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Allosteric Modulator of Dopamine Transporter Inhibits Cocaine-induced Behaviors in Rats
Journal article   Open access   Peer reviewed

Allosteric Modulator of Dopamine Transporter Inhibits Cocaine-induced Behaviors in Rats

Yibin Xu, Stacia I Lewandowski, Ejaaz Ravi Moazzam, Joseph M Salvino and Ole V Mortensen
The journal of pharmacology and experimental therapeutics, Forthcoming
09 Oct 2026
DOI: https://doi.org/10.1016/j.jpet.2026.105044
Featured in Collection :   Drexel's Newest Publications
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https://doi.org/10.1016/j.jpet.2026.105044View
Published, Version of Record (VoR) Open Access via Drexel Libraries Read and Publish Program 2026 Open CC BY-NC-ND V4.0

Abstract

Psychostimulant use disorders (PUD), particularly cocaine use disorder (CUD), is marked by compulsive drug seeking and high relapse rates. Cocaine blocks the dopamine transporter (DAT), preventing dopamine (DA) reuptake leading to elevated DA signaling—a key driver of its addictive properties. Although behavioral interventions such as contingency management have demonstrated efficacy in treating stimulant use disorders, their long-term effectiveness and accessibility remain limited, and no FDA-approved pharmacotherapy for PUD currently exists, highlighting the need for novel treatment options. We investigated the therapeutic potential of KM822, a novel allosteric DAT modulator that binds to a distinct domain different from the cocaine/DA binding site. When infused into the nucleus accumbens (NAc), KM822 significantly attenuated cocaine-induced hyperlocomotion of an intracranial dose of 25 μg cocaine, with no significant effect observed at higher cocaine doses tested. To assess the impact of KM822 on cocaine's rewarding properties, we used the conditioned place preference (CPP) test. KM822 pretreatment during conditioning successfully blocked the development of cocaine-induced CPP. To model relapse, we evaluated cocaine-primed reinstatement in the CPP assay and found that KM822 pretreatment before cocaine-priming effectively blocked reinstatement behavior. Importantly, KM822 alone did not produce preference in the CPP test, suggesting KM822 has low abuse potential. At the protein level, KM822 alone did not significantly alter c-Fos expression, a marker of neuronal activation, but attenuated cocaine-induced c-Fos expression. Together, these findings demonstrate that KM822 can inhibit cocaine-related behaviors and neural responses and serve as a proof of concept for the therapeutic potential of allosterically targeting DAT.

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