The dopamine receptor D₄ is a dopamine D2-like

G protein-coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...

encoded by the gene on chromosome 11 at 11p15.5. The structure of DRD4 was recently reported in complex with the antipsychotic drug

nemonapride Nemonapride (エミレース, Emilace ( JP)) is an atypical antipsychotic approved in Japan for the treatment of schizophrenia. It was launched by Yamanouchi in May 1991. Nemonapride acts as a D2 and D3 receptor antagonist, and is also a p ...

. As with other dopamine receptor subtypes, the D₄ receptor is activated by the

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neuro ...

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...

. It is linked to many neurological and psychiatric conditions including

schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social withdra ...

and

bipolar disorder Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of depression and periods of abnormally elevated mood that last from days to weeks each. If the elevated mood is severe or associated with ...

ADHD Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inapp ...

, addictive behaviors,

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...

, and

eating disorders An eating disorder is a mental disorder defined by abnormal eating behaviors that negatively affect a person's physical or mental health. Only one eating disorder can be diagnosed at a given time. Types of eating disorders include binge eating ...

such as

anorexia nervosa Anorexia nervosa, often referred to simply as anorexia, is an eating disorder characterized by low weight, food restriction, body image disturbance, fear of gaining weight, and an overpowering desire to be thin. ''Anorexia'' is a term of Gr ...

. A weak association has been drawn between DRD4 and

borderline personality disorder Borderline personality disorder (BPD), also known as emotionally unstable personality disorder (EUPD), is a personality disorder characterized by a long-term pattern of unstable interpersonal relationships, distorted sense of self, and strong ...

. It is also a target for drugs which treat

and

. 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 Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal transd ...

Genetics

The human protein is coded by the ''DRD4'' on chromosome 11 located in 11p15.5. There are slight variations (

mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mi ...

s/ polymorphisms) in the human gene: * A 48-base pair

VNTR A variable number tandem repeat (or VNTR) is a location in a genome where a short nucleotide sequence is organized as a tandem repeat. These can be found on many chromosomes, and often show Polymorphism (biology), variations in length (number of ...

exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequen ...

3 *

C-521T In genetics, rs1800955 (also written as C-521T and -521C/T) is a single nucleotide polymorphism (SNP). It is located in the promoter region of the ''DRD4'' gene. This gene codes for the dopamine receptor D4. Due to the dopamine hypothesis of schi ...

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 48 bp Mutations in this gene have been associated with various behavioral phenotypes, including

autonomic nervous system The autonomic nervous system (ANS), formerly referred to as the vegetative nervous system, is a division of the peripheral nervous system that supplies viscera, internal organs, smooth muscle and glands. The autonomic nervous system is a control ...

dysfunction, attention deficit/hyperactivity disorder,

Gene Overview of All Published Schizophrenia-Association Studies for DRD4
– SzGene database at

Schizophrenia Research Forum Schizophrenia Research Forum is a web knowledge environment dedicated to news, information resources, and discussion about research on schizophrenia. It hosts a number of resources such as What We Know About Schizophrenia, Animal Models and Drugs in ...

. and the personality trait of novelty seeking.

48-base pair VNTR

The 48-base pair variable number tandem repeat (

) in

3 range from 2 to 11 repeats. Dopamine is more potent at the D4 receptor with 2 allelic repeat or 7 allelic repeats than the variant with 4 allelic repeats. DRD4-7R, the 7-repeat (7R) variant of ''DRD4'' (DRD4 7-repeat polymorphism), has been linked to a susceptibility for developing

in several meta-analyses and other psychological traits and disorders. Adults and children with the DRD4 7-repeat polymorphism show variations in auditory-evoked

gamma oscillations A gamma wave or gamma Rhythm is a pattern of neural oscillation in humans with a frequency between 25 and 140 Hz, the 40- Hz point being of particular interest. Gamma rhythms are correlated with large scale brain network activity and cognitive ...

, which may be related to attention processing. 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 normal characteristic of exploratory and excitable people), a 2008

meta-analysis A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. Meta-analyses can be performed when there are multiple scientific studies addressing the same question, with each individual study reporting me ...

compared 36 published studies of novelty seeking and the polymorphism and found no effect. Results are consistent with novelty-seeking behavior being a

complex trait Complex traits, also known as quantitative traits, are traits that do not behave according to simple Mendelian inheritance laws. More specifically, their inheritance cannot be explained by the genetic segregation of a single gene. Such traits show ...

associated with many genes, and the variance attributable to ''DRD4'' by itself being very small. 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 not strong, research in animals has suggested stronger associations and new evidence suggests that human encroachment may exert selection pressure in favor of ''DRD4'' variants associated with novelty seeking.

Cognition

Several studies have shown that

agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...

s that activate the D4 receptor increase working memory performance and fear acquisition in monkeys and rodents according to a U-shaped

dose response curve Dose or Dosage may refer to: Music * Dose (Gov't Mule album), ''Dose'' (Gov't Mule album), 1998 * Dose (Latin Playboys album), ''Dose'' (Latin Playboys album) * Dosage (album), ''Dosage'' (album), by the band Collective Soul * Dose (song), "Dose" ...

. However,

antagonists An antagonist is a character in a story who is presented as the chief foe of the protagonist. Etymology The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...

of the D4 receptor reverse stress-induced or drug-induced working memory deficits.

Gamma oscillations A gamma wave or gamma Rhythm is a pattern of neural oscillation in humans with a frequency between 25 and 140 Hz, the 40- Hz point being of particular interest. Gamma rhythms are correlated with large scale brain network activity and cognitive ...

, which may be correlated with cognitive processing, can be increased by D4R agonists, but are not significantly reduced by D4R antagonists.

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

executive control Executive ( exe., exec., execu.) may refer to: Role or title * Executive, a senior management role in an organization ** Chief executive officer (CEO), one of the highest-ranking corporate officers (executives) or administrators ** Executive dir ...

in 4-year-olds.

Ligands

Agonists

WAY-100635 WAY-100635 is a piperazine drug and research chemical widely used in scientific studies. It was originally believed to act as a selective 5-HT1A receptor antagonist, but subsequent research showed that it also acts as potent full agonist at the ...

: potent full

, with 5-HT_1A antagonistic component *

A-412,997 A-412,997 is a drug which acts as a dopamine agonist that is used in scientific research. It is the first drug developed that is a highly selective agonist for the D4 subtype, with significantly improved selectivity over older D4-preferring comp ...

: full agonist, > 100-fold selective over a panel of seventy different receptors and ion channels *

ABT-724 ABT-724 is a drug which acts as a dopamine agonist, and is selective for the D4 subtype. It was developed as a possible drug for the treatment of erectile dysfunction, although poor oral bioavailability means alternative drugs such as ABT-670 ...

- 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 *

F-15063 F-15,063 is an orally active potential antipsychotic, and an antagonist at the D2/ D3 receptors, partial agonist at the D4 receptor, and agonist at the 5-HT1A receptors. It has greater efficacy at the 5-HT1A receptors than other antipsychotics, ...

: antipsychotic with partial D4 agonism * (''E'')-1-aryl-3-(4-pyridinepiperazin-1-yl)propanone oximes * PIP3EA: partial agonist *

Flibanserin Flibanserin, sold under the brand name Addyi, is a medication approved for the treatment of pre-menopausal women with hypoactive sexual desire disorder (HSDD). The medication improves sexual desire, increases the number of satisfying sexual eve ...

- partial agonist *

PD-168,077 PD-168,077 is a drug which acts as a dopamine agonist A dopamine agonist (DA) is a compound that activates dopamine receptors. There are two families of dopamine receptors, D2-like and D1-like, and they are all G protein-coupled receptors. D1- ...

- D₄ selective but also binds to α1A, α2C and 5HT_1A *

CP-226,269 CP-226,269 is a drug which acts as a dopamine agonist selective for the D4 subtype, which is used for researching the role of D4 receptors in the brain. Synthesis The piperazine used has dual use in the synthesis of ABT-724, ABT-670, Azapero ...

- D₄ selective but also binds to D₂, D₃, α2A, α2C and 5HT_1A *

Ro10-5824 Ro10-5824 is a drug which acts as a dopamine Receptor (biochemistry), receptor partial agonist selective for the Dopamine receptor D4, D4 subtype, and has nootropic effects in animal studies. References

Dopamine agonists Hoffmann-La Roche ...

– partial agonist *

Roxindole Roxindole (EMD-49,980) is a dopaminergic and serotonergic drug which was originally developed by Merck KGaA for the treatment of schizophrenia. In clinical trials its antipsychotic efficacy was only modest but it was unexpectedly found to produc ...

– D₄ selective but also D₂ and D₃ autoreceptor agonist, 5HT_1A receptor agonist, serotonin reuptake inhibitor) * Apomorphine – D₄ selective but also D₂ and D₃ agonist, α- adrenergic and serotonergic weak antagonist

Antagonists

* A-381393: potent, subtype selective antagonist (>2700-fold) * FAUC 213 *

L-745,870 L-745,870 is a drug which acts as a dopamine receptor antagonist selective for the D4 subtype, and has antipsychotic Antipsychotics, also known as neuroleptics, are a class of psychotropic medication primarily used to manage psychosis (i ...

* L-750,667 * ML-398 * S 18126 - also σ₁ affinity *

Fananserin Fananserin (RP-62203) is a drug which acts as a potent antagonist at both the 5HT2A receptor, and the Dopamine D4 receptor, but without blocking other dopamine receptors such as D2. It has sedative and antipsychotic effects, and has been resea ...

– mixed 5-HT_2A / D₄ antagonist * Olanzapine, an atypical antipsychotic * Buspirone, an anxiolytic

Inverse agonists

* FAUC F41:

inverse agonist In pharmacology, an inverse agonist is a drug that binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the agonist. A neutral antagonist has no activity in the absence of an agonist or inverse agon ...

, subtype selectivity of more than 3 orders of magnitude over D₂ and D₃

In popular culture

Michael Connelly Michael Joseph Connelly (born July 21, 1956) is an American author of detective novels and other crime fiction, notably those featuring LAPD Detective Hieronymus "Harry" Bosch and criminal defense attorney Mickey Haller. Connelly is the bes ...

’s 2020 crime novel '' Fair Warning'' (ISBN 978-0-316-53942-5) revolves around a serial killer who uses DNA profiles obtained on the

Dark Web The dark web is the World Wide Web content that exists on ''darknets'': overlay networks that use the Internet but require specific software, configurations, or authorization to access. Through the dark web, private computer networks can communi ...

to target female victims, specifically those whose DRD4 profiles allegedly make them more susceptible to risk taking and sexual promiscuity.

References

External links

*
Current Research on the DRD₄ Gene
* * * * {{DEFAULTSORT:Dopamine Receptor D4 Dopamine receptors Biology of attention deficit hyperactivity disorder Genes on human chromosome 11