Decreased prefrontal dopamine D1 receptors in schizophrenia revealed by PET

Schizophrenia is believed to involve altered activation of dopamine receptors, and support for this hypothesis comes from the antipsychotic effect of antagonists of the dopamine D2 receptor (D2R). D2R is expressed most highly in the striatum, but most of the recent positron emission tomography (PET) studies have failed to show any change in D2R densities in the striatum of schizophrenics, raising 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 the control of working memory, and working memory dysfunction is a prominent feature of schizophrenia. We have 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, binding of radioligand to D1R was reduced in the prefrontal cortex of schizophrenics. This reduction was related to the severity of the negative symptoms (for instance, emotional withdrawal) and to poor performance in the Wisconsin Card Sorting Test. We propose that dysfunction of D1R signalling in the prefrontal cortex may contribute to the negative symptoms and cognitive deficits seen in schizophrenia.