DELTA-9-TETRAHYDROCANNABINOL AFFECTS MESOLIMBIC DOPAMINERGIC ACTIVITYIN THE FEMALE RAT-BRAIN - INTERACTIONS WITH ESTROGENS

In this work, we studied the possible estrogenic modulation of the eff ects of delta9-tetrahydrocannabinol (THC) on mesolimbic dopaminergic a ctivity, by examining the effects of an acute dose of this cannabinoid : (i) during the estrous cycle; (ii) after ovariectomy, chronic estrog en-replacement and tamoxifen (TMX)-induced blockade of estrogenic rece ptors; and (iii) combined with a single and physiological injection of estradiol to ovariectomized rats. THC significantly decreased the den sity of D 1 dopaminergic receptors and non-significantly increased the L-3,4-dihydroxyphenylacetic acid (DOPAC) content in the limbic forebr ain of ovariectomized rats chronically replaced with estrogens. The de crease in D 1 receptors was also produced by TMX, whereas the coadmini stration of both THC and TMX did not lead to a major decrease. In addi tion to the trend of THC increasing DOPAC content, this cannabinoid wa s also able to increase the ratio between DOPAC and dopamine, although this last effect only occurred after coadministration of THC and TMX, which had been ineffective administered individually. All these effec ts were not seen when THC was administered to normal cycling rats duri ng each phase of estrous cycle and to ovariectomized rats without chro nic estrogen replacement or only submitted to a single and acute dose of estradiol. This observation might be related to the fact that the d ensity of limbic cannabinoid receptors increased in chronic estrogen-r eplaced ovariectomized rats versus normal cycling, ovariectomized or a cutely estrogen-treated ovariectomized rats. Interestingly, THC admini stration in ovariectomized rats was followed by a slight, although sig nificant, increase in tyrosine hydroxylase activity, which was also ob served after coadministration of THC with a short-time and acute dose of estradiol. In summary, THC stimulated the presynaptic activity of m esolimbic dopaminergic neurons, but accompanied by a decrease in their postsynaptic sensitivity. These effects did not appear in normal cycl ing rats being only evident after ovariectomy and chronic estrogen rep lacement, which might be related to changes in binding characteristics of cannabinoid receptors in this area. Moreover, some of them appeare d after TMX-induced blockade of estrogenic cytosolic receptors, which likely suggests the existence of a certain estrogenic modulation of th e actions of THC on mesolimbic neurons. On the contrary, coadministrat ion of THC with a single and shortly tested dose of estradiol was alwa ys ineffective in modifying THC effects.