The dopamine D4 receptor is essential for hyperactivity and impaired behavioral inhibition in a mouse model of attention deficit/hyperactivity disorder

被引:115
作者
Avale, ME
Falzone, TL
Gelman, DM
Low, MJ
Grandy, DK
Rubinstein, M
机构
[1] Univ Buenos Aires, Fac Ciencias Exactas & Nat, CONICET, INGEBI,Inst Invest Ingn Genet & Biol Mol, RA-1428 Buenos Aires, DF, Argentina
[2] Univ Buenos Aires, Fac Ciencias Exactas & Nat, Dept Fisiol Biol Mol & Celular, RA-1428 Buenos Aires, DF, Argentina
[3] Oregon Hlth & Sci Univ, Vollum Inst, Portland, OR 97201 USA
[4] Oregon Hlth & Sci Univ, Dept Behav Neurosci, Portland, OR 97201 USA
[5] Oregon Hlth & Sci Univ, Dept Physiol & Pharmacol, Portland, OR 97201 USA
[6] Ctr Estudios Cient, Valdivia, Chile
基金
美国国家科学基金会;
关键词
amphetamine; methylphenidate; ADHD; 6-hydroxydopamine; D4R knockout mouse;
D O I
10.1038/sj.mp.4001474
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:718 / 726
页数:9
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