Long-term administration of Delta9-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 Delta(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.
Department of Pharmacology and Toxicology, Institute for Drug and Alcohol Studies, Virginia Commonwealth University Medical College of Virginia, Box 980524, MCV Campus, 1112 East Clay St., Richmond, VA 23298, USA. deselley@hsc.vcu.edu.
Dana E
DE
Selley
Michael P
MP
Cassidy
Billy R
BR
Martin
Laura J
LJ
Sim-Selley
D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D002531:Cerebellum / Q000187:drug effects* / Q000201:enzymology; D013759:Dronabinol / Q000008:administration & dosage / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism*; D018080:Receptors, GABA-B / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D000067956:Adenylyl Cyclase Inhibitors; D043682:Receptor, Adenosine A1; D043884:Receptor, Cannabinoid, CB1; D018080:Receptors, GABA-B; D013759:Dronabinol; D019204:GTP-Binding Proteins