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, and is also a p ...

. 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 dopamine. 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 wit ...

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, 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 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. 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 replication, DNA or viral repl ...

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 variations in length (number of repeats) among individ ...

in exon 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 sch ...

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 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 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 ...

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 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 (

) in exon 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 ADHD 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 The Ariaal are northern Kenyan pastoralists. They claim descent from cattle-owning Samburu who captured significant herds of camels and learned how to manage them from their eastern neighbours, the Rendille. This led them to adopt the Rendille ...

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 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 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 agonists 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, ri ...

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 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 ...

: 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 * 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 eve ...

- 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 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 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-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 – 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, 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 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