Hyperactivity and impaired response habituation in hyperdopaminergic mice

Abnormal dopaminergic transmission is implicated in schizophrenia, attentio n deficit hyperactivity disorder, and drug addiction. In an attempt to mode l aspects of these disorders, we have generated hyperdopaminergic mutant mi ce by reducing expression of the dopamine transporter (DAT) to 10% of wild- type levels (DAT knockdown). Fast-scan cyclic voltammetry and in vivo micro dialysis revealed that released dopamine was cleared at a slow rate in knoc kdown mice, which resulted in a higher extracellular dopamine concentration . Unlike the DAT knockout mice, the DAT knockdown mice do not display a gro wth retardation phenotype, They have normal home cage activity but display hyperactivity and impaired response habituation in novel environments. In a ddition, we show that both the indirect dopamine receptor agonist amphetami ne and the direct agonists apomorphine and quinpirole inhibit locomotor act ivity in the DAT knockdown mice, leading to the hypothesis that a shift in the balance between dopamine auto and heteroreceptor function may contribut e to the therapeutic effect of psychostimulants in attention deficit hypera ctivity disorder.