title: Key role of the dopamine D4receptor in the modulation of corticostriatal glutamatergic neurotransmission.
abstract: Polymorphic variants of the dopamine D4receptor gene (DRD4) have been repeatedly associated with numerous neuropsychiatric disorders. Yet, the functional role of the D4receptor and the functional differences of the products ofDRD4polymorphic variants remained enigmatic. Immunohistochemical and optogenetic-microdialysis experiments were performed in knock-in mice expressing a D4receptor with the long intracellular domain of a humanDRD4polymorphic variant associated with attention deficit hyperactivity disorder (ADHD). When compared with the wild-type mouse D4receptor, the expanded intracellular domain of the humanized D4receptor conferred a gain of function, blunting methamphetamine-induced cortical activation and optogenetic and methamphetamine-induced corticostriatal glutamate release. The results demonstrate a key role of the D4receptor in the modulation of corticostriatal glutamatergic neurotransmission. Furthermore, these data imply that enhanced D4receptor-mediated dopaminergic control of corticostriatal transmission constitutes a vulnerability factor of ADHD and other neuropsychiatric disorders.
authors.affiliation: Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural research Program, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Jordi
authors.identifier: 0000-0002-4745-0151
authors.initials: J
authors.lastname: Bonaventura
authors.affiliation: Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural research Program, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: César
authors.initials: C
authors.lastname: Quiroz
authors.affiliation: Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural research Program, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Ning-Sheng
authors.initials: NS
authors.lastname: Cai
authors.affiliation: Institute of Investigation in Genetic Engineering and Molecular Biology, Buenos Aires 1428, Argentina.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Rubinstein
authors.affiliation: Medications Development Program, National Institute on Drug Abuse, Intramural research Program, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Gianluigi
authors.identifier: 0000-0001-9526-9878
authors.initials: G
authors.lastname: Tanda
authors.affiliation: Integrative Neurobiology Section, National Institute on Drug Abuse, Intramural research Program, National Institutes of Health, Baltimore, MD 21224, USA.
authors.forename: Sergi
authors.initials: S
authors.lastname: Ferré
mesh_terms: D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology; D055879:Gene Knock-In Techniques; D018698:Glutamic Acid / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D000072417:Protein Domains; D050638:Receptors, Dopamine D4 / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission
chemical_list: D050638:Receptors, Dopamine D4; D018698:Glutamic Acid
keywords: Dopamine D4 receptor; attention deficit hyperactivity disorder; basal ganglia; dopamine; glutamate; methamphetamine; polymorphic variant; substance use disorders