D2 dopamine receptor subtype-mediated hyperactivity and amphetamine responses in a model of ADHD.
Low doses of psychostimulants produce beneficial behavioral effects in ADHD patients but the mechanisms underlying the response are not understood. Here we use the hyperactive mouse mutant coloboma to identify D2-like dopamine receptor subtypes that mediate the hyperactivity and response to amphetamine; we have previously demonstrated that D1-like dopamine receptors are not involved. Targeted deletion of the D2, but not the D3 or the D4, dopamine receptor in coloboma mice eliminated the hyperactivity; depleting D2 dopamine receptors also restored the excess dopamine overflow that may drive the hyperactivity to normal concentrations. Similar to its effects on ADHD patients, amphetamine reduced the hyperactivity of coloboma mice. The D2 dopamine receptor-selective antagonist L-741,626, but not D3 or D4 dopamine receptor-selective antagonists, blocked the amphetamine-induced reduction in locomotor activity. Thus, the D2 dopamine receptor subtype mediates both the hyperactivity and response to amphetamine, suggesting a specific target for novel therapeutics in ADHD.
Departments of Pharmacology and Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA.
Xueliang
X
Fan
Ming
M
Xu
Ellen J
EJ
Hess
D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy* / Q000503:physiopathology*; D001578:Benzopyrans / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000503:physiopathology; D004295:Dihydroxyphenylalanine / Q000494:pharmacology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D005110:Extracellular Space / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D010880:Piperidines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism*; D050637:Receptors, Dopamine D3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D050638:Receptors, Dopamine D4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
C099630:3-((4-(4-chlorophenyl)piperazin-1-yl)methyl)-1H-pyrrolo(2,3-b)pyridine; D001578:Benzopyrans; D015259:Dopamine Agents; D065127:Dopamine D2 Receptor Antagonists; D007211:Indoles; D010880:Piperidines; D011725:Pyridines; D011758:Pyrroles; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C408389:S 33084; D050638:Receptors, Dopamine D4; D004295:Dihydroxyphenylalanine; C104750:3-(4-(4-chlorophenyl-4-hydroxypiperidino)methyl)indole; D000661:Amphetamine; D004298:Dopamine