Dopaminergic sensitization: implications for the pathogenesis of schizophrenia.

1. Which transmitters are primarily or secondarily involved in the pathogenesis of schizophrenia has been extensively studied during the last years. This review concentrates on the two systems, that most constantly have been found dysfunctioning in patients; that are the dopaminergic and glutamatergic systems. 2. Numerous neuropathological defects have been found in schizophrenia, but it is as yet unknown which changes are causative and which reflect maladaptive reactions. 3. All findings, however, involve the cortico-striato-thalamo-cortical circuits, which are central for attention and information processing. 4. The article focuses on the consequence of transmitter dysfunction for perception and for the ability of the individual to adapt to a constantly changing environment. Both clinical and experimental studies point to a primary/early cortical defect involving the glutamatergic system, and to a later developed intermittent hyperactivity of the dopaminergic system superimposed on a basal hypodopaminergic state. 5. The authors have previously demonstrated, how it is possible to potentiate mesolimbic dopaminergic activity by intermittent electrical stimulations of the cells in the ventral tegmental area, and that influence on the central mesolimbic dopamine cells is essential for the strengthened neuroplastic response. A changed neuroplastic response to environmental stimulation due to dopaminergic sensitization can explain how an episodic, subcortical hyperactivity can act on a basic glutamatergic and dopaminergic hypofunction to produce psychotic symptoms. Based on our own and others clinical and experimental findings, the "filter" hypothesis for schizophrenia and the state-dependence of schizophrenic symptoms, the authors present a hypothesis for spontaneous mesolimbic dopaminergic sensitization and progressive evolution of psychosis.