α2-Adrenergic agonists including xylazine and dexmedetomidine inhibit norepinephrine transporter function in SK-N-SH cells

► We report that α2 adrenergic agonists directly block NET binding of nisoxetine. ► The agents suppressed NET function in an acute and dose-dependent manner. ► This was independent of α2 signaling, and accompanied by reduced NET substrate affinity. ► α2 agonists are competitive NET inhibitors that interact with the nisoxetine binding site.