Received for publication October 7, 2005.
Revised May 31, 2006.
Accepted for publication May 31, 2006.

Prolonged recovery rate of CB₁ receptor adaptation after cessation of chronic cannabinoid administration

Abstract

Chronic cannabinoid administration produces region-dependent CB₁ receptor desensitization and downregulation. This study examined the time course for normalization of CB₁ receptors and G-protein activation using [³H]SR141716A and [³⁵S]GTPS binding, respectively, in hippocampus and striatum/globus pallidus (GP). Mice were treated with escalating doses of ⁹-THC or 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 post-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 post-treatment in striatum/GP and hippocampus, respectively. The mechanism of CB₁ binding site downregulation was investigated after chronic 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 downregulation. In contrast, CB₁ receptor protein, as determined by immunoblot analysis, matched the downregulation 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 chronic drug treatment, and that CB₁ receptor signaling recovers more quickly in striatum/GP than hippocampus. Moreover, downregulation of CB₁ receptor binding sites does not appear to result mainly from transcriptional regulation, suggesting that adaptive regulation of CB₁ receptors in brain primarily occurs at the protein level.

Key words: Cannabinoid, Gi family, Desensitization/uncoupling, Receptor degradation, Receptor binding studies, Regulation of gene expression

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