The current status of the dopamine hypothesis of schizophrenia

The dopamine hypothesis of schizophrenia is still almost entirely based on pharmacologic evidence. Even though a disturbed dopamine function has not yet been established beyond doubt in schizophrenia, recent basic research on dopaminergic mechanisms opens up possibilities for the development of more sophisticated pharmacologic tools, capable of discovering subtypes of dopamine receptors, which may turn out to be abnormal in schizophrenia. Such tools may also prove therapeutically useful. Schizophrenia is probably a heterogeneous group of disorders with mixed biopathology. To facilitate the search for nondopaminergic mechanisms of possible pathogenetic importance in subgroups of schizophrenia, a hypothetical model is presented that tries to explain the role of subcortical dopaminergic pathways for mental functions and their interaction with other systems. It is proposed that corticostriatothalamocortical negative feedback loops, also involving the mesencephalic reticular formation, are modulated by mesostriatal dopamine pathways to control a thalamic filter mechanism. The psychotomimetic actions of dopaminergic agents and phencyclidine may be due to interference with these feedback mechanisms.