Unraveling Dopamine D₃ Receptor Function in Response to Psychostimulants Using a Genetic Approach^a

The dopamine D₃ receptor is expressed mostly in the limbic regions of the brain that influence reward-related behaviors, including responses to psychostimulants. However, the lack of ligands with sufficient D₃ receptor specificity has hampered our understanding of its possible involvement in mediating psychostimulant actions. To unravel dopamine D₃ receptor function and underlying mechanisms in response to psychostimulants, we used a genetic approach and generated D₃ receptor gene mutant mice. Our analysis indicates that the D₃ mutant mice exhibit enhanced behavioral sensitivity to cocaine, amphetamine and combined injections of D₁- and D₂-class receptor agonists. By contrast, the combined electrophysiological effects of the same D₁- and D₂-class agonists on single neurons within the nucleus accumbens were not changed in the D₃ mutant mice. We propose that the D₃ receptor modulates responses to psychostimulants by inhibiting the cooperative effects of postsynaptic D₁- and other D₂-class receptors at systems level. The continuous use of the gene targeting approach will provide essential information regarding the molecular and cellular basis of psychostimulant actions and allow the development of new strategies in the prevention and cure of drug abuse.