Behavioral and dopamine transporter binding properties of the modafinil analog ( S , S )-CE-158: reversal of the motivat
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ORIGINAL INVESTIGATION
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 Renee A. Rotolo 1 & Predrag Kalaba 2,3 & Vladimir Dragacevic 2 & Rose E. Presby 1 & Julia Neri 1 & Emily Robertson 1 & Jen-Hau Yang 1 & Merce Correa 1,4 & Vasiliy Bakulev 5 & Natalia N. Volkova 5 & Christian Pifl 6 & Gert Lubec 3 & John D. Salamone 1 Received: 4 June 2020 / Accepted: 27 July 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
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 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. Keywords Dopamine . Transport . Synthesis . Motivation . Depression . Fatigue . Anergia . Modafinil
Introduction Motivational symptoms such as anergia, fatigue, and effortrelated dysfunctions are common and debilitating features of
major depressive disorder, schizophrenia, Parkinson’s disease and other psychiatric and neurological disorders (Tylee et al. 1999; Demyttenaere et al. 2005; Treadway et al. 2012; Barch et al. 2014; Chong et al. 2015). Motivational symptoms are
* Gert Lubec [email protected]
3
Department of Neuroproteomics, Paracelsus Medical University, Salzburg, Austria
* John D. Salamone [email protected]
4
Àrea de Psicobiologia, Campus de Riu Sec, U
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