Increased vulnerability to cocaine in mice lacking dopamine D3 receptors

Abstract

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 D(3)R 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 D(3)R deletion increases vulnerability to cocaine, and that reduced D(3)R availability in the brain may constitute a risk factor for the development of cocaine addiction.

Fig. 1.

Cocaine-taking and cocaine-seeking behavior in WT and D₃^−/− mice during acquisition and maintenance of cocaine self-administration and during extinction and reinstatement of drug-seeking behavior. (A and B) Active and inactive lever responding in each phase of the experiment. (C and D) Total number of cocaine infusions in daily test sessions and infusion rate during the acquisition phase of cocaine self-administration. *P < 0.05; **P < 0.01; ***P < 0.001 compared with WT control group. ^#P < 0.05 compared with last day of extinction.

Fig. 2.

Cocaine self-administration under different cocaine doses (A and B) and PR reinforcement conditions (C) in WT and D₃^−/− mice. *P < 0.05; **P < 0.01; ***P < 0.001 compared with WT.

Fig. 3.

Extracellular DA levels in the NAc before and after cocaine injection in WT and D₃^−/− mice. (A, C, and E) Extracellular DA concentrations (nM) before and after different doses of cocaine administration. (B, D, and F) NAc DA response to cocaine (expressed as percent of precocaine baseline). *P < 0.05; **P < 0.01; ***P < 0.001 compared with precocaine baseline. ^#P < 0.05; ^##P < 0.01; ^###P < 0.001 compared with WT mice.

Fig. 4.

D₃R deletion up-regulates DAT, but not TH, expression in the striatum. (A) Representative immunoblot showing molecular sizes and densities of DAT, TH, and β-actin in PFC, midbrain, and striatum of WT and D₃^−/− mice. (B) Mean densities (normalized first to β-actin and then to WT mice) of TH and DAT in these brain regions. (C and E) Representative DAT immunostaining in the VTA or striatum of WT and D₃^−/− mice. (D and F) Mean DAT densities in the VTA or striatum of WT and D₃^−/− mice. D. Striatum, dorsal striatum; V. Striatum, ventral striatum. (Scale bars: 100 μm in C; 250 μm in E). *P < 0.05; **P < 0.01 compared with WT mice.