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 Chromosome 11 is one of the 23 pairs of chromosomes in humans. Humans normally have two copies of this chromosome. Chromosome 11 spans about 135 million base pairs (the building material of DNA) and represents between 4 and 4.5 percent of the tot ...

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 An antagonist ...

. As with other

dopamine receptor Dopamine receptors are a class of G protein-coupled receptors that are prominent in the vertebrate central nervous system (CNS). Dopamine receptors activate different effectors through not only G-protein coupling, but also signaling through diffe ...

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. Neu ...

dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. Dopamine constitutes about 80% o ...

. 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 w ...

and

bipolar disorder Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of Depression (mood), depression and periods of abnormally elevated Mood (psychology), mood that last from days to weeks each. If the elevat ...

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-inap ...

, 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 beco ...

, 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 Gre ...

. 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 Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction: :A ...

, 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 tra ...

Genetics

The human protein is coded by the ''DRD4'' on

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, m ...

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

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 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 internal organs, smooth muscle and glands. The autonomic nervous system is a control system t ...

dysfunction,

attention deficit/hyperactivity disorder 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-inappr ...

Gene Overview of All Published Schizophrenia-Association Studies for DRD4
– SzGene database at Schizophrenia Research Forum. and the personality trait of

novelty seeking In Cloninger's model of psychobiology, novelty seeking (NS) is an inherited, unlearned, temperamental bias toward novel signals from the environment. It can be measured along a spectrum from low to high (as with 3 other temperamental domains) and ...

48-base pair VNTR

The 48-base pair variable number tandem repeat ( VNTR) 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

(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 m ...

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 ag ...

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. However, antagonists 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 Cognitive development is a field of study in neuroscience and psychology focusing on a child's development in terms of information processing, conceptual resources, perceptual skill, language learning, and other aspects of the developed adult bra ...

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 in 4-year-olds.

Ligands

Agonists

* WAY-100635: potent full

, 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 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 m ...

- 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: 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 even ...

- 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 – D₄ selective but also D₂ and D₃ autoreceptor agonist, 5HT_1A receptor agonist,

serotonin reuptake inhibitor A serotonin reuptake inhibitor (SRI) is a type of drug which acts as a reuptake inhibitor of the neurotransmitter serotonin (5-hydroxytryptamine, or 5-HT) by blocking the action of the serotonin transporter (SERT). This in turn leads to incre ...

) *

Apomorphine Apomorphine, sold under the brand name Apokyn among others, is a type of aporphine having activity as a non- selective dopamine agonist which activates both D2-like and, to a much lesser extent, D1-like receptors. It also acts as an antag ...

– D₄ selective but also D₂ and D₃ agonist, α-

adrenergic Adrenergic means "working on adrenaline (epinephrine) or noradrenaline (norepinephrine)" (or on their receptors). When not further qualified, it is usually used in the sense of enhancing or mimicking the effects of epinephrine and norepinephrine ...

and

serotonergic Serotonergic () or serotoninergic () means "pertaining to or affecting serotonin". Serotonin is a neurotransmitter. A synapse is serotonergic if it uses serotonin as its neurotransmitter. A serotonergic neuron ''produces'' serotonin. A substance is ...

weak antagonist

Antagonists

* A-381393: potent, subtype selective antagonist (>2700-fold) * FAUC 213 * L-745,870 * L-750,667 * ML-398 * S 18126 - also σ₁ affinity * Fananserin – mixed 5-HT_2A / D₄ antagonist *

Olanzapine Olanzapine (sold under the trade name Zyprexa among others) is an atypical antipsychotic primarily used to treat schizophrenia and bipolar disorder. For schizophrenia, it can be used for both new-onset disease and long-term maintenance. It is t ...

, an atypical antipsychotic *

Buspirone Buspirone, sold under the brand name Buspar, among others, is a medication primarily used to treat anxiety disorders, particularly generalized anxiety disorder. Benefits support its short-term use. It is taken by mouth, and it may take up to fo ...

, 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 ago ...

, 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 bestse ...

’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 comm ...

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