Attention deficit/hyperactivity disorder (
ADHD) is characterized by inattention, impulsivity, and
motor hyperactivity. Several lines of research support a crucial role for the
dopamine transporter (DAT) gene in this
psychiatric disease. Consistently, the most commonly prescribed medications in
ADHD treatment are stimulant drugs, known to preferentially act on DAT. Recently, a knock-in mouse [DAT-
cocaine insensitive (DAT-CI)] has been generated carrying a
cocaine-insensitive DAT that is functional but with reduced
dopamine uptake function. DAT-CI mutants display enhanced striatal extracellular
dopamine levels and basal
motor hyperactivity. Herein, we showed that DAT-CI animals present higher striatal
dopamine turnover, altered basal phosphorylation state of
dopamine and cAMP-regulated phosphoprotein 32 kDa (DARPP32) at Thr75 residue, but preserved D(2) receptor (D(2)R) function. However, although we demonstrated that striatal D(1) receptor (D(1)R) is physiologically responsive under basal conditions, its stimulus-induced activation strikingly resulted in paradoxical electrophysiological, behavioral, and biochemical responses. Indeed, in DAT-CI animals, (1) striatal LTP was completely disrupted, (2) R-(+)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (
SKF 81297) treatment induced paradoxical motor calming effects, and (3)
SKF 81297 administration failed to increase
cAMP/protein kinase A (PKA)/DARPP32 signaling. Such biochemical alteration selectively affected
dopamine D(1)Rs since
haloperidol, by blocking the tonic inhibition of D(2)R, unmasked a normal activation of striatal
adenosine A(2A) receptor-mediated cAMP/PKA/DARPP32 cascade in mutants. Most importantly, our studies highlighted that
amphetamine,
nomifensine, and
bupropion, through increased striatal dopaminergic transmission, are able to revert
motor hyperactivity of DAT-CI animals. Overall, our results suggest that the paradoxical motor calming effect induced by these drugs in DAT-CI mutants depends on selective aberrant phasic activation of D(1)R/cAMP/PKA/DARPP32 signaling in response to increased striatal extracellular
dopamine levels.