{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T16:37:16Z","timestamp":1793637436470,"version":"4.5.1"},"reference-count":122,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,9,30]],"date-time":"2022-09-30T00:00:00Z","timestamp":1664496000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000026","name":"National Institute on Drug Abuse","doi-asserted-by":"publisher","award":["Intramural funds"],"award-info":[{"award-number":["Intramural funds"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>The functional and pharmacological significance of the dopamine D<jats:sub>4<\/jats:sub> receptor (D<jats:sub>4<\/jats:sub>R) has remained the least well understood of all the dopamine receptor subtypes. Even more enigmatic has been the role of the very prevalent human <jats:italic>DRD4<\/jats:italic> gene polymorphisms in the region that encodes the third intracellular loop of the receptor. The most common polymorphisms encode a D<jats:sub>4<\/jats:sub>R with 4 or 7 repeats of a proline-rich sequence of 16 amino acids (D<jats:sub>4.4<\/jats:sub>R and D<jats:sub>4.7<\/jats:sub>R). <jats:italic>DRD4<\/jats:italic> polymorphisms have been associated with individual differences linked to impulse control-related neuropsychiatric disorders, with the most consistent associations established between the gene encoding D<jats:sub>4.7<\/jats:sub>R and attention-deficit hyperactivity disorder (ADHD) and substance use disorders. The function of D<jats:sub>4<\/jats:sub>R and its polymorphic variants is being revealed by addressing the role of receptor heteromerization and the relatively avidity of norepinephrine for D<jats:sub>4<\/jats:sub>R. We review the evidence conveying a significant and differential role of D<jats:sub>4.4<\/jats:sub>R and D<jats:sub>4.7<\/jats:sub>R in the dopaminergic and noradrenergic modulation of the frontal cortico-striatal pyramidal neuron, with implications for the moderation of constructs of impulsivity as personality traits. This differential role depends on their ability to confer different properties to adrenergic \u03b1<jats:sub>2A<\/jats:sub> receptor (\u03b1<jats:sub>2A<\/jats:sub>R)-D<jats:sub>4<\/jats:sub>R heteromers and dopamine D<jats:sub>2<\/jats:sub> receptor (D<jats:sub>2<\/jats:sub>R)-D<jats:sub>4<\/jats:sub>R heteromers, preferentially localized in the perisomatic region of the frontal cortical pyramidal neuron and its striatal terminals, respectively. We also review the evidence to support the D<jats:sub>4<\/jats:sub>R as a therapeutic target for ADHD and other impulse-control disorders, as well as for restless legs syndrome.<\/jats:p>","DOI":"10.3389\/fendo.2022.1014678","type":"journal-article","created":{"date-parts":[[2022,9,30]],"date-time":"2022-09-30T08:10:29Z","timestamp":1664525429000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":48,"title":["Functional and pharmacological role of the dopamine D4 receptor and its polymorphic variants"],"prefix":"10.3389","volume":"13","author":[{"given":"Sergi","family":"Ferr\u00e9","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annabelle 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