Substitution profiles of N-methyl-d-aspartate antagonists in ethanol-discriminating inbred mice

Abstract 

C57BL/6J (B6) and DBA/2J (D2) inbred mice show pronounced differences in ethanol-induced behaviors, such as loss of righting reflex and locomotor activation, among others. They also differ in measures of conditioned place preference and oral self-administration of ethanol. In the current study, I examined whether B6 and D2 mice differed in their expression of the N-methyl-d-aspartate (NMDA) receptor–mediated component of the discriminative stimulus effects of ethanol. B6 and D2 mice were trained to discriminate ethanol (1.5 g/kg, i.p.) from saline in a two-choice, milk-reinforced operant procedure. After training was completed, substitution and response rate dose-effect curves were generated for ethanol; the uncompetitive NMDA antagonists phencyclidine and ketamine; and the competitive NMDA antagonist d-CPPene. Dose-effect curves were also generated for midazolam, cocaine, m-chlorophenylpiperazine (mCPP), morphine, and gamma-hydroxybutyric acid (GHB). B6 and D2 mice learned the ethanol-versus-saline discrimination. Phencyclidine produced near full substitution for ethanol in both strains, whereas ketamine fully substituted for ethanol only in B6 mice. d-CPPene partially substituted for ethanol in both strains. Moderate doses of phencyclidine produced greater response rate–increasing effects in B6 mice than in D2 mice, and high doses of phencyclidine were more potent for suppressing response rates in D2 mice. In contrast, d-CPPene had similar response rate–increasing effects in both strains, but high doses produced more potent response rate–decreasing effects in B6 mice. Among the other drugs tested, only midazolam produced substantial substitution for ethanol. Taken together, these findings seem to indicate that the behavioral effects of NMDA antagonists differ between strains, but that the NMDA-mediated component of the discriminative stimulus effects of ethanol is similar in B6 and D2 mice.

Keywords: Ethanol, Drug discrimination, Operant, NMDA, C57BL/6J, DBA/2J, Mice