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Chronic ▵ 9 ‐Tetrahydrocannabinol Treatment Produces a Time‐Dependent Loss of Cannabinoid Receptors and Cannabinoid Receptor‐Activated G Proteins in Rat Brain
Author(s) -
Breivogel Christopher S.,
Childers Steven R.,
Deadwyler Sam A.,
Hampson Robert E.,
Vogt Leslie J.,
SimSelley Laura J.
Publication year - 1999
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.1999.0732447.x
Subject(s) - cannabinoid , cannabinoid receptor , chemistry , gtp' , endocrinology , receptor , medicine , pharmacology , biology , biochemistry , antagonist , enzyme
Abstract : Chronic treatment of rats with ▵ 9 ‐tetrahydrocannabinol (▵ 9 ‐THC) results in tolerance to its acute behavioral effects. In a previous study, 21‐day ▵ 9 ‐THC treatment in rats decreased cannabinoid activation of G proteins in brain, as measured by in vitro autoradiography of guanosine‐5′‐ O ‐(3‐[ 35 S]thiotriphosphate) ([ 35 S]GTPγS) binding. The present study investigated the time course of changes in cannabinoid‐stimulated [ 35 S]GTPγS binding and cannabinoid receptor binding in both brain sections and membranes, following daily ▵ 9 ‐THC treatments for 3, 7, 14, and 21 days. Autoradiographic results showed time‐dependent decreases in WIN 55212‐2‐stimulated [ 35 S]GTPγS and [ 3 H]WIN 55212‐2 binding in cerebellum, hippocampus, caudate‐putamen, and globus pallidus, with regional differences in the rate and magnitude of down‐regulation and desensitization. Membrane binding assays in these regions showed qualitatively similar decreases in WIn 55212‐2‐stimulated [ 35 S]GTPγS binding and cannabinoid receptor binding (using [ 3 H]SR141716A), and demonstrated that decreases in ligand binding were due to decreases in maximal binding values, and not ligand affinities. These results demonstrated that chronic exposure to ▵ 9 ‐THC produced time‐dependent and region‐specific down‐regulation and desensitization of brain cannabinoid receptors, which may represent underlying biochemical mechanisms of tolerance to cannabinoids.