title: The dopamine D4 receptor is essential for hyperactivity and impaired behavioral inhibition in a mouse model of attention deficit/hyperactivity disorder.
abstract: The dopamine D4 receptor (D4R) is a candidate gene for attention deficit/hyperactivity disorder (ADHD) based on genetic studies reporting that particular polymorphisms are present at a higher frequency in affected children. However, the direct participation of the D4R in the onset or progression of ADHD has not been tested. Here, we generated a mouse model with high face value to screen candidate genes for the clinical disorder by neonatal disruption of central dopaminergic pathways with 6-hydroxydopamine (6-OHDA). The lesioned mice exhibited hyperactivity that waned after puberty, paradoxical hypolocomotor responses to amphetamine and methylphenidate, poor behavioral inhibition in approach/avoidance conflict tests and deficits in continuously performed motor coordination tasks. To determine whether the D4R plays a role in these behavioral phenotypes, we performed 6-OHDA lesions in neonatal mice lacking D4Rs (Drd4(-/-)). Although striatal dopamine contents and tyrosine hydroxylase-positive midbrain neurons were reduced to the same extent in both genotypes, Drd4(-/-) mice lesioned with 6-OHDA did not develop hyperactivity. Similarly, the D4R antagonist PNU-101387G prevented hyperactivity in wild-type 6-OHDA-lesioned mice. Furthermore, wild-type mice lesioned with 6-OHDA showed an absence of behavioral inhibition when tested in the open field or the elevated plus maze, while their Drd4(-/-) siblings exhibited normal avoidance for the unprotected areas of these mazes. Together, our results from a combination of genetic and pharmacological approaches demonstrate that D4R signaling is essential for the expression of juvenile hyperactivity and impaired behavioral inhibition, relevant features present in this ADHD-like mouse model.
authors.affiliation: Instituto de Investigaciones en Ingeniería Genética y Biología Molecular (CONICET), Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Vuelta de Obligado 2490, 1428-Buenos Aires, Argentina.
authors.forename: M E
authors.initials: ME
authors.lastname: Avale
authors.forename: T L
authors.initials: TL
authors.lastname: Falzone
authors.forename: D M
authors.initials: DM
authors.lastname: Gelman
authors.forename: M J
authors.initials: MJ
authors.lastname: Low
authors.forename: D K
authors.initials: DK
authors.lastname: Grandy
authors.forename: M
authors.initials: M
authors.lastname: Rubinstein
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D021461:Animals, Outbred Strains; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology*; D001522:Behavior, Animal / Q000502:physiology; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D003342:Corpus Striatum / Q000166:cytology / Q000503:physiopathology; D003714:Denervation; D004195:Disease Models, Animal; D008297:Male; D008774:Methylphenidate / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000502:physiology; D009434:Neural Pathways; D016627:Oxidopamine; D010641:Phenotype; D017448:Receptors, Dopamine D2 / Q000235:genetics* / Q000502:physiology*; D050638:Receptors, Dopamine D4; D013378:Substantia Nigra / Q000166:cytology / Q000503:physiopathology; D013565:Sympatholytics
chemical_list: D000697:Central Nervous System Stimulants; C493600:Drd4 protein, mouse; D017448:Receptors, Dopamine D2; D013565:Sympatholytics; D050638:Receptors, Dopamine D4; D008774:Methylphenidate; D016627:Oxidopamine; D000661:Amphetamine