Neurobehavioral Impact of Disease-Associated Variation in the Dopamine Transporter

Abstract

Our lab has created a construct valid mouse model based on the dopamine transporter (DAT) Val559 coding variant to elucidate neurobiological mechanisms supporting ADHD and other dopamine (DA)-linked comorbid disorders. Previously we demonstrated that the DAT Val559 mice have altered behavioral response to amphetamine, postulating that it was through a constitutively active D2-DAT interaction that resulted in reduced vesicular release. We have now further explored this altered drug response by examining downstream signaling proteins that are known to play a role in amphetamine induced locomotor behavior. Additionally, we sought to extend our analysis to understand the effects of life long expression of this variant on behavior associated with clinically-relevant phenotypes. We utilized the 5-choice serial reaction time task to probe for evidence of alterations in cognitive, attention, and impulsivity domains. We observed a schedule-dependent impulsivity in the DAT Val559 mice relative to WT controls, and demonstrated that the DAT Val559 mice specifically express a waiting impulsivity and not a deficit in motor inhibition as assessed by the Go/NoGo paradigm. Additionally, we determined that the waiting impulsivity was driven by an enhanced motivational state, rather than an alteration in the ability of the DAT Val559 mice to time intervals. Finally, DAT Val559 mice were demonstrated to be more susceptible to the formation of a dysregulated perseverative checking behavior under a devaluated state across goal-directed and habit contexts. Ultimately the DAT Val599 mouse represents a salient opportunity to understand perturbed behaviors seen in neuropsychiatric conditions associated with DAergic dysfunction.