Vesicular monoamine transporter-2 inhibitor JPC-141 prevents methamphetamine-induced dopamine toxicity and blocks methamphetamine self-administration in rats

Authors

Cassie M. Chandler
Justin R. Nickell, University of KentuckyFollow
A. George Wilson, University of Kentucky
John P. Culver, University of KentuckyFollow
Peter A. Crooks, University of Arkansas for Medical SciencesFollow
Michael T. Bardo, University of KentuckyFollow
Linda P. Dwoskin, University of KentuckyFollow

Abstract

Previous research has demonstrated therapeutic potential for VMAT2 inhibitors in rat models of methamphetamine use disorder. Here, we report on the neurochemical and behavioral effects of 1-(2-methoxyphenethyl)-4-phenethypiperazine (JPC-141), a novel analog of lobelane. JPC-141 potently inhibited (Ki = 52 nM) [3H]dopamine uptake by VMAT2 in striatal vesicles with 50 to 250-fold greater selectivity for VMAT2 over dopamine, norepinephrine and serotonin plasmalemma transporters. Also, JPC-141 was 57-fold more selective for inhibiting VMAT2 over [3H]dofetilide binding to hERG channels expressed by HEK293, suggesting relatively low potential for cardiotoxicity. When administered in vivo to rats, JPC-141 prevented the METH-induced reduction in striatal dopamine content when given either prior to or after a high dose of METH, suggesting a reduction in METH-induced dopaminergic neurotoxicity. In behavioral assays, JPC-141 decreased METH-stimulated locomotor activity in METH-sensitized rats at doses of JPC-141 which did not alter locomotor activity in the saline control group. Moreover, JPC-141 specifically decreased iv METH self-administration at doses that had no effect on food-maintained responding. These findings support the further development of VMAT2 inhibitors as pharmacotherapies for individuals with methamphetamine use disorder.

Document Type

Article

Publication Date

10-2024

Notes/Citation Information

0006-2952/© 2024 Elsevier Inc. All rights reserved.

Digital Object Identifier (DOI)

https://doi.org/10.1016/j.bcp.2024.116189

Funding Information

This research was supported by funding from the National Institute on Drug Abuse grant U01 DA013519 and T32 DA016176.

Repository Citation

Chandler, Cassie M.; Nickell, Justin R.; Wilson, A. George; Culver, John P.; Crooks, Peter A.; Bardo, Michael T.; and Dwoskin, Linda P., "Vesicular monoamine transporter-2 inhibitor JPC-141 prevents methamphetamine-induced dopamine toxicity and blocks methamphetamine self-administration in rats" (2024). Psychology Faculty Publications. 220.
https://uknowledge.uky.edu/psychology_facpub/220