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
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Title
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 respondingAuthor (s)
Date
2020Publisher
SpringerISSN
0033-3158; 1432-2072Bibliographic citation
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/s00213-020-05625-6Type
info:eu-repo/semantics/articlePublisher version
https://link.springer.com/article/10.1007/s00213-020-05625-6Version
info:eu-repo/semantics/publishedVersionSubject
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 ... [+]
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 tetrabenazineinduced 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 higheffort 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. [-]
Is part of
Psychopharmacology (2020) 237.Investigation project
PSI2015-68497-RRights
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