title: Functional interaction and cross-tolerance between ethanol and Δ9-THC: possible modulation by mouse cerebellar adenosinergic A1/GABAergic-A receptors.
abstract: We have previously shown a functional motor interaction between ethanol and Δ(9)-tetrahydrocannabinol (Δ(9)-THC) that involved cerebellar adenosinergic A1 and GABAergic A receptor modulation. We now report the development of cross-tolerance between intracerebellar Δ(9)-THC and intraperitoneal ethanol using ataxia as the test response in male CD-1 mice. The drugs [Δ(9)-THC (20 μg), N(6)-cyclohexyladenosine, CHA (12 ng), muscimol (20 ng)] used in the study were directly microinfused stereotaxically via guide cannulas into the cerebellum except ethanol. Δ(9)-THC, infused once daily for 5 days followed 16 h after the last infusion by acute ethanol (2g/kg) and Rotorod evaluation, virtually abolished ethanol ataxia indicating development of cross-tolerance. The cross-tolerance was also observed when the order of ethanol and Δ(9)-THC treatment was reversed, i.e., ethanol injected once daily for 5 days followed 16 h after the last ethanol injection by Δ(9)-THC infusion. The cross-tolerance appeared within 24-48 h, lasted over 72 h and was maximal in 5-day ethanol/Δ(9)-THC-treated animals. Finally, tolerance in chronic ethanol/Δ(9)-THC/-treated animals developed not only to ethanol/Δ(9)-THC-induced ataxia, respectively, but also to the ataxia potentiating effect of CHA and muscimol, indicating modulation by cerebellar adenosinergic A1 and GABAA receptors. A practical implication of these results could be that marijuana smokers may experience little or no negative effects such as ataxia following alcohol consumption. Clinically, such antagonism of ethanol-induced ataxia can be observed in marijuana users thereby encouraging more alcohol consumption and thus may represent a risk factor for the development of alcoholism in this segment of population.
authors.affiliation: Department of Pharmacology, Brody School of Medicine, East Carolina University, Greenville, NC 27834, USA. Electronic address: darm@ecu.edu.
authors.forename: M Saeed
authors.initials: MS
authors.lastname: Dar
mesh_terms: D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D063386:Cannabinoid Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology; D002492:Central Nervous System Depressants / Q000008:administration & dosage / Q000494:pharmacology; D002524:Cerebellar Ataxia / Q000139:chemically induced* / Q000503:physiopathology; D002531:Cerebellum / Q000187:drug effects* / Q000503:physiopathology; D013759:Dronabinol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D004347:Drug Interactions; D004361:Drug Tolerance; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D058785:GABA-A Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008845:Microinjections; D009118:Muscimol / Q000008:administration & dosage / Q000494:pharmacology; D058906:Purinergic P1 Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology; D043682:Receptor, Adenosine A1 / Q000187:drug effects / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*
chemical_list: D063386:Cannabinoid Receptor Agonists; D002492:Central Nervous System Depressants; D058785:GABA-A Receptor Agonists; D058906:Purinergic P1 Receptor Agonists; D043682:Receptor, Adenosine A1; D011963:Receptors, GABA-A; D009118:Muscimol; C003403:tetrahydrocannabivarin 9; C027513:N(6)-cyclohexyladenosine; D000431:Ethanol; D013759:Dronabinol; D000241:Adenosine
keywords: Cross-tolerance; Ethanol ataxia; Functional interaction; Intracerebellar infusion; Rotorod; Δ(9)-THC