Monoaminergic synapses and schizophrenia: 45 years of neuroleptics

In 1952 Delay and Deniker introduced the first antipsychotic, chlorpromazine, into the treatment of mental patients. They subsequently defined the word 'neuroleptic' to describe drugs as different as reserpine and chlorpromazine which seemed to have similar effects on the mental life of patients. In the 1960s the hypothesis was developed, mainly due to Carlsson, that the principal mode of action of neuroleptics was to interfere with synaptic transmission mediated by dopamine (DA) in the brain. This concept was given substantial credence with the discovery by Seeman and Snyder in the 1970s that many of the neuroleptics acted as DA receptor blockers. Subsequently two different classes of DA receptor were defined on the basis of their coupling to adenylate cyclase by Kebabian. In the 1980s molecular biology led to the cloning of five different DA receptors, and at the end of this period vanTol and his colleagues cloned the D4 DA receptor, which has been of considerable interest in the 1990s as it is greatly elevated in the brains of schizophrenics. This historical review ends with a consideration of the possibility that in addition to DA receptors, serotonin and perhaps other transmitter receptors are involved in the aetiology of schizophrenia.