Unraveling Dopamine D Receptor Function in Response to Psychostimulants Using a Genetic Approach.

The dopamine D 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 D receptor specificity has hampered our understanding of its possible involvement in mediating psychostimulant actions. To unravel dopamine D receptor function and underlying mechanisms in response to psychostimulants, we used a genetic approach and generated D receptor gene mutant mice. Our analysis indicates that the D mutant mice exhibit enhanced behavioral sensitivity to cocaine, amphetamine and combined injections of D- and D-class receptor agonists. By contrast, the combined electrophysiological effects of the same D- and D-class agonists on single neurons within the nucleus accumbens were not changed in the D mutant mice. We propose that the D receptor modulates responses to psychostimulants by inhibiting the cooperative effects of postsynaptic D- and other D-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.