Long-Term Administration of Δ9-Tetrahydrocannabinol Desensitizes CB1-, Adenosine A1-, and GABAB-Mediated Inhibition of Adenylyl Cyclase in Mouse Cerebellum

Cannabinoid CB 1 receptors in the cerebellum mediate the inhibitory effects of Δ 9 -tetrahydrocannabinol (THC) on motor coordination. Intracellular effects of CB 1 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 A 1 and GABA B , with the cannabinoid system on this signaling pathway to influence motor function. Previous studies have shown that brain CB 1 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 CB 1 , adenosine A 1 , 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, CB 1 receptors produced less than additive inhibition of adenylyl cyclase with GABA B and A 1 receptors, indicating that these receptors are localized on overlapping populations of cells. Long-term THC treatment produced CB 1 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 A 1 receptors was unaffected. It is noteworthy that heterologous attenuation of GABA B and A 1 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 A 1 agonists.