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Vesicular monoamine transporter-2 inhibitor JPC-141 prevents methamphetamine-induced dopamine toxicity and blocks methamphetamine self-administration in rats.
Chandler, Cassie M; Nickell, Justin R; George Wilson, A; Culver, John P; Crooks, Peter A; Bardo, Michael T; Dwoskin, Linda P.
Afiliación
  • Chandler CM; Department of Psychology, University of Kentucky, Lexington, KY, United States.
  • Nickell JR; Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, United States.
  • George Wilson A; Department of Psychology, University of Kentucky, Lexington, KY, United States.
  • Culver JP; Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, United States.
  • Crooks PA; Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock, AR, United States.
  • Bardo MT; Department of Psychology, University of Kentucky, Lexington, KY, United States.
  • Dwoskin LP; Department of Pharmaceutical Sciences, University of Kentucky, Lexington, KY, United States. Electronic address: ldwoskin@uky.edu.
Biochem Pharmacol ; 228: 116189, 2024 10.
Article en En | MEDLINE | ID: mdl-38580165
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Autoadministración / Dopamina / Proteínas de Transporte Vesicular de Monoaminas / Metanfetamina Límite: Animals / Humans / Male Idioma: En Revista: Biochem Pharmacol Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Autoadministración / Dopamina / Proteínas de Transporte Vesicular de Monoaminas / Metanfetamina Límite: Animals / Humans / Male Idioma: En Revista: Biochem Pharmacol Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido