Dopamine receptor signaling and current and future antipsychotic drugs

All currently efficacious antipsychotic drugs have as part of their mechanism the ability to attenuate some or all of the signaling through the dopamine D₂ receptor. More recently, the dopamine D₁ receptor has been hypothesized to be a promising target for the treatment of negative and/or cognitive aspects of schizophrenia that are not improved by current antipsychotics. Although cAMP has been presumed to be the primary messenger for signaling through the dopamine receptors, the last decade has unveiled a complexity that has provided exciting avenues for the future discovery of antipsychotic drugs (APDs). We review the signaling mechanisms of currently approved APDs at dopamine D₂ receptors, and note that aripiprazole is a compound that is clearly differentiated from other approved drugs. Although aripiprazole has been postulated to cause dopamine stabilization due to its partial D₂ agonist properties, a body of literature suggests that an alternative mechanism, functional selectivity, is of primary importance. Finally, we review the signaling at dopamine D₁ receptors, and the idea that drugs that activate D₁ receptors may have use as APDs for improving negative and cognitive symptoms. We address the current state of drug discovery in the D₁ area and its relationship to novel signaling mechanisms. Our conclusion is that although the first APD targeting dopamine receptors was discovered more than a half-century ago, recent research advances offer the possibility that novel and/or improved drugs will emerge in the next decade.