Functional and pharmacological role of the dopamine D₄ receptor and its polymorphic variants

The functional and pharmacological significance of the dopamine D₄ receptor (D₄R) has remained the least well understood of all the dopamine receptor subtypes. Even more enigmatic has been the role of the very prevalent human DRD4 gene polymorphisms in the region that encodes the third intracellular loop of the receptor. The most common polymorphisms encode a D₄R with 4 or 7 repeats of a proline-rich sequence of 16 amino acids (D_4.4R and D_4.7R). DRD4 polymorphisms have been associated with individual differences linked to impulse control-related neuropsychiatric disorders, with the most consistent associations established between the gene encoding D_4.7R and attention-deficit hyperactivity disorder (ADHD) and substance use disorders. The function of D₄R and its polymorphic variants is being revealed by addressing the role of receptor heteromerization and the relatively avidity of norepinephrine for D₄R. We review the evidence conveying a significant and differential role of D_4.4R and D_4.7R in the dopaminergic and noradrenergic modulation of the frontal cortico-striatal pyramidal neuron, with implications for the moderation of constructs of impulsivity as personality traits. This differential role depends on their ability to confer different properties to adrenergic α_2A receptor (α_2AR)-D₄R heteromers and dopamine D₂ receptor (D₂R)-D₄R heteromers, preferentially localized in the perisomatic region of the frontal cortical pyramidal neuron and its striatal terminals, respectively. We also review the evidence to support the D₄R as a therapeutic target for ADHD and other impulse-control disorders, as well as for restless legs syndrome.