The effect of the methylxanthines caffeine, theophylline and isobutylmethylxanthine (IBMX) on ethanol-induced ataxia and loss of righting reflex was investigated in three strains of mice. A significant potentiation of ethanol-induced ataxia was produced in all strains of mice at 20, 45 and 75 min after ethanol in mice pretreated with 62.5 mg/kg caffeine and 12.5 mg/kg IBMX. In mice pretreated with 40 mg/kg caffeine potentiation of ethanol-induced ataxia was observed only at 20 min after ethanol. Theophylline pretreatment produced no alteration in ethanol-induced ataxia. The results of methylxanthine pretreatment on ethanol-induced ataxia were similar, regardless of a shorter (10 min) or longer (75 min) pretreatment time. The methylxanthines produced no effect on motor coordination or behavior when administered separately. Although ethanol-induced loss of righting reflex was shortened by theophylline, neither caffeine nor IBMX altered the duration of loss of righting reflex. It is possible that inhibition of adenosine uptake, a known effect of the methylxanthines, may be a more likely explanation for the modulation of the behavioral effects of ethanol.

Many classes of CNS-acting drugs have been suggested to act at least partially via inhibition of adenosine uptake. Synaptosomal uptake of [3H]adenosine and the effect of acute ethanol on it were studied in a rat brain area known to be involved in the coordination and modulation of normal motor activity, the cerebellum. Uptake of [3H]adenosine was found to be linear with time (about 40 sec) and increasing concentrations (up to 1.5 microM) of adenosine. The uptake of [3H]adenosine was inhibited by dilazep (IC50 = 2.5 x 10(-7) M) in a dose-dependent manner. Pharmacologically and/or toxicologically relevant concentrations of ethanol (2.5 to 100 mM) significantly inhibited the uptake of [3H]adenosine between 12 and 15%. Lineweaver-Burk plots indicated that both in vitro (25 mM) and in vivo (1.5 g/kg i.p.; 30 mM blood level) ethanol lowered Km as well as Vmax values for adenosine uptake to nearly the same extent. In the case of in vivo ethanol, no ethanol was present during the assay since synaptosome preparation would wash out residual ethanol. The results of the present study indicate possible membranal alterations by in vivo ethanol. It is concluded that the uptake of [3H]adenosine is inhibited by intoxicating concentrations of ethanol in vitro and by acute ethanol (1.5 g/kg) in vivo. This may partially explain the modulatory role of endogenous adenosine in ethanol-induced motor disturbances.

Using rotorod performance as the test response, possible modulation and co-modulation of ethanol-induced motor incoordination by the cerebellar kappa-opioid and adenosine A1 receptors was studied. A dose-related accentuation of ethanol-induced motor incoordination was observed after direct cerebellar microinfusion of three kappa-opioid receptor agonists: U-50488, U-62066, and bremazocine. On the contrary, significant and dose-related attenuation of ethanol's motor impairment was produced by intracerebellar nor-binaltorphimine, a kappa-opioid receptor antagonist. Furthermore, the accentuation by kappa-agonists was virtually abolished by kappa-antagonist nor-binaltorphimine. Therefore, the accentuation and attenuation by kappa-opioid receptor agonists/antagonist, respectively, was through specific kappa-opioid receptors. Pretreatment with the intracerebellar adenosine A1-selective agonist, N6-cyclohexyladenosine, further enhanced the ethanol-induced motor incoordination and its accentuation by intracerebellar kappa-opioid receptor agonists. Ethanol-induced motor incoordination was markedly attenuated by intracerebellar pertussis toxin (PTX) pretreatment, suggesting an involvement of PTX-sensitive G protein in the expression of motor incoordinating effect of ethanol. Additionally, the intracerebellar PTX also markedly attenuated the accentuation by kappa-opioid agonists of ethanol-induced motor impairment, suggesting participation of PTX-sensitive GTP-binding G protein (Gi, Go) in the kappa-opioid modulation of ethanol's motor impairment. It also confirms that kappa-opioid receptors are linked to PTX-sensitive G protein. The functional similarity between kappa-opioid and adenosine A1 receptors in increasing ethanol's motor incoordination, together with their anatomical co-localization primarily on the axons and axonal terminals of the cerebellar granule cells, suggests a possible common catalytic unit of adenylate cyclase as the basis of modulation of ethanol-induced motor incoordination by both receptor mechanisms.

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