Sensitivity to the hypnotic action of ethanol has been found to increase in SS/Ibg (SS) but not in LS/Ibg (LS) mice after intracerebroventricular (icv) administration of calcium. In the present investigation, a correlation was found between calcium-induced changes in behavioral sensitivity and in the sensitivity of cerebellar Purkinje neurons to the depressant effects of locally applied ethanol. Cerebellar Purkinje neuron sensitivity was measured as the dose of ethanol pressure ejected from a multibarreled micropipette required to produce a 50% depression of spontaneous firing rate of single neurons. Administration of 0.2-0.4 mumol calcium chloride into the lateral ventricle of the brain increased the sensitivity of SS but not LS mice to the hypnotic behavioral effect of systemically administered ethanol. Similarly, Purkinje neuron sensitivity to locally applied ethanol was also enhanced in SS but not in LS mice 15 min following administration of calcium (0.25 mumol) icv. Furthermore, locally applied ethanol was more effective in depressing spontaneous Purkinje neuron discharge in SS mice when a 1 mM calcium solution was concomitantly pressure ejected with ethanol from the micropipette. Magnesium chloride did not mimic the effects of calcium on either behavioral or electrophysiological effects of ethanol, suggesting that the action of calcium is not a nonspecific effect of divalent cations. These data suggest that calcium-dependent processes may be involved in behavioral and electrophysiological effects associated with ethanol intoxication. Further research will be required to determine if the genetically selected difference in ethanol sensitivity expressed in LS and SS mice is regulated by calcium mechanisms.