Dopamine receptor D4

The dopamine receptor D4 is a is_associated_with::G protein-coupled receptor encoded by the gene. As with other is_associated_with::dopamine receptor subtypes, the D4 receptor is activated by the is_associated_with::neurotransmitter is_associated_with::dopamine. It is linked to many neurological and psychiatric conditions including is_associated_with::schizophrenia and is_associated_with::bipolar disorder, addictive behaviors, is_associated_with::Parkinsons disease, and is_associated_with::eating disorders such as is_associated_with::anorexia nervosa.

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

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

There are slight variations (mutations/polymorphisms) in the human gene:
 * A 48-base pair is_associated_with::VNTR in is_associated_with::exon 3
 * is_associated_with::C-521T in the promoter
 * 13-base pair deletion of bases 235 to 247 in exon 1
 * 12 base pair repeat in exon I.
 * is_associated_with::Val194Gly
 * A polymorphic tandem duplication of 120 bp

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

48-base pair VNTR
The 48-base pair is_associated_with::VNTR in is_associated_with::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 is_associated_with::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 is_associated_with::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 is_associated_with::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 is_associated_with::-521C/T, showed an association with novelty seeking. In any case, 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 is_associated_with::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 is_associated_with::effortful control in 4-year-olds.

Agonists

 * is_associated_with::WAY-100635: potent full is_associated_with::agonist, with 5-HT1A antagonistic component
 * is_associated_with::A-412,997: full agonist, > 100-fold selective over a panel of seventy different receptors and ion channels
 * is_associated_with::ABT-724 - developed for treatment of erectile dysfunction
 * is_associated_with::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
 * is_associated_with::Flibanserin - partial agonist
 * is_associated_with::PD-168,077 - D4 selective but also binds to α1A, α2C and 5HT1A
 * is_associated_with::CP-226,269 - D4 selective but also binds to D2, D3, α2A, α2C and 5HT1A
 * is_associated_with::Ro10-5824 - partial agonist
 * is_associated_with::Roxindole (also D2 and D3 autoreceptor partial agonist, is_associated_with::5HT1A receptor is_associated_with::agonist, is_associated_with::serotonin reuptake inhibitor)
 * is_associated_with::Apomorphine also adenergic and 5ht agonist, most affinity for the D4 subtype

Antagonists

 * A-381393: potent, subtype selective antagonist (>2700-fold)
 * FAUC 213
 * is_associated_with::L-745,870
 * L-750,667
 * S 18126: also σ1 affin
 * is_associated_with::Fananserin - mixed 5-HT2A / D4 antagonist
 * is_associated_with::Clozapine, an atypical antipsychotic
 * is_associated_with::Buspirone, an anxiolytic

Inverse agonists

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