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Prolonged Recovery Rate of CB₁ Receptor Adaptation after Cessation of Long-Term Cannabinoid Administration

Department of Pharmacology and Toxicology and Institute for Drug and Alcohol Studies, Virginia Commonwealth University, Medical College of Virginia Campus, Richmond, Virginia

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]GTPS binding), respectively, in hippocampus and striatum/globus pallidus (GP). Mice were treated with escalating doses of ⁹-tetrahydrocannabinol (⁹-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]GTPS 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 ⁹-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.

Address correspondence to: Dr. Dana E. Selley, Department of Pharmacology and Toxicology, Box 980524, 1112 East Clay Street, Richmond, VA 23298. E-mail: deselley{at}vcu.edu

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