Downregulation of rat brain cannabinoid binding sites after chronic Δ9-tetrahydrocannabinol treatment

Abstract

Specific cannabinoid receptors have been recently described in extrapyramidal and limbic areas and presumably might mediate the effects of marijuana exposure on behavioral processes related to those areas. In this work, we examined whether cannabinoid receptors exhibit downregulation as a consequence of the chronic exposure to Δ 9-tetrahydrocannabinol (THC), which might explain certain tolerance phenomena observed in relation to motor and limbic effects of marijuana. To this end, we first characterized the binding of cannabinoid receptors, by using [ 3H]CP-55,940 binding assays, in the striatum, limbic forebrain, and ventral mesencephalon of male rats, and, second, we measured the density and affinity of those receptors in these brain areas after 7 days of a daily treatment with THC. Development of a tolerance phenomenon was behaviorally tested by using an open-field technique. Results were as follows. The three areas studies presented specific and saturable binding for the cannabinoid ligand, as revealed by their corresponding association and dissociation curves, displacement by THC, saturation curves, and Scatchard plots. A chronic treatment with THC produced the expected tolerance phenomenon: The decrease caused by an dose in spontaneous locomotor (49.4%) and exploratory (59.7%) activities and, mainly, the increase in the time spent by the rat in inactivity (181.7%) were diminished after 7 days of daily treatment (39.4, 40.4, and 31.7%, respectively). This tolerance was accompanied by significant decreases in the density of cannabinoid receptors in the striatum and limbic forebrain, the areas where nerve terminals for nigrostriatal and mesolimbic dopaminergic systems, respectively, which play an important role in those processes, are located. This downregulation phenomenon was also observed in the ventral mesencephalon, the area where cell bodies for both dopaminergic neuronal systems are clustered, but the decrease was smaller and nonsignificant. No modifications were seen in the affinity of these receptors by chronic exposure to THC. In summary, a chronic treatment with THC produced downregulation of cannabinoid receptors in the striatum and limbic forebrain and a nonsignificant trend in the ventral mesencephalon. This observation might explain the tolerance phenomena observed in the effects of THC on motor and limbic behaviors after chronic exposures.