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Front Pharmacol. 2019 Jun 28;10:682. doi: 10.3389/fphar.2019.00682. eCollection 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.

Author information

1
Department of Psychological Sciences, University of Connecticut, Storrs, CT, United States.
2
Department of Pharmaceutical Chemistry, Faculty of Life Sciences, University of Vienna, Vienna, Austria.
3
Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria.
4
X-ray Structure Analysis Centre, Faculty of Chemistry, University of Vienna, Vienna, Austria.
5
Department of Biomedical Sciences, University of Cagliari, National Institute of Neuroscience (INN), Cagliari, Italy.
6
Àrea de Psicobiologia, Universitat Jaume I, Castelló, Spain.
7
Department of Neuroproteomics, Paracelsus Medical University, Salzburg, Austria.

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.

KEYWORDS:

anergia; depression; dopamine; fatigue; modafinil; motivation; synthesis; transport

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