Prefrontal Dopamine D₁Receptors and Working Memory in Schizophrenia

TLDR

Studies show that appropriate stimulation of dopamine D1 receptors in the dorsolateral prefrontal cortex is essential for working memory, and deficits in this system are linked to the working memory impairments observed in schizophrenia, possibly due to mesocortical dopamine dysfunction. The study quantified D1 receptor availability using PET with the selective antagonist [11C]NNC 112 in 16 schizophrenia patients (seven drug‑naïve, nine drug‑free) and 16 matched healthy controls. Patients exhibited significantly higher [11C]NNC 112 binding potential in the DLPFC, which strongly predicted poorer n‑back performance, indicating that altered D1 receptor transmission contributes to working memory deficits and may reflect an ineffective compensatory upregulation of receptor availability.

Abstract

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; <i>p</i> = 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.