DIFFERENTIAL-EFFECTS OF CHRONIC TREATMENT WITH EITHER DOPAMINE D-1 OR D-2 RECEPTOR AGONISTS ON THE ACUTE NEUROENDOCRINE ACTIONS OF THE HIGHLY POTENT SYNTHETIC CANNABINOID HU-210 IN MALE-RATS

Acute exposure to Delta(9)-tetrahydrocannabinol (THC), the main psychoactive constituent of marijuana, produces a well-characterized set of neuroendocrine effects. The recent description of both brain cannabinoid receptors (CB-1) and anandamide, their proposed endogenous ligand, has renewed the interest in cannabinoid actions in the brain. However, the neurobiological mechanisms underlying the neuroendocrine effects of natural cannabinoids are not yet fully understood because of several mechanisms involved in their actions. In this work we have studied the role of hypothalamic dopaminergic receptors in the mediation of the acute neuroendocrine effects of (-)-Delta(8)-tetrahydrocannabinol-dimethyl-heptyl (HU-210, 20 mu g/kg), a highly potent agonist of CB-1. The use of this low dose of HU-210 precludes the multiple unspecific effects which appear with an equipotent dose of THC. Rats were exposed during 21 days to either the dopamine (DA) D-2 receptor agonist quinpirole (1 mg/kg, daily), the DA D-1 receptor agonist SKF 38393 (8 mg/kg, twice a day) or vehicle (twice a day). Twenty-four hours after the last injection, a single dose of HU-210 (20 mu g/kg) was administered intraperitoneally, and the animals were sacrificed 90 min later. Acute exposure to HU-210 produced both a decrease in plasma prolactin and a rise of plasma corticosterone levels. HU-210 treatment also resulted in both an increase in the L-3,4-dihydroxyphenylacetic acid/DA ratio and a decrease in noradrenaline contents, measured in the medial basal hypothalamus. These neuroendocrine actions were prevented by chronic exposure to quinpirole, but not after chronic SKF 38393 treatment. HU-210 induced also a decrease in plasma luteinizing hormone levels, which was not affected by the pretreatment with any of the two DA agonists tested. These results suggest a role of DA D-2, but not D-1, receptors in the regulation of several cannabinoid-receptor-mediated endocrine effects within the hypothalamus. However, we have also observed that the acute behavioral effects of HU-210, especially catalepsy, were enhanced after chronic SKF 38393 treatment. This experimental group also exhibited a clear HU-210-induced rise in both plasma adrenocorticotropic hormone and corticosterone levels. Since CB-1-agonist-induced catalepsy is a very stressful experience, these findings might indicate a possible contribution of limbic inputs to the hypothalamus in the cannabinoid activation of the pituitary-adrenal axis.