Ethanol- and cocaine-induced locomotion are genetically related to increases in accumbal dopamine.

Neuroanatomical research suggests that interactions between dopamine and glutamate within the mesolimbic dopamine system are involved in both drug-induced locomotor stimulation and addiction. Therefore, genetically determined differences in the locomotor responses to ethanol and cocaine may be related to differences in the effects of these drugs on this system. To test this, we measured drug-induced changes in dopamine and glutamate within the nucleus accumbens (NAcc), a major target of mesolimbic dopamine neurons, using in vivo microdialysis in selectively bred FAST and SLOW mouse lines, which were bred for extreme sensitivity (FAST) and insensitivity (SLOW) to the locomotor stimulant effects of ethanol. These mice also show a genetically correlated difference in stimulant response to cocaine (FAST > SLOW). Single injections of ethanol (2 g/kg) or cocaine (40 mg/kg) resulted in larger increases in dopamine within the NAcc in FAST compared with SLOW mice. There was no effect of either drug on NAcc glutamate levels. These experiments indicate that response of the mesolimbic dopamine system is genetically correlated with sensitivity to ethanol- and cocaine-induced locomotion. Because increased sensitivity to the stimulating effects of ethanol appears to be associated with greater risk for alcohol abuse, genetically determined differences in the mesolimbic dopamine response to ethanol may represent a critical underlying mechanism for increased genetic risk for alcoholism.