Kappa opioid receptor antagonism restores phosphorylation, trafficking and behavior induced by a disease-associated dopamine transporter variant

Dopamine transporter (DAT) variants linked to neuropsychiatric disorders show abnormal dopamine efflux, and kappa opioid receptor (KOR) antagonism is tested as a non-addictive way to normalize these disruptions. Using a preclinical mouse model expressing the human DAT Val559 variant (linked to ADHD, ASD, and bipolar disorder), the study shows that KOR stimulation increases DAT surface trafficking and phosphorylation at Thr53, effects that the Val559 mutant produces constitutively. In ex vivo preparations, KOR antagonism rescues these biochemical effects. In vivo, KOR antagonism also corrects abnormal dopamine release and sex-dependent behavioral abnormalities in DAT Val559 mice. With the aim of improving dopamine-linked brain disorder treatments while avoiding high abuse liability seen in current psychostimulants, the results support KOR antagonism as a potential pharmacological strategy.