Functional Interaction and Cross-Tolerance Between Ethanol and Δ9-THC: Possible Modulation by Mouse Cerebellar Adenosinergic A1/GABAergic-A Receptors.

We have previously shown a functional motor interaction between ethanol and Delta(9)-tetrahydrocannabinol (Delta(9)-THC) that involved cerebellar adenosinergic A(1) and GABAergic A receptor modulation. We now report the development of cross-tolerance between intracerebellar Delta(9)-THC and intraperitoneal ethanol using ataxia as the test response in male CD-1 mice. The drugs [Delta(9)-THC (20 mu g), 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. Delta(9)-THC, infused once daily for 5 days followed 16 h after the last infusion by acute ethanol (2 g/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 Delta(9)-THC treatment was reversed, i.e., ethanol injected once daily for 5 days followed 16 h after the last ethanol injection by Delta(9)-THC infusion. The cross-tolerance appeared within 24-48 h, lasted over 72 h and was maximal in 5-day ethanol/Delta(9)-THC-treated animals. Finally, tolerance in chronic ethanol/Delta(THC)-T-9/-treated animals developed not only to ethanol/Delta(9)-THC-induced ataxia, respectively, but also to the ataxia potentiating effect of CHA and muscimol, indicating modulation by cerebellar adenosinergic A(1) and GABA(A) 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. (C) 2014 Elsevier B.V. All rights reserved.