Recent evidence for dopamine abnormalities in schizophrenia.

Neuroreceptor imaging has been used to examine dopamine function in schizophrenia. The evidence from PET and SPECT studies suggests that there is excess dopamine release subcortically, in the striatum, and that dopaminergic transmission may be abnormal in the cortex also, because of an upregulation in D1 receptors. We have found that patients with schizophrenia have higher subcortical levels of intrasynaptic dopamine (and have a greater proportion of D2 receptors occupied by dopamine) at baseline than controls. Those patients who had the highest levels of dopamine were the ones whose positive symptoms responded best to six weeks of treatment with an antipsychotic. Recent studies have also produced new evidence of dopaminergic disturbance in the cortex. When controls were compared with patients with schizophrenia, we found a significant increase in D1 receptors in patients, but only in the dorsolateral prefrontal cortex. Patients were also studied while they undertook a test of working memory. While there was no relationship between test performance and D1 binding potential for controls, those patients with the highest densities (most pathological levels) of D1 receptors performed the worst on the test. Both the D1 upregulation and the poor working memory may be secondary to a chronic, possibly neurodevelopmental deficit in dopamine innervation of the dorsolateral prefrontal cortex in schizophrenia. The D1 binding potential may prove to be a good biomarker with which to identify those patients suffering from schizophrenia who are most likely to benefit from treatment with a D1 agonist. A D1 receptor radiotracer that is sensitive to endogenous dopamine competition would be very valuable in the further exploration of this area.