THE DOPAMINE D-3 RECEPTOR AND SCHIZOPHRENIA - PHARMACOLOGICAL, ANATOMICAL AND GENETIC APPROACHES

Antipsychotic drug therapy mainly rests on the use of antagonists of d opamine D-2-like (D-2, D-3 and D-4) receptors, for which all clinicall y active compounds have high affinity. The D-3 receptor has a restrict ed expression in brain limbic areas, associated with cognitive functio ns and motivated behavior. D-3 selective agonists and antagonists reve al an inhibitory role on motor behaviors for the D-3 receptor, opposit e to that of the D-2 receptor. An opposing role for D-2 and D-3 recept ors is also suggested by the contrasted effects of D-2/D-3 antagonists on neurotensin expression in discrete subdivisions of nucleus accumbe ns, where D-2 and D-3 receptors are selectively expressed. Tolerance t o the motor but not to the therapeutic effects of neuroleptics is obse rved after repeated administration, which upregulates the D-2, but not the D-3 receptor in animals. In genetic association studies, an exces s of homozygosity for both alleles of the Ball polymorphism at the D-3 receptor gene was found in schizophrenic patients, suggesting that th is gene may have subtle influence on the liability to develop schizoph renia. These results suggest the D-3 receptor as an important target f or antipsychotic drug action, and D-3 receptor selective antagonists a s promising therapeutic agents.