Enhancement of the behavioral toxicity induced by combined administration of ethanol with methylxanthines: evaluation by discrete avoidance in mice.

Ethanol, at 1.6 and 3.2 g/kg p.o., disrupted the discrete lever-press and shuttle avoidances in mice, eliciting decrease in the avoidance rate. The response rate was increased by 3.2 g/kg of ethanol in the shuttle avoidance. The single p.o. administration of caffeine 3-30 mg/kg, theophylline 3-100 mg/kg, or theobromine 3-100 mg/kg produced no significant change in both response rate and the avoidance rate in the lever-press avoidance. In the shuttle avoidance, up to 3 mg/kg of caffeine, and 10 and 30 mg/kg of theophylline or theobromine significantly increased the response rate, though there was no significant change in the avoidance rate at any doses of these methylxanthines. Intermediate doses of methylxanthines ameliorated the ethanol (1.6 g/kg)-induced decrease in the avoidance rate with an increase in the response rate, indicating non-specific amelioration of the avoidance rate. The ethanol (3.2 g/kg)-induced decrease in the avoidance rate was enhanced by methylxanthines in a dose-dependent manner. However, in the shuttle avoidance, the response rate was sometimes increased by the combined administration of methylxanthines and ethanol. The present result suggest that, although ethanol and methylxanthines possess CNS depressant and stimulant actions, respectively, methylxanthines do not specifically ameliorate, but rather may worsen, the ethanol-induced avoidance disruption, indicating an enhancement of the behavioral toxicity.