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 s uch as a drug or a stressor results in an enhanced response at subsequent e xposures. Sensitization of mesolimbic dopamine systems has been postulated by several authors to underlie the development of dopaminergic abnormalitie s 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 o f this process to drug-induced psychosis and schizophrenia. Results of rece nt brain imaging studies relevant to the question of sensitization in schiz ophrenia are then discussed. These studies indicate that schizophrenia is a ssociated with increased amphetamine-induced dopamine release. This exagger ated response was detected in patients experiencing an episode of clinical deterioration but not in clinically stable patients. Since increased stimul ant-induced dopamine release is a hallmark of sensitization, these results support the view that schizophrenia is associated with a process of endogen ous sensitization. Based on the preclinical evidence that dopamine projecti on to the prefrontal cortex acts as a buffer that oppose the development of sensitization in subcortical dopamine projections, we propose that, in sch izophrenia, neurodevelopmental abnormalities of prefrontal dopaminergic sys tems might result in a state of enhanced vulnerability to sensitization dur ing late adolescence and early adulthood. It is also proposed that D-2 rece ptor blockade, if sustained, might allow for an extinction of this sensitiz ation process, with possible re-emergence upon treatment discontinuation. A better understanding of the neurocircuitry associated with endogenous sens itization and its consequence in schizophrenia might be important for the d evelopment of better treatment and relapse prevention strategies. (C) 2000 Elsevier Science B.V. All rights reserved.