Time-Course of the Cannabinoid Receptor Down-Regulation in the Adult Rat Brain Caused by Repeated Exposure to D9-Tetrahydrocannabinol

KEY WORDS cannabinoid receptor binding; cannabinoid receptor mRNA levels; D9-tetrahydrocannabinol; autoradiography; in situ hybridization; chronic exposure; down-regulation ABSTRACT Recent studies have demonstrated that the pharmacological tolerance observed after prolonged exposure to plant or synthetic cannabinoids in adult individuals seems to have a pharmacodynamic rather than pharmacokinetic basis, because down-regulation of cannabinoid receptors was assessed in the brain of cannabinoid-tolerant rats. In the present study, we have examined the time-course of cannabinoid receptor down-regulation by analyzing cannabinoid receptor binding, using autoradiography, and mRNA expression, using in situ hybridization, in several brain structures of male adult rats daily exposed to D9-tetrahydrocannabinol (D9-THC) for 1, 3, 7, or 14 days. With only the exception of a few number of areas, most of the brain regions exhibited a progressive decrease in cannabinoid receptor binding. Two facts deserve to be mentioned. First, the pattern of this down-regulation process presented significant regional differences in terms of onset of the decrease and magnitude reached. Second, the loss of cannabinoi