Regulation of working memory by dopamine D4 receptor in rats

Working memory is regulated by neurotransmitters in prefrontal cortex (PFC), including dopamine and norepinephrine. Previous studies of dopamine function in working memory have focused on the D-1 and D-2 receptors, with most evidence suggesting a dominant role for the D-1 receptor. Since the dopamine D-4 receptor is highly expressed in PFC, we hypothesize that it may also contribute to working memory. To test this hypothesis, we examined behavioral effects of L-745,870, a highly selective, centrally active, D-4 antagonist, using a delayed alternation task in rats. Task performance was dose-dependently affected by the D-4 antagonist, depending on individual baseline functional status of working memory. In rats with good baseline performance, the D-4 antagonist had no effects at low doses, whereas high doses disrupted working memory. In rats with poor baseline working memory, the D-4 antagonist significantly improved working memory at low doses, and higher doses were not distinguishable from vehicle controls. Effects of the D-4 antagonist among poor performers were most robust when task demand for working memory was high, with lesser effects at lower demand level, suggesting that such effects were selective for working memory. The present findings indicate a significant role of the D-4 receptor in working memory, and suggest innovative, D-4-based, treatment of cognitive deficits associated with neuropsychiatric disorders.