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Long-Term Administration of ⁹-Tetrahydrocannabinol Desensitizes CB₁-, Adenosine A₁-, and GABA_B-Mediated Inhibition of Adenylyl Cyclase in Mouse Cerebellum

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

Cannabinoid CB₁ receptors in the cerebellum mediate the inhibitory effects of ⁹-tetrahydrocannabinol (THC) on motor coordination. Intracellular effects of CB₁ receptors include inhibition of adenylyl cyclase via activation of G_i/o proteins. There is evidence for the convergence of other neuronal receptors, such as adenosine A₁ and GABA_B, with the cannabinoid system on this signaling pathway to influence motor function. Previous studies have shown that brain CB₁ receptors are desensitized and down-regulated by long-term THC treatment, but few studies have examined the effects of long-term THC treatment on downstream effector activity in brain. Therefore, these studies examined the relationship between CB₁, adenosine A₁, and GABA_B receptors in cerebella of mice undergoing prolonged treatment with vehicle or THC at the level of G protein activation and adenylyl cyclase inhibition. In control cerebella, CB₁ receptors produced less than additive inhibition of adenylyl cyclase with GABA_B and A₁ receptors, indicating that these receptors are localized on overlapping populations of cells. Long-term THC treatment produced CB₁ receptor down-regulation and desensitization of both cannabinoid agonist-stimulated G protein activation and inhibition of forskolin-stimulated adenylyl cyclase. However, G protein activation by GABA_B or A₁ receptors was unaffected. It is noteworthy that heterologous attenuation of GABA_B and A₁ receptor-mediated inhibition of adenylyl cyclase was observed, even though absolute levels of basal and forskolin- or G_s-stimulated activity were unchanged. These results indicate that long-term THC administration produces a disruption of inhibitory receptor control of cerebellar adenylyl cyclase and suggest a potential mechanism of cross-tolerance to the motor incoordinating effects of cannabinoid, GABA_B, and A₁ agonists.

Address correspondence to: Dr. Dana E. Selley, Department of Pharmacology and Toxicology, Virginia Commonwealth University, Box 980524, MCV Campus, 1112 East Clay St., Richmond, VA 23298. E-mail: deselley{at}hsc.vcu.edu

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