Elsevier

Biochemical Pharmacology

Volume 56, Issue 10, 15 November 1998, Pages 1331-1338
Biochemical Pharmacology

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

https://doi.org/10.1016/S0006-2952(98)00185-3Get rights and content

Abstract

CB1 cannabinoid receptors are located in hypothalamic nuclei and their activation alters several hypothalamic neurotransmitters resulting in, among other things, decreased prolactin (PRL) and luteinizing hormone (LH) secretion from the anterior pituitary gland. In the present study, we addressed two related objectives to further explore this complex regulation. First, we examined whether changes in γ-aminobutyric acid (GABA) and/or dopamine (DA) inputs in the medial basal hypothalamus might occur in parallel to the effects resulting from the activation of CB1 receptors on PRL and gonadotrophin secretion in male rats. Thus, the acute administration of (-)-Δ9-tetrahydrocannnabinol (Δ9-THC) produced, as expected, a marked decrease in plasma PRL and LH levels, with no changes in follicle-stimulating hormone (FSH) levels. This was paralleled by an increase in the contents of GABA, but not of DA, in the medial basal hypothalamus and, to a lesser extent, in the anterior pituitary gland. The co-administration of Δ9-THC and SR141716, a specific antagonist for CB1 receptors, attenuated both PRL and LH decrease and GABA increase, thus asserting the involvement of the activation of CB1 receptors in these effects. As a second objective, we tested whether the prolonged activation of these receptors might induce tolerance with regard to the decrease in PRL and LH release, and whether this potential tolerance might be related to changes in CB1-receptor binding and/or mRNA expression. The chronic administration of R-methanandamide (AM356), a more stable analog of anandamide, the putative endogenous cannabinoid ligand, produced a marked decrease in plasma PRL and LH levels, with no changes in FSH. The decreases were of similar magnitude to those caused by a single injection of this cannabimimetic ligand, thus suggesting the absence of tolerance. In parallel, the analysis of CB1-receptor binding and mRNA expression in several hypothalamic structures proved that the acute or chronic administration of AM356 did not affect either the binding or the synthesis of these receptors. In summary, the activation of CB1 receptors in hypothalamic nuclei produced the expected decrease in PRL and LH secretion, an effect which might be related to an increase in GABAergic activity in the hypothalamus-anterior pituitary axis. The prolonged activation of these receptors for five days did not elicit tolerance in terms of an attenuation in the magnitude of the decrease in PRL and LH, and, accordingly, did not alter CB1-receptor binding and mRNA levels in the hypothalamic nuclei examined.

Section snippets

Animals, treatments, and sampling

Male Wistar rats were housed from birth in a room with a controlled photoperiod (lights on: 8 a.m.–8 p.m.) and temperature (23 ± 1°). They had free access to standard food (Panlab) and water. As adults (>8 weeks; 250 ± 25 g), the animals were used for two different experiments (all experiments were conducted according to European Animal Care Guides).

In Experiment I, the animals were subjected to a single i.p. injection of SR141716 (3 mg/kg of weight) a specific CB1-receptor antagonist that was

Experiment I: involvement of changes in GABA and/or DA hypothalamic inputs in cannabinoid-induced decreases in PRL and LH secretion

As expected, the acute administration of Δ9-THC produced a marked decrease in plasma PRL [F(3, 20) = 2.997, P < 0.05] and LH [F(3, 17) = 3.055, P <0.05] levels (Fig. 1 ), with no changes in FSH [F(3, 20) = 0.502, not significant] levels (Table 1). This was paralleled by an increase in the contents of GABA (Fig. 2 ), but not of DA (Table 1), in the medial basal hypothalamus [GABA: F(3, 18) = 4.993, P < 0.05; DA: F(3, 20) = 1.96, not significant], whereas in the anterior pituitary gland only a

Discussion

The present study confirms previous observations from our laboratory 3, 5, 6, 7, 8, 17, 19, 20, 21 and others 1, 2, 4, 9, 10, 12, 18, 42, 43, which demonstrated that the administration of Δ9-THC and related cannabinoids inhibits the secretion of PRL and LH. The present study provides new evidence that indicates that the effect of Δ9-THC on PRL and LH release is caused by the activation of CB1 receptors, which are expected to produce, among other effects, an enhancement of GABAergic activity in

Acknowledgements

This work was supported by grants from Comision Interministerial de Ciencia y Tecnologia (PM96-0049: R. M., J. R., L. G. G., S. G., J. A. R. and J. J. F. R.), Fondo de Investigaciones Sanitarias (Spain) (94/0299: R. M. M. and M. A. V.) and National Institute on Drug Abuse (NIDA) (DA 3801 and DA 9158: A. M.). The authors are indebted to Sanofi Recherche for the gift of SR141716, the NIDA for kindly supplying Δ9-THC, and to the National Institutes of Health for providing the reagents for PRL, LH

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