PET receptor studies on scgizophrenia and extrapyramidal side effects.

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Schizophrenia is believed to involve altered activation of dopamine receptors, and support for this hypothesis comes from the antipsychotic effect of dopamine D2 receptor (D2R) antagonists. D2R is expressed most highly in the striatum, but recent studies using positron emission topography (PET) have failed to show any change in D2R densities in the striatum of schizophrenics. This raises the possibility that other receptors may also be involved. In particular, the dopamine D1 receptor (D1R), which is highly expressed in the prefrontal cortex, has been implicated in control of working memory, and working memory dysfunction is a prominent feature of schizophrenia. We therefore used PET to examine the distribution of D1R and D2R in brains of drug-naive or drug-free schizophrenic patients. Although no differences were observed in the striatum relative to control subjects, D1R binding was reduced in the prefrontal cortex of schizophrenics. This reduction was related to the severity of negative symptoms (for instance emotional withdrawal), and to poor performance in the Wisconsin Card Sort Test (WCST). We propose that dysfunction of D1R signaling in the PFC may contribute to the negative symptoms and cognitive deficits seen in schizophrenia.