Probing cortical dopamine function in schizophrenia: what can D1 receptors tell us?

Schizophrenia is characterized by positive symptoms, negative symptoms and cognitive impairment. Positive symptoms may be related to excessive dopamine (DA) function, as suggested by the common antidopaminergic properties of antipsychotic medications, which are most effective at treating positive symptoms. Negative symptoms and impairment in higher cognitive functions are thought to be related to a dysfunction of the dorsolateral prefrontal cortex (DLPFC), possibly related to inappropriate stimulation of D1 receptors. In the last few years we have clearly demonstrated excess subcortical DA transmission and now have indirect evidence for cortical dopamine deficit. We studied 16 drug free patients with schizophrenia (7 drug naïve and 9 previously treated) and 16 matched controls, using positron emission tomography (PET) and [(11)C]NNC 112, a novel radiotracer for PET imaging of the D1 receptor, and the n-back task, a test of working memory. We observed a significant upregulation in D1 binding in the DLPFC in patients with schizophrenia compared to controls. This increase was present in both drug naïve and previously treated patients and was regionally selective. Furthermore, the increase was correlated with poor performance on the n-back task (r(2)=0.45, p=0.004). This upregulation of D1 receptors might be secondary to a sustained deficit in prefrontal DA function, as postmortem studies revealed deficits in DA innervation in the prefrontal cortex in schizophrenia.