TY - JOUR T1 - Prolonged Recovery Rate of CB<sub>1</sub> Receptor Adaptation after Cessation of Long-Term Cannabinoid Administration JF - Molecular Pharmacology JO - Mol Pharmacol SP - 986 LP - 996 DO - 10.1124/mol.105.019612 VL - 70 IS - 3 AU - Laura J. Sim-Selley AU - Nicole S. Schechter AU - W. Kirk Rorrer AU - George D. Dalton AU - Jerry Hernandez AU - Billy R. Martin AU - Dana E. Selley Y1 - 2006/09/01 UR - http://molpharm.aspetjournals.org/content/70/3/986.abstract N2 - Long-term cannabinoid administration produces region-dependent CB1 receptor desensitization and down-regulation. This study examined the time course for normalization of CB1 receptors and G-protein activation using 3H-labeled N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboximide hydrochloride (SR141716A) and guanosine 5′-O-(3-[35S]thio)triphosphate ([35S]GTPγS binding), respectively, in hippocampus and striatum/globus pallidus (GP). Mice were treated with escalating doses of Δ9-tetrahydrocannabinol (Δ9-THC) or R(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo-[1,2,3-de]-1,4-benzoxazinyl]-(1-naphthalenyl)methanone mesylate (WIN55,212-2) for 15 days, and tissue was collected 1, 3, 7, or 14 days after final injection. [3H]SR141716A and WIN55,212-2-stimulated [35S]GTPγS binding were decreased in both regions 1 day after treatment. WIN55,212-2-stimulated G-protein activation in striatum/GP returned to control level at 3 days after cessation of treatment with either drug but did not return to control level in hippocampus until 14 days. CB1 receptor binding did not recover to control levels until day 7 or 14 after treatment in striatum/GP and hippocampus, respectively. The mechanism of CB1 binding site down-regulation was investigated after long-term Δ9-THC treatment. Analysis of CB1 receptor mRNA in hippocampus and striatum/GP showed that transcriptional regulation could not explain prolonged recovery rates from CB1 receptor down-regulation. In contrast, CB1 receptor protein, as determined by immunoblot analysis, matched the down-regulation and recovery rates of CB1 receptor binding sites relatively closely. These data demonstrate that cannabinoid-induced decreases in CB1 receptor function persist for relatively long time periods after cessation of long-term drug treatment and that CB1 receptor signaling recovers more quickly in striatum/GP than hippocampus. Moreover, down-regulation of CB1 receptor binding sites does not seem to result mainly from transcriptional regulation, suggesting that adaptive regulation of CB1 receptors in brain primarily occurs at the protein level. The American Society for Pharmacology and Experimental Therapeutics ER -