Effects of ethanol and NMDA antagonists on operant behavior in ethanol withdrawal seizure-prone and-resistant mice

The acute effects of ethanol (EtOH) on fixed-ratio performance were studied in separate lines of mice selectively bred for differences in severity of handling-induced convulsions following withdrawal from EtOH. Because modulation of N methyl-D-aspartate (NMDA) receptors has been implicated in production of the acute and withdrawal-induced effects of EtOH, we also tested NMDA and three NMDA antagonists. Withdrawal seizure-resistant (WSR2) mice were more sensitive to the response rate-decreasing effects of EtOH than were withdrawal seizure-prone (WSP2) mice. Similar to EtOH, NPC 12626 (a competitive NMDA antagonist) and phencyclidine (a non-competitive NMDA antagonist) decreased responding in WSR2 mice at doses that did not affect responding in WSP2 mice. Although a second non-competitive NMDA antagonist, dizocilpine, produced line differences in the same direction as did PCP, these differences were not statistically significant. In contrast, NMDA produced nearly equipotent dose-dependent response rate decreases in both lines. Combined with the results of previous in vitro studies which showed that the number of NMDA receptors in the hippocampi of WSR2 and WSP2 mice differ, the results of the present study suggest that the interaction of EtOH with NMDA receptors may contribute to differences in the acute effects of ethanol on schedule-controlled behavior in WSP2 and WSR2 mice.