The role of endogenous sensitization in the pathophysiology of schizophrenia: implications from recent brain imaging studies.

Long-term sensitization is a process whereby exposure to a given stimulus such as a drug or a stressor results in an enhanced response at subsequent exposures. Sensitization of mesolimbic dopamine systems has been postulated by several authors to underlie the development of dopaminergic abnormalities associated with schizophrenia. In this review, core features of stimulant-induced sensitization of dopamine systems in rodents are briefly reviewed, as well as the behavioral and clinical evidence suggesting the relevance of this process to drug-induced psychosis and schizophrenia. Results of recent brain imaging studies relevant to the question of sensitization in schizophrenia are then discussed. These studies indicate that schizophrenia is associated with increased amphetamine-induced dopamine release. This exaggerated response was detected in patients experiencing an episode of clinical deterioration but not in clinically stable patients. Since increased stimulant-induced dopamine release is a hallmark of sensitization, these results support the view that schizophrenia is associated with a process of endogenous sensitization. Based on the preclinical evidence that dopamine projection to the prefrontal cortex acts as a buffer that oppose the development of sensitization in subcortical dopamine projections, we propose that, in schizophrenia, neurodevelopmental abnormalities of prefrontal dopaminergic systems might result in a state of enhanced vulnerability to sensitization during late adolescence and early adulthood. It is also proposed that D(2) receptor blockade, if sustained, might allow for an extinction of this sensitization process, with possible re-emergence upon treatment discontinuation. A better understanding of the neurocircuitry associated with endogenous sensitization and its consequence in schizophrenia might be important for the development of better treatment and relapse prevention strategies.