Habituation to test procedure modulates the involvement of dopamine D2-but not D1-receptors in ethanol-induced locomotor stimulation in mice

Rationale: Novelty associated with behavioral testing has been shown to enhance psychostimulant- and morphine-induced locomotor stimulation. Evidence has demonstrated that novelty increases dopamine (DA) activity, and habituation to a novel environment reduces such activation. However, it is not clear whether novelty modulates ethanol-induced behavioral stimulation and whether DA plays a role in this effect. Objectives: The present work sought to demonstrate a role of habituation to test procedure as a factor that could modulate the involvement of DA in ethanol-induced locomotor stimulation. Methods: Non-habituated (NH) and habituated (H) Swiss mice pretreated with DA D1- (SCH23390; 0-0.045 mg/kg) or D2-receptor (sulpiride; 0-50 mg/kg) antagonists were tested for ethanol (0-2.5 g/kg)-induced locomotor stimulation. Experiments with amphetamine (0-4 mg/kg), morphine (0-5 mg/kg) and caffeine (0-15 mg/kg) were designed to compare their results to those obtained with ethanol. The effect of the non-selective opioid receptor antagonist naltrexone (0-1.5 mg/kg) was also tested on ethanol-induced locomotor stimulation. Results: NH and H animals did not differ in their locomotor response to ethanol or caffeine; however, amphetamine- and morphine-induced stimulation was greater in NH than in H mice. SCH23390 only reduced ethanol-induced stimulation at doses that also reduced spontaneous activity in both NH and H mice. Sulpiride decreased ethanol-stimulated behavior only in the NH condition. Habituation did not modify the effect of sulpiride on amphetamine-, morphine- or caffeine-induced activation. Naltrexone reduced ethanol-induced stimulation regardless of habituation. Conclusions: The present data suggest that the participation of DA D2-receptors in ethanol-induced behavioral stimulation requires the presence of novelty. Results also support the involvement of neurotransmitter systems other than DA (i.e., endogenous opioid system) as important substrates mediating ethanol-induced locomotor activation.