Sara González a , Jorge Manzanares b , Fernando Berrendero a , Tibor Wenger c , Javier Corchero b , Tiziana Bisogno d , Julián Romero a , José A. Fuentes b , Vincenzo Di Marzo d , José A. Ramos a , Javier Fernández-Ruiz a
16 August 1999
Most data on effects of natural and synthetic cannabinoids on anterior pituitary hormone secretion point out to a primary impact on the hypothalamus. There is also some evidence, however, of possible direct actions of these compounds on the anterior pituitary, although the presence of cannabinoid receptors in the pituitary has not been documented as yet. In the present study, we evaluated the presence of cannabinoid CB<sub>1</sub> receptor-mRNA transcripts in the pituitary gland by in situ hybridization. We observed CB<sub>1</sub> receptor-mRNA transcripts in the anterior pituitary and to a lesser extent in the intermediate lobe whereas they were absent in the neural lobe. We then examined whether CB<sub>1</sub> receptor-mRNA levels in both pituitary lobes responded to chronic activation by a specific agonist, as did receptors located in adjacent hypothalamic nuclei and in other brain regions. Daily administration of CP-55,940 for 18 days produced a small, but statistically significant paradoxical increase in CB<sub>1</sub> receptor-mRNA levels in the anterior pituitary, with no changes in the intermediate lobe, in contrast to reduced CB<sub>1</sub> receptor-mRNA levels observed in the ventromedial hypothalamic nucleus (VMN), and to decreased CB<sub>1</sub> receptor binding in the VMN and the arcuate nucleus. The time-course of up-regulation of CB<sub>1</sub> receptor-mRNA transcripts in the anterior lobe was biphasic; daily administration of Δ<sup>9</sup>-tetrahydrocannabinol produced an early and marked decrease in CB<sub>1</sub> receptor-mRNA levels after 1 and 3 days, followed by normalization after 7 days and by a small increase after 14 days. We also checked whether endogenous cannabinoid ligands are present in the anterior pituitary and the hypothalamus. Although anandamide itself was detected only in trace amounts, concentrations of its precursor N-arachidonoyl-phosphatidyl-ethanolamine and of 2-arachidonoyl-glycerol were found in both tissues, suggesting that endocannabinoids may be synthetized in the anterior pituitary. In summary, CB<sub>1</sub> receptors and corresponding ligands seem to be expressed in cells of the anterior and intermediate lobes of the pituitary, but the response of CB<sub>1</sub> receptor-mRNA transcripts in the anterior lobe to chronic agonist activation is different than the desensitization observed in hypothalamic nuclei.