Received for publication March 19, 2004.
Revised July 28, 2004.
Accepted for publication July 28, 2004.

Chronic Administration of ⁹-THC Desensitizes CB₁-, Adenosine A₁- and GABA_B-Mediated Inhibition of Adenylyl Cyclase in Mouse Cerebellum

Abstract

Cannabinoid CB₁ receptors in the cerebellum mediate inhibitory effects of ⁹-THC (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 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 downregulated by chronic THC treatment, but few studies have examined the effects of chronic THC on downstream effector activity in brain. Therefore, these studies examined the relationship between CB₁, adenosine A₁ and GABA_B receptors in cerebella of chronic vehicle and THC-treated mice at the level of G-protein activation and adenylyl cyclase inhibition. In naïve 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. Chronic THC treatment produced CB₁ receptor downregulation 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. Interestingly, heterologous attenuation of GABA_B and A₁ receptor-mediated inhibition adenylyl cyclase was observed, even though absolute levels of basal, forskolin- or G_s-stimulated activity were unchanged. These results indicate that chronic 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.

Key words: Adenosine, Cannabinoid, GABAB, Gi family, Adenylyl cyclases, Desensitization/uncoupling

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