INVOLVEMENT OF KAPPA-OPIOIDS IN THE MOUSE CEREBELLAR ADENOSINERGIC MODULATION OF ETHANOL-INDUCED MOTOR INCOORDINATION

Using rotorod performance as the test response, possible modulation an d co-modulation of ethanol-induced motor incoordination by the cerebel lar kappa-opioid and adenosine A(1) receptors was studied. A dose-rela ted accentuation of ethanol-induced motor incoordination was observed after direct cerebellar microinfusion of three kappa-opioid receptor a gonists: U-50488, U-62066, and bremazocine, On the contrary, significa nt and dose-related attenuation of ethanol's motor impairment was prod uced by intracerebellar nor-binaltorphimine, a kappa-opioid receptor a ntagonist. Furthermore, the accentuation by kappa-agonists was virtual ly abolished by kappa-antagonist nor-binaltorphimine. Therefore, the a ccentuation and attenuation by kappa-opioid receptor agonists/antagoni st, respectively, was through specific kappa-opioid receptors, Pretrea tment with the intracerebellar adenosine A(1)-selective agonist, N-6-c yclohexyladenosine, further enhanced the ethanol-induced motor incoord ination and its accentuation by intracerebellar kappa-opioid receptor agonists, Ethanol-induced motor incoordination was markedly attenuated by intracerebellar pertussis toxin (PTX) pretreatment, suggesting an involvement of PTX-sensitive G protein in the expression of motor inco ordinating effect of ethanol, Additionally, the intracerebellar PTX al so markedly attenuated the accentuation by kappa-opioid agonists of et hanol-induced motor impairment, suggesting participation of PTX-sensit ive GTP-binding G protein (G(i) G(o)) in the kappa-opioid modulation o f ethanol's motor impairment. It also confirms that kappa-opioid recep tors are linked to PTX-sensitive G protein. The functional similarity between kappa-opioid and adenosine A(1) receptors in increasing ethano l's motor incoordination, together with their anatomical co-localizati on primarily on the axons and axonal terminals of the cerebellar granu le cells, suggests a possible common catalytic unit of adenylate cycla se as the basis of modulation of ethanol-induced motor incoordination by both receptor mechanisms.