Mouse cerebellar GABA(B) participation in the expression of acute ethanol-induced ataxia and in its modulation by the cerebellar adenosinergic A(1) system

The possible modulation and of co-modulation by the cerebellar GABA(B) and adenosine A(1) receptors of ethanol-induced motor impairment were investigated in the mice using rotorod performance as the test response. Direct cerebellar microinfusion of GABA(B) agonist, baclofen, and antagonist, phaclofen, into the permanently cannulated mice, produced a dose-dependent accentuation and attenuation, respectively, of ethanol-induced motor impairment. The baclofen and phaclofen exhibited accentuation and attenuation, respectively, via GABA(B) receptors linked to pertussis toxin-sensitive G protein. A comodulation by the cerebellar adenosine A(1) receptors was also observed because intracerebellar microinfusion of adenosine agonists N-6-cyclohexyladenosine (CHA), 5'-N-ethylcarbox-amidoadenosine (NECA), and 2-p-(2-carboxyethyl)-phenylethylamino-5'-N-ethylcarbox-amidoadenosine (CGS-21680), and antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), also accentuated and attenuated, respectively, ethanol-induced motor impairment. The accentuation of ethanol-induced motor impairment by baclofen was further enhanced after the intracerebellar microinfusion of CHA, suggesting a co-modulation by the co-localized adenosine A(1) receptors. A similar response was observed after the intracerebellar microinfusion of adenosine A( )= A(2) agonist NECA and the several-fold higher dose of adenosine A(2)-selective agonist CGS-21680. Ethanol-induced motor impairment was markedly blocked by intracerebellar A(1)-selective antagonist, DPCPX, as well as by the intracerebellar pertussis toxin pretreatment suggesting again a co-modulation by the adenosine A(1) receptors and the involvement of pertussis toxin-sensitive G protein, respectively. The almost 25-fold higher dose of CGS-21680 to accentuate and DPCPX to attenuate, respectively, ethanol-induced motor impairment together with the reported cerebellar localization of adenosine A(1) subtype only, suggested A(1) receptor activation by NECA and CGS-21680. The functional similarity between GABA(B) and adenosine A(1), receptors associated with their anatomical co-localization on the cerebellar granule cells, mainly axons and axonal terminals, may suggest a possible common adenylate cyclase catalytic unit as the basis of modulation of ethanol's motor impairment by these two receptor mechanisms.