Aberrant dopamine (DA) signaling is implicated in schizophrenia, bipolar disorder (BPD), autism spectrum disorder (ASD), substance use disorder, and attention-deficit/hyperactivity disorder (ADHD). Treatment of these disorders remains inadequate. We established that the human DA transporter (DAT) coding variant (DAT Val559), identified in individuals with ADHD, ASD, or BPD, exhibits anomalous DA efflux (ADE) that is blocked by therapeutic amphetamines and methylphenidate. As the latter agents have high abuse liability, we exploited DAT Val559 knock-in mice to identify non-addictive agents that can normalize DAT Val559 functional and behavioral effects ex vivo and in vivo. Kappa opioid receptors (KORs) are expressed by DA neurons and modulate DA release and clearance, suggesting that targeting KORs might offset the effects of DAT Val559. We establish that enhanced DAT Thr53 phosphorylation and increased DAT surface trafficking associated with DAT Val559 expression are mimicked by KOR agonism of wildtype preparations and rescued by KOR antagonism of DAT Val559 ex vivo preparations. Importantly, KOR antagonism also corrected in vivo DA release and sex-dependent behavioral abnormalities. Given their low abuse liability, our studies with a construct valid model of human DA associated disorders reinforce considerations of KOR antagonism as a pharmacological strategy to treat DA associated brain disorders.

Kappa Opioid Receptor Antagonism Rescues Genetic Perturbation of Dopamine Homeostasis: Molecular, Physiological and Behavioral Consequences