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

Abstract

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.

Keywords: attention-deficit hyperactivity disorder; dopamine D4 receptor; impulsivity; polymorphic variants; restless legs syndrome.

Figure 1

Schematic representation of cortico-striatal glutamatergic terminals and their modulatory D_4.4Rs (left terminal) and D_4.7Rs (right terminal), which form heteromers with D₂Rs. Heteromerization of D₂R with D_4.7R promotes a gain of function of the dopaminergic-mediated inhibition of glutamate (GLU) release, as compared with heteromerization with D_4.4R, since it increases the potency for dopamine (DA) and the constitutive activity of the D₂R. In addition, the population of D_4.7Rs not forming heteromers with D₂Rs is larger than with D_4.4Rs, which increases the potency of DA to inhibit GLU release, because of the higher affinity of DA for D4Rs versus D2Rs. The scheme is based on results obtained from experiments in mammalian transfected cells and from in vitro and in vivo experiments in rodents (see text).

Figure 2

Schematic representation of the perisomatic region of frontal cortical P neurons and their modulatory D_4.4Rs (left neuron) and D_4.7Rs (right neuron), which form heteromers with α_2ARs. Heteromerization of α_2AR with D_4.7R promotes a gain of function of the noradrenergic-mediated inhibition of neuronal excitability, as compared with heteromerization with D_4.4R, since it increases the potency of norepinephrine (NE). In addition, high concentrations of NE promote a decrease in the potency of NE in the α_2AR-D_4.4R but not in the α_2AR-D_4.7R heteromer (see text). Furthermore, the population of D_4.7Rs not forming heteromers with α_2AR is larger than with D_4.4Rs, which also increases the population of α_2AR not forming heteromers and therefore the potency of NE to decrease neuronal excitability. The increased proportion of D_4.7Rs not forming heteromers additionally increases the ability of DA to decrease neuronal excitability. The scheme is based on results obtained from experiments in mammalian transfected cells and from in vitro experiments in rodents (see text).

Figure 3

Scheme of personality traits as endophenotypes of SUD, with their linkage to specific brain circuits and genes. Positive emotionality/extroversion (PEM/E) is modulated by the central dopaminergic (DA) system and is moderated by the D₂R gene. Negative emotionality/neuroticism (NEM/N) is modulated by a circuit that involves the right anterior cingulate cortex (rACC), ventromedial prefrontal cortex (vmPFC) and the amygdala and is moderated by the gene of the serotonin transporter (5-HTT). Action impulsivity (AI) is modulated by a circuit that includes the pre-supplementary motor area (preSMA), the right inferior frontal gyrus (rIFG), the striatum and the subthalamic nucleus (STN). Choice impulsivity (CI) is modulated by a circuit that includes the ventromedial prefrontal cortex (vmPFC), the posterior cingular cortex (pCC) and the nucleus accumbens (NAc). AI and CI are moderated by the genes of the dopamine transported (DAT) and the enzyme cathecol-O-methyltransferase (COMT), respectively. In addition, AI and CI are both moderated by the genes of D₄R and α_2AR. “+” and “-” indicate that individuals with low PEM, high NEM, high AI and high CI are most vulnerable (least resilient) to develop SUD [modified from ref (71)].