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 respon se. 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 ethano l-induced motor impairment. The baclofen and phaclofen exhibited accen tuation 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 mi croinfusion of adenosine agonists N-6-cyclohexyladenosine (CHA), 5'-N- ethylcarbox-amidoadenosine (NECA), and )-phenylethylamino-5'-N-ethylca rbox-amidoadenosine (CGS-21680), and antagonist, 8-cyclopentyl-1,3-dip ropylxanthine (DPCPX), also accentuated and attenuated, respectively, ethanol-induced motor impairment. The accentuation of ethanol-induced motor impairment by baclofen was further enhanced after the intracereb ellar microinfusion of CHA, suggesting a co-modulation by the co-local ized adenosine A(1) receptors. A similar response was observed after t he intracerebellar microinfusion of adenosine A( )= A(2) agonist NECA and the several-fold higher dose of adenosine A(2)-selective agonist C GS-21680. Ethanol-induced motor impairment was markedly blocked by int racerebellar A(1)-selective antagonist, DPCPX, as well as by the intra cerebellar pertussis toxin pretreatment suggesting again a co-modulati on by the adenosine A(1) receptors and the involvement of pertussis to xin-sensitive G protein, respectively. The almost 25-fold higher dose of CGS-21680 to accentuate and DPCPX to attenuate, respectively, ethan ol-induced motor impairment together with the reported cerebellar loca lization of adenosine A(1) subtype only, suggested A(1) receptor activ ation by NECA and CGS-21680. The functional similarity between GABA(B) and adenosine A(1), receptors associated with their anatomical co-loc alization on the cerebellar granule cells, mainly axons and axonal ter minals, may suggest a possible common adenylate cyclase catalytic unit as the basis of modulation of ethanol's motor impairment by these two receptor mechanisms.