The Novel Atypical Dopamine Uptake Inhibitor (S)-CE-123 Partially Reverses the Effort-Related Effects of the Dopamine Depleting Agent Tetrabenazine and Increases Progressive Ratio Responding
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Título
The Novel Atypical Dopamine Uptake Inhibitor (S)-CE-123 Partially Reverses the Effort-Related Effects of the Dopamine Depleting Agent Tetrabenazine and Increases Progressive Ratio RespondingAutoría
Fecha de publicación
2019-06-28Editor
Frontiers MediaCita bibliográfica
ROTOLO, Renee;DRAGACEVIC, Vladimir; KALABA, Predrag; URBAN, Ernst; ZEHL, Martin; ROLLER, Alexander; WACKERLIG, Judith; LANGER, Thierry; PISTIS, Marco; DE LUCA, Maria Antonietta; CARIA, Francesca; SCHWARTZ, Rebecca; PRESBY, Rose; YANG, Jen-Hau; SAMELS, Shanna; CORREA SANZ, Mercé; LUBEC, Gert; SALAMONE, John D. (2019). The Novel Atypical Dopamine Uptake Inhibitor (S)-CE-123 Partially Reverses the Effort-Related Effects of the Dopamine Depleting Agent Tetrabenazine and Increases Progressive Ratio Responding. Frontiers in Pharmacology, v. 10Tipo de documento
info:eu-repo/semantics/articleVersión de la editorial
https://www.frontiersin.org/articles/10.3389/fphar.2019.00682/fullVersión
info:eu-repo/semantics/publishedVersionPalabras clave / Materias
Resumen
Animal studies of effort-based choice behavior are being used to model effort-related
motivational dysfunctions in humans. With these procedures, animals are offered a choice
between high-effort instrumental actions ... [+]
Animal studies of effort-based choice behavior are being used to model effort-related
motivational dysfunctions in humans. With these procedures, animals are offered a choice
between high-effort instrumental actions leading to highly valued reinforcers vs. low effort/
low reward options. Several previous studies have shown that dopamine (DA) uptake
inhibitors, including GBR12909, lisdexamfetamine, methylphenidate, and PRX-14040,
can reverse the effort-related effects of the vesicular monoamine transport blocker
tetrabenazine, which inhibits DA storage. Because many drugs that block DA transport
act as major stimulants that also release DA, and produce a number of undesirable
side effects, there is a need to develop and characterize novel atypical DA transport
inhibitors. (S)-CE-123 ((S)-5-((benzhydrylsulfnyl) methyl)thiazole) is a recently developed
analog of modafnil with the biochemical characteristics of an atypical DA transport
blocker. The present paper describes the enantioselective synthesis and initial chemical
characterization of (S)-CE-123, as well as behavioral experiments involving effort-based
choice and microdialysis studies of extracellular DA. Rats were assessed using the fxed
ratio 5/chow feeding choice test. Tetrabenazine (1.0 mg/kg) shifted choice behavior,
decreasing lever pressing and increasing chow intake. (S)-CE-123 was coadministered
at doses ranging from 6.0 to 24.0 mg/kg, and the highest dose partially but signifcantly
reversed the effects of tetrabenazine, although this dose had no effect on fxed ratio
responding when administered alone. Additional experiments showed that (S)-CE-123
signifcantly increased lever pressing on a progressive ratio/chow feeding choice task and
that the effective dose (24.0 mg/kg) increased extracellular DA in nucleus accumbens core.
In summary, (S)-CE-123 has the behavioral and neurochemical profle of a compound
that can block DA transport, reverse the effort-related effects of tetrabenazine, and
increase selection of high-effort progressive ratio responding. This suggests that (S)-CE-
123 or a similar compound could be useful as a treatment for effort-related motivational
dysfunction in humans. [-]
Publicado en
Frontiers in Pharmacology (2019), v. 10Proyecto de investigación
Fondazione di Sardegna (Esercizio finanziario 2017), FIR 2019, Fondo di Sviluppo e Coesione 2014-2020(Project RASSR03071; CUP F76C18000830002).Derechos de acceso
info:eu-repo/semantics/openAccess
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