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Potential therapeutics for effort-related motivational dysfunction: assessing novel atypical dopamine transport inhibitors

Neuropsychopharmacology (2024)Cite this article

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Abstract

People with depression and other neuropsychiatric disorders can experience motivational dysfunctions such as fatigue and anergia, which involve reduced exertion of effort in goal-directed activity. To model effort-related motivational dysfunction, effort-based choice tasks can be used, in which rats can select between obtaining a preferred reinforcer by high exertion of effort vs. a low effort/less preferred option. Preclinical data indicate that dopamine transport (DAT) inhibitors can reverse pharmacologically-induced low-effort biases and increase selection of high-effort options in effort-based choice tasks. Although classical DAT blockers like cocaine can produce undesirable effects such as liability for misuse and psychotic reactions, not all DAT inhibitors have the same neurochemical profile. The current study characterized the effort-related effects of novel DAT inhibitors that are modafinil analogs and have a range of binding profiles and neurochemical actions (JJC8-088, JJC8-089, RDS3-094, and JJC8-091) by using two different effort-related choice behavior tasks in male Sprague-Dawley rats. JJC8-088, JJC8-089, and RDS3-094 significantly reversed the low-effort bias induced by the VMAT-2 inhibitor tetrabenazine, increasing selection of high-effort fixed ratio 5 lever pressing vs. chow intake. In addition, JJC8-089 reversed the effects of tetrabenazine in female rats. JJC8-088 and JJC8-089 also increased selection of high-effort progressive ratio responding in a choice task. However, JJC8-091 failed to produce these outcomes, potentially due to its unique pharmacological profile (i.e., binding to an occluded conformation of DAT). Assessment of a broad range of DAT inhibitors with different neurochemical characteristics may lead to the identification of compounds that are useful for treating motivational dysfunction in humans.

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Fig. 1: The effects of JJC8-088 on TBZ-induced changes on the FR/chow feeding choice procedure during the 30 min session (A-B).
Fig. 2: The effects of JJ8-089 on TBZ-induced changes on the FR/chow feeding choice procedure during the 30 min session (A-B).
Fig. 3: The effects of RDS3-094 on TBZ-induced changes on the FR/chow feeding choice procedure during the 30 min session (A-B).
Fig. 4: The effects of JJC8-091 on TBZ-induced changes on the FR/chow feeding choice procedure during the 30 min session (A-B).
Fig. 5: The effects of JJ8-089 on TBZ-induced changes on the FR/chow feeding choice procedure in female rats (A, B).

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Data availability

Data files will be provided upon request (john.salamone@uconn.edu).

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Acknowledgements

This research was partially supported by grants to JS from NIMH (R01MH121350) and the University of Connecticut Research Foundation.

Funding

Funding from the NIDA-Intramural Research Program was provided to AHN (Z1A DA000389). AO was supported by the NIDA-Intramural Research Program’s Scientific Director’s Fellowship for Diversity in Research

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  1. These authors contributed equally: Alev Ecevitoglu, Nicolette Meka.

Authors and Affiliations

  1. Psychological Sciences, University of Connecticut, Storrs, CT, 06269-1020, USA

    Alev Ecevitoglu, Nicolette Meka, Renee A. Rotolo, Gayle A. Edelstein, Sonya Srinath, Kathryn R. Beard, Carla Carratala-Ros, Rose E. Presby & John D. Salamone

  2. Area de Psicobiología. Universitat Jaume I, Castelló, Spain

    Carla Carratala-Ros & Mercè Correa

  3. Medicinal Chemistry Section, NIDA-Intramural Research Program, Baltimore, MD, 21224, USA

    Jianjing Cao, Amarachi Okorom & Amy H. Newman

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  1. Alev Ecevitoglu
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Contributions

Alev Ecevitoglu, Renee A. Rotolo, Nicolette Meka: data collection and analysis, manuscript preparation; Gayle Edelstein, Sonya Srinath, Carla Ros, Kathryn Beard, Rose E. Presby: data collection and analysis; Jianjing Cao, Amarachi Okorom: compound synthesis and characterization; Merce Correa: conceptualization, research supervision, manuscript preparation. John D. Salamone, Amy H. Newman: conceptualization, methodology, formal analysis, manuscript preparation; funding acquisition.

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Ecevitoglu, A., Meka, N., Rotolo, R.A. et al. Potential therapeutics for effort-related motivational dysfunction: assessing novel atypical dopamine transport inhibitors. Neuropsychopharmacol. (2024). https://doi.org/10.1038/s41386-024-01826-1

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