It’s not all DAT: harnessing the potential of organic cation transporter 3 inhibition to selectively attenuate amphetamine reinforcement and dopamine release

Afflicting over 50 million people worldwide and demonstrating growing global trends of abuse, amphetamine-type stimulant abuse poses a significant public health burden. No effective pharmacological treatments exist for amphetamine-type stimulant use disorders, underscoring a critical need to identify novel, effective therapeutic targets. Amphetamine exerts its actions in part by targeting high-affinity, low-capacity monoamine transporters, particularly the dopamine transporter (DAT). However, therapeutic interventions targeting DAT have been so far unsuccessful. Emerging evidence supports a role for the low-affinity, high-capacity organic cation transporter 3 (OCT3) in the actions of amphetamine. Here we use in vivo electrochemical and behavioral approaches, as well as constitutive and temporally-inducible OCT3 knockout mice, to establish OCT3 as a critical mediator of neurochemical and behavioral actions of amphetamine. We demonstrate that OCT3 substantially contributes to amphetamine-evoked dopamine efflux in dorsal striatum and is key to reinforcing effects of amphetamine in intravenous self-administration assays. Our novel findings provide convergent evidence to suggest that OCT3 plays a central role in mediating abuse-related effects of amphetamine, establishing OCT3 as a potential novel target for the development of therapeutics to treat amphetamine-type stimulant use disorders.