Increased vulnerability to cocaine in mice lacking dopamine D3 receptors

Neuroimaging studies using positron emission tomography suggest that reduced dopamine D-2 receptor availability in the neostriatum is associated with increased vulnerability to drug addiction in humans and experimental animals. The role of D-3 receptors (D(3)Rs) in the neurobiology of addiction remains unclear, however. Here we report that D3R KO (D-3(-/-)) mice display enhanced cocaine self-administration and enhanced motivation for cocaine-taking and cocaine-seeking behavior. This increased vulnerability to cocaine is accompanied by decreased dopamine response to cocaine secondary to increased basal levels of extracellular dopamine in the nucleus accumbens, suggesting a compensatory response to decreased cocaine reward in D-3(-/-) mice. In addition, D-3(-/-) mice also display up-regulation of dopamine transporters in the striatum, suggesting a neuroadaptative attempt to normalize elevated basal extracellular dopamine. These findings suggest that D3R deletion increases vulnerability to cocaine, and that reduced D3R availability in the brainmay constitute a risk factor for the development of cocaine addiction.