Selective Dopamine D4 Receptor Agonists for the Treatment of Working Memory Deficits

Dopamine is a critical regulator of working memory, a mechanism for short-term information storage. Deficits in working memory occur in diseases with dopamine imbalance such as ADHD, schizophrenia and Parkinson’s Disease. However, a targeted treatment for working memory deficits is not available. In rodent models with working memory deficits, we show that selective activation of the dopamine D4 receptor (D4R) improves working memory. Based on these findings we propose that drugs that selectively activate the D4 receptor are novel class drugs for the treatment for working memory deficits.

D4R is found in abundance in the frontal cortex and hippocampus, brain regions that regulate working memory function. We examined two rodent models with working memory deficits, a prenatal nicotine exposure mouse model and the spontaneously hypertensive rat model. In both the models, activity and expression of the D4R are significantly decreased in the frontal cortex. Although dopamine D2 receptors expression and activity are also decreased in the frontal cortex of these models, improvements in working memory produced by psycho-stimulant administration were accompanied by increases in the activity of only the D4R and not the D2 receptor. Therefore, it can be concluded that selective increase in frontal cortical D4R activity is associated with improvement of deficient working memory.

Dopaminergic drugs that activate or antagonize multiple dopaminergic receptors or that produce global increases in brain dopamine content have failed as effective treatments for working memory deficits because of their pleotropic actions. Our discovery suggests that drugs that selectively target the D4 receptor and improve its function are effective treatments for working memory deficits.