Molecular mechanisms underlying behavioral effects of cocaine: Lessons from knockout mice

Transgenic and gene knockout techniques are now important methods for the research of the molecular bases of drug action. This review examines the effect of gene knockouts on the behavioral consequences of cocaine administration, especially cocaine locomotor activation and rewarding/reinforcing actions. These studies document interacting effects of products of several genes in providing the primary sites for cocaine reward. They highlight the influences of different gene products expressed in different brain circuits on cocaine reward and cocaine-stimulated locomotion. These influences do not produce equivalent consequences for all behavioral effects of cocaine, allowing genetic dissociation of the mechanisms of the different sequelae of cocaine administration. The data also point to substantial compensatory changes in the brains of single- and multiple- gene knockout mice. Studies of gene knockouts from several neurotransmitter and cellular regulatory systems support a broad based approach to thinking about cocaine actions that supplements traditional neuropharmacological approaches.