The effects of Δ9-tetrahydrocannabinol physical dependence on brain cannabinoid receptors

The effects of chronic Delta(9)-tetrahydrocannabinol on cannabinoid receptor levels and receptor-G-protein coupling were investigated. Male Sprague-Dawley rats were infused continuously with low or high dose regimens of Delta(9)-tetrahydrocannabinol or vehicle for 4 days. Following treatment, rats were sacrificed for cannabinoid CB1 receptor binding analysis or challenged with the cannabinoid CB1 receptor antagonist, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide HCl (SR141716A). The rats receiving Delta(9)-tetrahydrocannabinol exhibited antagonist-precipitated withdrawal signs. Each brain region (cerebellum, cortex, hippocampus and basal ganglia) from high-dose rats showed 30-70% decreases in [H-3] (-)-cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4-(3-hydroxyphenyl)cyclohexanol (WIN55212-2) B-max values, indicating receptor down-regulation. Most regions showed decreased WIN552122-stimulated [S-35]guanosine-5'-O-3-thiotripliosphate (GTPgammaS) binding, indicating desensitization of cannabinoid CB1 receptors. Additional receptor binding assays in cerebellar membranes showed a significantly greater decrease in agonist than in antagonist B-max values, indicating a lower fraction of coupled receptors after treatment. Concentration-effect analysis of five agonists revealed that the treatment resulted in greater decreases in the efficacy of low-efficacy agonists. (C) 2002 Elsevier Science B.V. All rights reserved.