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

Abstract

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 co-modulation by the cerebellar adenosine A 1 receptors was also observed because intracerebellar microinfusion of adenosine agonists N 6-cyclohexyladenosine (CHA), 5′-N-ethylcarboxamidoadenosine (NECA), and 2-p-(2-carboxyethyl)-phenyl-ethylamino-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 1 = 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.