Historical Overview: Introduction to the Dopamine Receptors

Abstract

A long-term search for the mechanism of action of antipsychotic drugs was motivated by a search for the cause of schizophrenia. The research between 1963 and 1975 led to the discovery of the antipsychotic receptor, now known as the dopamine D2 receptor, the target for all antipsychotic medications. There are now five known dopamine receptors, all cloned. Although no appropriate animal model or brain biomarker exists for schizophrenia, it is known that the many fac- tors and genes associated with schizophrenia invariably elevate the high-affinity state of the D2 receptor or D2High by 100–900% in animals, resulting in dopamine supersensitivity. These factors include brain lesions; sensitization by amphetamine, phencyclidine, cocaine, or corticosterone; birth injury; social isolation; and more than 15 gene deletions in the pathways for the neurotransmission mediated by recep- tors for glutamate (NMDA), dopamine, GABA, acetylcholine, and norepinephrine. The elevation of D2High receptors may be the unifying mechanism for the various causes of schizophrenia.