Prefrontal Dopamine D₁ Receptors and Working Memory in Schizophrenia

Studies in nonhuman primates documented that appropriate stimulation of dopamine (DA) D₁ receptors in the dorsolateral prefrontal cortex (DLPFC) is critical for working memory processing. The defective ability of patients with schizophrenia at working memory tasks is a core feature of this illness. It has been postulated that this impairment relates to a deficiency in mesocortical DA function. In this study, D₁ receptor availability was measured with positron emission tomography and the selective D₁ receptor antagonist [¹¹C]NNC 112 in 16 patients with schizophrenia (seven drug-naive and nine drug-free patients) and 16 matched healthy controls. [¹¹C]NNC 112 binding potential (BP) was significantly elevated in the DLPFC of patients with schizophrenia (1.63 ± 0.39 ml/gm) compared with control subjects (1.27 ± 0.44 ml/gm; p = 0.02). In patients with schizophrenia, increased DLPFC [¹¹C]NNC 112 BP was a strong predictor of poor performance at the n-back task, a test of working memory. These findings confirm that alteration of DLPFC D₁ receptor transmission is involved in working memory deficits presented by patients with schizophrenia. Increased D₁ receptor availability observed in patients with schizophrenia might represent a compensatory (but ineffective) upregulation secondary to sustained deficiency in mesocortical DA function.