Co-modulation of acute ethanol-induced motor impairment by mouse cerebellar adenosinergic A 1 and GABA A receptor systems

Abstract

We have previously demonstrated that cerebellar adenosine modulates ethanol ataxia. Using Rotorod method, we investigated the role of cerebellar GABA A receptors in the adenosinergic modulation of ethanol ataxia in mice. Direct cerebellar microinfusion of GABA A agonist, muscimol (2.5, 5 and 10 ng) and antagonist, bicuculline (50, 100 and 200 ng), via permanently implanted guide cannulas, produced a marked and dose-dependent accentuation and attenuation, respectively, of ethanol (2 g/kg; IP) ataxia. The accentuation of ethanol ataxia by intracerebellar muscimol was through GABA A receptor because intracerebellar pretreatment with bicuculline virtually abolished muscimol effect. Intracerebellar microinfusion of adenosine A 1 agonist, N 6-cyclohexyladenosine (CHA: 4 ng), and antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX: 100 ng) markedly accentuated and attenuated, respectively, ethanol ataxia consistent with our previously published data. Intracerebellar microinfusion of CHA (4 ng) or DPCPX (100 ng) markedly enhanced and reduced, respectively, muscimol (10 ng)-induced accentuation of ethanol ataxia suggesting co-modulation of ethanol ataxia by cerebellar adenosinergic A 1 and GABA A receptors. Similarly, intracerebellar bicuculline (200 ng) pretreatment not only prevented CHA-induced accentuation of ethanol ataxia, but caused further decrease in ethanol ataxia. No change in the normal coordination was observed when microinfusion of the highest dose of muscimol, bicuculline, DPCPX or CHA alone or in combination was followed by saline injection instead of ethanol. The results of the present study suggest a functional similarity between GABA A and adenosine A 1 receptors even though both receptor types are known to couple to different signaling system and their location is on the opposite ends of the cerebellar granule cells, axons and axonal terminals (i.e., GABA A at the granule cells and adenosine A 1 on axons and axonal terminals of the granule cells) and act as co-modulators of ethanol ataxia.