GABA release with highly significant release only at 10 Ϫ9 M AEA.…”

Section: Discussionsupporting

confidence: 79%

“…The activation of the endocannabinoid system is in parallel with changes in the activity of several neurotransmitters, including GABA and dopamine (20). In vitro studies demonstrated that EtOH, as well as THC, increases GABA content in the MBH (21,22). It has been shown that GABA inhibits the release of LHRH (11) and that stimulatory neurotransmitters such as norepinephrine act through cAMP to increase the release of LHRH (23).…”

mentioning

confidence: 99%

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

Fernández‐Solari

Scorticati

Mohn

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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We hypothesized that ethanol (EtOH) might act through the endocannabinoid system to inhibit luteinizing hormone-releasing hormone (LHRH) release. Therefore, we examined the mechanism by which EtOH and anandamide (AEA), an endogenous cannabinoid, inhibit LHRH release from incubated medial basal hypothalamic explants. In previous work, we demonstrated that EtOH inhibits the N-methyl-D-aspartic acid-stimulated release of LHRH by increasing the release of two neurotransmitters: ␤-endorphin and ␥-aminobutyric acid (GABA). In the present work, bicuculline, a GABAergic antagonist, completely prevented the inhibition of AEA (10 ؊9 M) on N-methyl-D-aspartic acid-induced LHRH release, but naltrexone, a -opioid receptor antagonist, had no effect. AEA also significantly increased GABA release but had no effect on ␤-endorphin release. Therefore, AEA could inhibit LHRH release by increasing GABA but not ␤-endorphin release. Because EtOH and AEA acted similarly to inhibit LHRH release, we investigated whether both substances would affect the adenylate cyclase activity acting through the same GTP-coupled receptors, the cannabinoid receptors 1 (CB1-rs). AEA and EtOH (10 ؊1 M) reduced the forskolin-stimulated accumulation of cAMP, but AM251, a specific antagonist of CB1-r, significantly blocked that inhibition. Additionally we investigated whether CB1-r is involved in the inhibition of LHRH by EtOH and AEA. AEA and EtOH reduced forskolin-stimulated LHRH release, but AM251 significantly blocked that inhibition. Also, we demonstrated that EtOH did not act by increasing AEA synthase activity to inhibit LHRH release in our experimental conditions. Therefore, our results indicate that EtOH inhibits the release of LHRH acting through the endocannabinoid system. anandamide ͉ cannabinoid receptor 1 ͉ cyclic adenosine monophosphate ͉ ␥-amino butyric acid

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Section: Discussionsupporting

confidence: 79%

mentioning

confidence: 99%

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

Fernández‐Solari

Scorticati

Mohn

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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“…D-9-THC failed to reduce prolactin release; this may be explained by the short sampling duration. However, consistent with preclinical evidence that chronic exposure to cannabinoids leads to a long lasting suppression of prolactin release (de Miguel et al, 1998b), frequent users of cannabis had significantly lower prolactin levels compared to controls.…”

Section: Tolerancesupporting

confidence: 63%

“…Perhaps, as discussed earlier, tolerance to the various effects of D-9-THC develops at different rates reviewed in Gonzalez et al, 2005. In animals, tolerance for some effects of cannabinoids (eg, analgesia, motor inhibition hypothermia) occurs within the range of 3-7 days (Abood et al, 1993;Pertwee et al, 1993;Rubino et al, 1997), whereas the memory (Hampson et al, 2003) and endocrine effects (de Miguel et al, 1998a;Gonzalez et al, 1999), take from weeks to months to develop. These data suggest that the neural mechanisms underlying the various different brain effects of cannabinoids adapt differentially to prolonged cannabinoid exposure reviewed in Gonzalez et al, 2005.…”

Section: Tolerancementioning

confidence: 97%

Blunted Psychotomimetic and Amnestic Effects of Δ-9-Tetrahydrocannabinol in Frequent Users of Cannabis

D’Souza

Ranganathan

Braley

et al. 2008

Neuropsychopharmacol

234

202

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Cannabis is one of the most widely used illicit substances and there is growing interest in the association between cannabis use and psychosis. Delta-9-Tetrahydrocannabinol (D-9-THC) the principal active ingredient of cannabis has been shown to induce psychotomimetic and amnestic effects in healthy individuals. Whether people who frequently use cannabis are either protected from or are tolerant to these effects of D-9-THC has not been established. In a 3-day, double-blind, randomized, placebo-controlled study, the dose-related effects of 0, 2.5, and 5 mg intravenous D-9-THC were studied in 30 frequent users of cannabis and compared to 22 healthy controls. D-9-THC (1) produced transient psychotomimetic effects and perceptual alterations; (2) impaired memory and attention; (3) increased subjective effects of 'high'; (4) produced tachycardia; and (5) increased serum cortisol in both groups. However, relative to controls, frequent users showed blunted responses to the psychotomimetic, perceptual altering, cognitive impairing, anxiogenic, and cortisol increasing effects of D-9-THC but not to its euphoric effects. Frequent users also had lower prolactin levels. These data suggest that frequent users of cannabis are either inherently blunted in their response to, and/or develop tolerance to the psychotomimetic, perceptual altering, amnestic, endocrine, and other effects of cannabinoids.

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“…19 Some authors have observed that chronic activation of cannabinoid (CB) receptor type-1 by cannabis may reduce PRL and luteinizing hormone (LH) levels, probably via interaction with the GABA (gamma-aminobutyric acid) receptor activation. 20,21 Activation of the hypothalamicpituitary-adrenal axis seems to occur after an acute response to inhalative cannabinoids. 22 However, in chronic consumers a reduction of cortisol response after insulinic stress has been shown, thus suggesting different pathophysiological mechanisms.…”

Section: Endothelial Dysfunction In Erectile Dysfunction a Aversa Et Almentioning

confidence: 99%

Early endothelial dysfunction as a marker of vasculogenic erectile dysfunction in young habitual cannabis users

et al. 2008

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Aim of the study was to evaluate whether endothelial dysfunction is a marker of erectile dysfunction (ED) in recreational drug abuse. Sixty-four non-consecutive men complaining of ED from at least 3 months were included. All patients underwent detailed history about recreational drug abuse and were then submitted to dynamic penile duplex ultrasound (PDU). According to pharmaco-stimulated peak systolic velocity (PSV) cutoff at 35 cm s À1 , patients were divided into two groups: organic (O; n ¼ 30) and non-organic (NO; n ¼ 34) ED. All subjects and 7 healthy age-matched subjects as controls, underwent veno-occlusive plethysmography (VOP) for the evaluation of endothelium-dependent dilatation of brachial arteries. Blood pressure, total and free testosterone, prolactin, estradiol, low-density lipoprotein and high-density lipoprotein cholesterol were also evaluated; patients were classified with regard to insulin resistance through the HOMA-IR index. Cannabis smoking was more frequent in O-ED vs NO-ED (78% vs 3%, Po0.001) in the absence of any concomitant risk factor or comorbidity for ED. VOP studies revealed impaired endotheliumdependent vasodilatation in O-ED but not in NO-ED and controls (12±6 vs 32±4 and 34 ± 5 ml min À1 , respectively; P ¼ 0.003). Overall patients showed a direct relationship between HOMA-IR and PSV (r 2 ¼ 0.47, Po0.0001), which was maintained in men with organic ED (r 2 ¼ 0.62, Po0.0001). In cannabis consumers, a direct relationship between HOMA-IR and VOP was also found (r 2 ¼ 0.74, Po0.0001). Receiver-operating characteristic (ROC) curve analysis revealed that VOP values below 17.22 ml min À1 were suggestive for vasculogenic ED. We conclude that early endothelial damage may be induced by chronic cannabis use (and endocannabinoid system activation); insulin resistance may be the hallmark of early endothelial dysfunction and may concur to determine vascular ED in the absence of obesity. Further studies are warranted to establish a direct relationship between cannabis abuse, onset of insulin resistance and development of vascular ED.

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Effects of cannabinoids on prolactin and gonadotrophin secretion: involvement of changes in hypothalamic γ-aminobutyric acid (GABA) inputs

Cited by 53 publications

References 36 publications

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

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

Blunted Psychotomimetic and Amnestic Effects of Δ-9-Tetrahydrocannabinol in Frequent Users of Cannabis

Early endothelial dysfunction as a marker of vasculogenic erectile dysfunction in young habitual cannabis users

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