Hyperactivity and impaired response habituation in hyperdopaminergic mice.
Abnormal dopaminergic transmission is implicated in schizophrenia, attention deficit hyperactivity disorder, and drug addiction. In an attempt to model aspects of these disorders, we have generated hyperdopaminergic mutant mice by reducing expression of the dopamine transporter (DAT) to 10% of wild-type levels (DAT knockdown). Fast-scan cyclic voltammetry and in vivo microdialysis revealed that released dopamine was cleared at a slow rate in knockdown mice, which resulted in a higher extracellular dopamine concentration. Unlike the DAT knockout mice, the DAT knockdown mice do not display a growth retardation phenotype. They have normal home cage activity but display hyperactivity and impaired response habituation in novel environments. In addition, we show that both the indirect dopamine receptor agonist amphetamine and the direct agonists apomorphine and quinpirole inhibit locomotor activity in the DAT knockdown mice, leading to the hypothesis that a shift in the balance between dopamine auto and heteroreceptor function may contribute to the therapeutic effect of psychostimulants in attention deficit hyperactivity disorder.
Zhuang
X
X
Center for Neurobiology and Behavior, Columbia University, New York, NY 10032, USA.
Oosting
R S
RS
Jones
S R
SR
Gainetdinov
R R
RR
Miller
G W
GW
Caron
M G
MG
Hen
R
R
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001289:Attention Deficit Disorder with Hyperactivity; D001552:Benzazepines / Q000494:pharmacology; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D050483:Dopamine Plasma Membrane Transport Proteins; D005260:Female; D006719:Homovanillic Acid / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009043:Motor Activity; D009419:Nerve Tissue Proteins; D011595:Psychomotor Agitation / Q000378:metabolism* / Q000503:physiopathology; D019257:Quinpirole / Q000494:pharmacology; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism
D000662:Amphetamines; D001552:Benzazepines; D002352:Carrier Proteins; D018491:Dopamine Agonists; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C493215:Slc6a3 protein, mouse; D015102:3,4-Dihydroxyphenylacetic Acid; D019257:Quinpirole; C067113:SK&F 81297; D001058:Apomorphine; D004298:Dopamine; D006719:Homovanillic Acid