Abstract
Cannabinoid CB1 receptors in the cerebellum mediate the inhibitory effects of Δ9-tetrahydrocannabinol (THC) on motor coordination. Intracellular effects of CB1 receptors include inhibition of adenylyl cyclase via activation of Gi/o proteins. There is evidence for the convergence of other neuronal receptors, such as adenosine A1 and GABAB, 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 GABAB 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 GABAB 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 GABAB or A1 receptors was unaffected. It is noteworthy that heterologous attenuation of GABAB and A1 receptor-mediated inhibition of adenylyl cyclase was observed, even though absolute levels of basal and forskolin- or Gs-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, GABAB, and A1 agonists.
- Received March 18, 2004.
- Accepted July 28, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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