EFFECTS OF CANNABINOIDS ON PROLACTIN AND GONADOTROPIN-SECRETION - INVOLVEMENT OF CHANGES IN HYPOTHALAMIC GAMMA-AMINOBUTYRIC-ACID (GABA) INPUTS

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 hormon e (LH) secretion from the anterior pituitary gland. In the present stu dy, we addressed two related objectives to further explore this comple x regulation. First, we examined whether changes in gamma-aminobutyric acid (GABA) and/or dopamine (DA) inputs in the medial basal hypothala mus might occur in parallel to the effects resulting from the activati on of CB1 receptors on PRL and gonadotrophin secretion in male rats. T hus, the acute administration of (-)-Delta(9)-tetrahydrocannnabinol (D elta(9)-THC) produced, as expected, a marked decrease in plasma PRL an d LH levels, with no changes in follicle-stimulating hormone (FSH) lev els. This was paralleled by an increase in the contents of GABA, but n ot of DA, in the medial basal hypothalamus and, to a lesser extent, in the anterior pituitary gland. The co-administration of Delta(9)-THC a nd 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 objec tive, we tested whether the prolonged activation of these receptors mi ght 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 administratio n 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 can nabimimetic ligand, thus suggesting the absence of tolerance. In paral lel, the analysis of CB1-receptor binding and mRNA expression in sever al hypothalamic structures proved that the acute or chronic administra tion of AM356 did not affect either the binding or the synthesis of th ese receptors. In summary, the activation of CB1 receptors in hypothal amic 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, acco rdingly, did not alter CB1-receptor binding and mRNA levels in the hyp othalamic nuclei examined. BIOCHEM PHARMACOL 56;10:1331-1338, 1998. (C ) 1998 Elsevier Science Inc.