Dopamine receptor D4

The dopamine receptor D₄ is a G protein-coupled receptor encoded by the DRD4 gene.

As with other dopamine receptor subtypes, the D₄ receptor is activated by the neurotransmitter dopamine. It is linked to many neurological and psychiatric conditions including schizophrenia and bipolar disorder, addictive behaviors, Parkinsons disease, and eating disorders such as anorexia nervosa.

It is also a target for drugs which treat schizophrenia and Parkinson disease. The D₄ receptor is considered to be D₂-like in which the activated receptor inhibits the enzyme adenylate cyclase, thereby reducing the intracellular concentration of the second messenger cyclic AMP.

Genetics

The human protein is coded by the DRD4 on chromosome 11 located in 11p15.5.

There are slight variations (mutations/polymorphisms) in the human gene:

• A 48-base pair VNTR in exon 3
• C-521T in the promoter
• 13-base pair deletion of bases 235 to 247 in exon 1
• 12 base pair repeat in exon 1.
• Val194Gly
• A polymorphic tandem duplication of 120 bp

Mutations in this gene have been associated with various behavioral phenotypes, including autonomic nervous system dysfunction, attention deficit/hyperactivity disorder, schizophrenia, and the personality trait of novelty seeking.

48-base pair VNTR

The 48-base pair VNTR in exon 3 range from 2 to 11 repeats.

DRD4-7R, the 7-repeat (7R) variant of DRD4, has been linked to a susceptibility for developing ADHD in several meta-analyses and other psychological traits and disorders.

The frequency of the alleles varies greatly between populations, e.g., the 7-repeat version has high incidence in America and low in Asia. "Long" versions of polymorphisms are the alleles with 6 to 10 repeats. 7R appears to react less strongly to dopamine molecules.

The 48-base pair VNTR has been the subject of much speculation about its evolution and role in human behaviors cross-culturally. The 7R allele appears to have been selected for about 40,000 years ago. In 1999 Chen and colleagues observed that populations who migrated farther in the past 30,000 to 1,000 years ago had a higher frequency of 7R/long alleles. They also showed that nomadic populations had higher frequencies of 7R alleles than sedentary ones. More recently it was observed that the health status of nomadic Ariaal men was higher if they had 7R alleles. However, in recently sedentary (non-nomadic) Ariaal those with 7R alleles seemed to have slightly deteriorated health.

Novelty seeking

Despite early findings of an association between the DRD4 48bp VNTR and novelty seeking (a characteristic of exploratory and excitable people), a 2008 meta-analysis compared 36 published studies of novelty seeking and the polymorphism and found no effect. The meta-analysis of 11 studies did find that another polymorphism in the gene, the -521C/T, showed an association with novelty seeking. While human results are controversial, an increasing body of animal evidence has linked DRD4 variants with novelty seeking, e.g.,,, and new evidence suggests that human encroachment may exert selection pressure in favor of DRD4 variants associated with novelty seeking. Novelty-seeking behavior is probably mediated by several genes, and the variance attributable to DRD4 by itself is not particularly large.

Cognitive development

Several studies have suggested that parenting may affect the cognitive development of children with the 7-repeat allele of DRD4. Parenting that has maternal sensitivity, mindfulness, and autonomy–support at 15 months was found to alter children's executive functions at 18 to 20 months. Children with poorer quality parenting were more impulsive and sensation seeking than those with higher quality parenting. Higher quality parenting was associated with better effortful control in 4-year-olds.

Ligands

File:D4 ligands.png

Chemical structures of representative D₄-preferring ligands.

Agonists

• WAY-100635: potent full agonist, with 5-HT_1A antagonistic component
• A-412,997: full agonist, > 100-fold selective over a panel of seventy different receptors and ion channels
• ABT-724 - developed for treatment of erectile dysfunction
• ABT-670 - better oral bioavailability than ABT-724
• FAUC 316: partial agonist, > 8600-fold selective over other dopamine receptor subtypes
• FAUC 299: partial agonist
• (E)-1-aryl-3-(4-pyridinepiperazin-1-yl)propanone oximes
• PIP3EA: partial agonist
• Flibanserin - partial agonist
• PD-168,077 - D₄ selective but also binds to α1A, α2C and 5HT_1A
• CP-226,269 - D₄ selective but also binds to D₂, D₃, α2A, α2C and 5HT_1A
• Ro10-5824 - partial agonist
• Roxindole (also D2 and D3 autoreceptor partial agonist, 5HT1A receptor agonist, serotonin reuptake inhibitor)
• Apomorphine also adenergic and 5ht agonist, most affinity for the D4 subtype

Antagonists

• A-381393: potent, subtype selective antagonist (>2700-fold)
• FAUC 213
• L-745,870
• L-750,667
• S 18126: also σ1 affin
• Fananserin - mixed 5-HT_2A / D₄ antagonist
• Clozapine, an atypical antipsychotic
• Buspirone, an anxiolytic

Inverse agonists

• FAUC F41: inverse agonist, subtype selectivity of more than 3 orders of magnitude over D₂ and D₃

See also

• dopamine hypothesis of psychosis

External links

• Current Research on the DRD₄ Gene
• Receptors, Dopamine D4 at the US National Library of Medicine Medical Subject Headings (MeSH)

This article incorporates text from the United States National Library of Medicine, which is in the public domain.