Targeting the dopamine D2 receptor in schizophrenia.

After a 12-year search for the antipsychotic receptor, the binding site was discovered and labelled by [3H]haloperidol in 1975. Of the various neurotransmitters, dopamine was the most potent in inhibiting the binding of [3H]haloperidol, indicating that the antipsychotic receptor was a dopamine receptor, now named the dopamine D2 receptor, a major targeting site in schizophrenia. All antipsychotic drugs, including traditional and newer antipsychotics, either bind to D2 in direct relation to their clinical potencies or hinder normal dopamine neurotransmission, as in the case of partial dopamine agonists. In fact, the antipsychotic concentrations found in the plasma water of treated patients closely match the predicted therapeutic absolute concentrations, adjusted for the 60-75% D2 occupancy needed for clinical efficacy. Antipsychotics that elicit low or no Parkinsonism or prolactinaemia are loosely attached to D2 and rapidly dissociate from D2, whereas those eliciting Parkinsonism stay tightly attached to D2 for many hours. Because animal models of psychosis (amfetamine sensitisation, brain lesions) all show a marked elevation in the number of high-affinity states of D2, the antipsychotics are thought to specifically target these D2High states in psychosis in general and schizophrenia in particular.