Abstract
Rationale
Atypical dopamine (DA) transport blockers such as modafinil and its analogs may be useful for treating motivational symptoms of depression and other disorders. Previous research has shown that the DA depleting agent tetrabenazine can reliably induce motivational deficits in rats, as evidenced by a shift towards a low-effort bias in effort-based choice tasks. This is consistent with human studies showing that people with major depression show a bias towards low-effort activities.
Objectives
Recent studies demonstrated that the atypical DA transport (DAT) inhibitor (S)-CE-123 reversed tetrabenazine-induced motivational deficits, increased progressive ratio (PROG) lever pressing, and increased extracellular DA in the nucleus accumbens. In the present studies, a recently synthesized modafinil analog, (S, S)-CE-158, was assessed in a series of neurochemical and behavioral studies in rats.
Results
(S, S)-CE-158 demonstrated the ability to reverse the effort-related effects of tetrabenazine and increase selection of high-effort PROG lever pressing in rats tested on PROG/chow feeding choice task. (S, S)-CE-158 showed a high selectivity for inhibiting DAT compared with other monoamine transporters, and systemic administration of (S, S)-CE-158 increased extracellular DA in the nucleus accumbens during the behaviorally active time course, which is consistent with the effects of (S)-CE-123 and other DAT inhibitors that enhance high-effort responding.
Conclusions
These studies provide an initial neurochemical characterization of a novel atypical DAT inhibitor, and demonstrate that this compound is active in models of effort-related choice. This research could contribute to the development of novel compounds for the treatment of motivational dysfunctions in humans.
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The authors would like to acknowledge Eurofins DiscoverX Corporation (Fremont, CA).
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This research was supported by grants the University of Connecticut Research Foundation (JS), University of Vienna (JS), and to MC from MINECO (PSI2015-68497-R) Spain. JS has received grants from, and done consulting work for, Pfizer, Roche, Shire, Prexa, Chronos, Blackthorn, Lundbeck and Acadia.
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Rotolo, R.A., Kalaba, P., Dragacevic, V. et al. Behavioral and dopamine transporter binding properties of the modafinil analog (S, S)-CE-158: reversal of the motivational effects of tetrabenazine and enhancement of progressive ratio responding. Psychopharmacology 237, 3459–3470 (2020). https://doi.org/10.1007/s00213-020-05625-6
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DOI: https://doi.org/10.1007/s00213-020-05625-6