INTRASTRIATAL RO15-4513 FUNCTIONALLY ANTAGONIZES ETHANOL-INDUCED MOTOR INCOORDINATION AND STRIATAL ADENOSINERGIC MODULATION OF ETHANOL-INDUCED MOTOR INCOORDINATION IN RATS

To study the role of the striatum in modulating the effects of adenosine agonists and benzodiazepine inverse agonists on acute ethanol-induced motor impairment, we evaluated the effect of direct intrastriatal Ro15-4513 [0.625, 1.25 and 2.5 ng], a partial inverse agonist of benzodiazepine receptor, on ethanol-induced motor incoordination. A significant and nearly dose-dependent antagonism by Ro15-4513 was observed, which suggests involvement of the striatum in ethanol-induced motor incoordination. No effect of IST Ro15-4513 on motor incoordination induced by Na-pentobarbital (10 mg/kg, i.p.) was noted, indicating the selectivity of the antiethanol action of Ro15-4513. The IST adenosine agonist N-6-cyclohexyladenosine (CHA) markedly accentuated ethanol-induced motor incoordination in a dose-related manner, suggesting a striatal adenosinergic modulation of ethanol-induced motor incoordination. The IST Ro15-4513 also significantly antagonized the accentuating effects of CHA on ethanol-induced motor incoordination. No change in normal motor coordination was observed after IST CHA or Ro15-4513 when followed by saline administration instead of ethanol. No accentuating effect by intrahippocampal CHA on ethanol-induced motor incoordination was seen, which suggests the selectivity of striatal adenosinergic modulation of ethanol-induced motor incoordination. There was no significant radioactivity present in the systemic circulation, in the CSF or in brain areas other than striatum after intrastriatal [H-3]Ro15-4513 or [H-3]CHA and ethanol injection. Data obtained so far support the involvement of striatum in ethanol's ataxia as well as striatal adenosinergic modulation of the central effect(s) of ethanol, possibly through Ro15-4513-sensitive mechanism(s).