Sensitivity to Ketamine, Alone or in Combination with Ethanol, Is Altered in Mice Selectively Bred for Sensitivity to Ethanol's Locomotor Effects

Background: Sensitivity to erthanol's locomotor activating and reinforcing effects may be influenced by some common neural mechanisms. Mice selectively bred in replicate for increased (FAST-1 and FAST-2) and decreased (SLOW-1 and SLOW-2) sensitivity to ethanol's locomotor stimulant effects are useful for investigating the neural substrates of ethanol's effects. Previous studies have suggested that differences in N-methyl-D-aspartate (NMDA) receptors may underlie differences in ethanol-induced locomotion in these mice. This study examined the responses of FAST and SLOW mice to ketamine, a fast-acting NMDA antagonist. In addition, reverse-selected lines (r-FAST-1, r-FAST-2, r-SLOW-1, and r-SLOW-2) were tested as a means of verifying correlations detected in the forward-selected lines. Two initial studies characterized ketamine-induced locomotion in DBA/2J (D2) mice, an inbred strain chosen for its high sensitivity to ethanol-induced locomotion. Methods: After a 2- to 3-day period of habituation to test procedures, mice were given intraperitoneal injections of ketamine alone (0, 5, 10, 20, 30, and 60 mg/kg) or in combination with 1 or 2g/kg ethanol. Locomotor activity was measured for 20 to 30 min in automated activity monitors. Results: When administered alone, ketamine dose-dependently stimulated the locomotor activity of D2 mice and also reduced the amount of ethanol-induced stimulation. Ketamine stimulated locomotion more in FAST mice than in SLOW mice. Reverse selection abolished these differences, because r-FAST and r-SLOW mice did not differ in their responses to ketamine. Ketamine potentiated ethanol's locomotor effects within FAST mice and potentiated ethanol's locomotor depressant effect within one replicate of SLOW mice. Conclusions: We propose that sensitivities to ethanol- and ketamine-induced locomotion are genetically correlated and that the combined effects of ethanol and ketamine in FAST mice reflect a leftward shift in ethanol's biphasic dose-response curve.