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.

Renee A Rotolo,Ernst Urban,Shanna Samels,Vladimir Dragacevic,Merce Correa,Marco Pistis,Alexander Roller,Francesca Caria,Judith Wackerlig,Jen-Hau Yang,Gert Lubec,Maria Antonietta De Luca,Thierry Langer,Martin Zehl,Rebecca Schwartz,Predrag Kalaba,Rose E Presby,John D Salamone

doi:10.3389/fphar.2019.00682

Abstract

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-((benzhydrylsulfinyl) methyl)thiazole) is a recently developed analog of modafinil 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 fixed 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 significantly reversed the effects of tetrabenazine, although this dose had no effect on fixed ratio responding when administered alone. Additional experiments showed that (S)-CE-123 significantly 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 profile 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.

Highlights

Motivational symptoms such as fatigue, anergia, and psychomotor slowing are seen in depression, Parkinson’s disease, and other disorders
The present paper describes the enantioselective synthesis and initial characterization of (S)-CE-123
Additional planned comparisons revealed that coadministration of the dose of 24.0 mg/kg (S)-CE123 with TBZ significantly attenuated the effects of TBZ on lever pressing {TBZ plus 24.0 mg/kg vs. TBZ/Veh [F(1,28) = 13.2866, p < 0.01]} and chow intake {TBZ plus 24.0 mg/kg vs. TBZ/Veh [F(1,28) = 61.014, p < 0.001]}

Summary

Introduction

Motivational symptoms such as fatigue, anergia, and psychomotor slowing are seen in depression, Parkinson’s disease, and other disorders These symptoms are often debilitating and can severely limit long-term functional outcomes (Demyttenaere et al, 2005; Salamone et al, 2006; Friedman et al, 2007; Fava et al, 2014; Rothschild et al, 2014; Chong et al, 2015; Salamone et al, 2016a; Salamone et al, 2016b; Salamone et al, 2016c; Salamone et al, 2017). Psychomotor stimulants that block DAT can have undesirable effects, such as abuse liability and induction of psychotic symptoms For these reasons, it is important to develop and assess drugs that are highly selective for DAT but show atypical neurochemical characteristics that may lower the side effect profile

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Conclusion