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 (D4.4R and D4.7R). 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 D4.7R 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 D4.4R and D4.7R 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 α2A receptor (α2AR)-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.

Humanized dopamine D4.7 receptor male mice display risk‐taking behavior and deficits of social recognition and working memory in light/dark‐dependent manner

“…This is aligned with the low reaction to the electric foot shock we found in the D 4.7 R mice. This was predicted from previous studies demonstrating that D 4.7 R provides a gain function of the effect of dopamine in inhibiting striatal glutamatergic neurotransmission (Bonaventura et al, 2017), which seems to involve differences in oligomerization with dopamine D2 receptors (D 2 R) and the properties of D 2 R-D 4.7 R heteromers (Ferré et al, 2022). of both the "Go" and "NoGo" GABAergic striatal efferent pathways, decreasing their respective ability to increase the reactivity to reward-related stimuli and to suppress the reactivity to non-rewarded-or aversive-related stimuli.…”

“…This is aligned with the low reaction to the electric foot shock we found in the D 4.7 R mice. This was predicted from previous studies demonstrating that D 4.7 R provides a gain of function of the effect of dopamine in inhibiting striatal glutamatergic neurotransmission (Bonaventura et al., 2017), which seems to involve differences in oligomerization with dopamine D2 receptors (D 2 R) and the properties of D 2 R–D 4.7 R heteromers (Ferré et al., 2022).…”

Presynaptic adenosine receptor heteromers as key modulators of glutamatergic and dopaminergic neurotransmission in the striatum

“…In a parallel study using the optogenetic-microdialysis technique in knock-in mice expressing a humanized D 4 R with an intracellular loop corresponding to a common polymorphic variant and their wild-type littermates, we could demonstrate that, in fact, presynaptic striatal D 4 Rs play a key role in the modulation of cortico-striatal transmission (Bonaventura et al, 2017). Furthermore, these D 4 Rs seem to heteromerize with D 2 Rs to a greater or lesser degree depending on the polymorphic variant of D 4 R (reviewed in Ferré et al, 2022b).…”

Pharmacology and Therapeutic Potential of Benzothiazole Analogues for Cocaine Use Disorder

“…D 1 -like (D 1 R, D 5 R) and D 2 -like (D 2 R, D 3 R, D 4 R) dopamine receptors are G protein-coupled receptors that regulate physiological functions such as movement, emotion, and cognition. 1,2 Compared to D 2 R and D 3 R, D 4 Rs have the lowest level of expression in the brain and are uniquely distributed primarily in the prefrontal cortex and hippocampus. In the prefrontal cortex, D 4 R plays important roles in cognition, attention, decision making, and executive function.…”

“…In the prefrontal cortex, D 4 R plays important roles in cognition, attention, decision making, and executive function. Common variations in the DRD4 gene are associated with novelty-seeking, risky behavior, attention-deficit hyperactivity disorder (ADHD) impulse control disorders, and substance use disorders (SUDs). − A better understanding of D 4 R-mediated signaling is essential to developing new pharmacotherapeutic treatments.…”