Prefronto-cortical dopamine D1 receptor sensitivity can critically influence working memory maintenance during delayed response tasks

The dopamine (DA) hypothesis of cognitive deficits suggests that too low or too high extracellular DA concentration in the prefrontal cortex (PFC) can severely impair the working memory (WM) maintenance during delay period. Thus, there exists only an optimal range of DA where the sustained-firing activity, the neural correlate of WM maintenance, in the cortex possesses optimal firing frequency as well as robustness against noisy distractions. Empirical evidences demonstrate changes even in the D1 receptor (D1R)-sensitivity to extracellular DA, collectively manifested through D1R density and DA-binding affinity, in the PFC under neuropsychiatric conditions such as ageing and schizophrenia. However, the impact of alterations in the cortical D1R-sensitivity on WM maintenance has yet remained poorly addressed. Using a quantitative neural mass model of the prefronto-mesoprefrontal system, the present study reveals that higher D1R-sensitivity may not only effectuate shrunk optimal DA range but also shift of the range to lower concentrations. Moreover, higher sensitivity may significantly reduce the WM-robustness even within the optimal DA range and exacerbates the decline at abnormal DA levels. These findings project important clinical implications, such as dosage precision and variability of DA-correcting drugs across patients, and failure in acquiring healthy WM maintenance even under drug-controlled normal cortical DA levels.