Functional and pharmacological role of the dopamine D(4) receptor and its polymorphic variants

The functional and pharmacological significance of the dopamine D(4) receptor (D(4)R) 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 D(4)R with 4 or 7 repeats of a proline-rich sequence of 16 amino acids (D(4.4)R and D(4.7)R). 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(4.7)R and attention-deficit hyperactivity disorder (ADHD) and substance use disorders. The function of D(4)R and its polymorphic variants is being revealed by addressing the role of receptor heteromerization and the relatively avidity of norepinephrine for D(4)R. We review the evidence conveying a significant and differential role of D(4.4)R and D(4.7)R 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(2A)R)-D(4)R heteromers and dopamine D(2) receptor (D(2)R)-D(4)R 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 D(4)R as a therapeutic target for ADHD and other impulse-control disorders, as well as for restless legs syndrome.