The long-acting D3 partial agonist MC-25-41 attenuates motivation for cocaine in sprague-dawley rats

Gregory L. Powell, Mark D. Namba, Annika Vannan, John Paul Bonadonna, Andrew Carlson, Rachel Mendoza, Peng Jen Chen, Robert R. Luetdke, Benjamin E. Blass, Janet L. Neisewander

Research output: Contribution to journalArticle

Abstract

The dopamine D3 receptor is a prime target for developing treatments for cocaine use disorders (CUDs). In this study, we conducted a pre-clinical investigation of the therapeutic potential of a long-acting, D3 receptor partial agonist, MC-25-41. Male rats were pre-treated with MC-25-41 (vehicle, 1.0, 3.0, 5.6, or 10 mg/kg, intraperitoneal (IP)) five minutes prior to tests of cocaine or sucrose intake on either a progressive ratio schedule of reinforcement or a variable interval 60 s multiple schedule consisting of 4, 15-min components with sucrose or cocaine available in alternating components. A separate cohort of rats was tested on a within-session, dose-reduction procedure to determine the effects of MC-25-41 on demand for cocaine using a behavioral economics analysis. Finally, rats were tested for effects of MC-25-41 on spontaneous and cocaine-induced locomotion. MC-25-41 failed to alter locomotion, but reduced reinforcement rates for both cocaine and sucrose on the low-effort, multiple schedule. However, on the higher-effort, progressive ratio schedule of cocaine reinforcement, MC-25-41 reduced infusions, and active lever presses at doses that did not alter sucrose intake. The behavioral economics analysis showed that MC-25-41 also increased cocaine demand elasticity compared to vehicle, indicating a reduction in consumption as price increases. Together, these results suggest that similar to other D3-selective antagonists and partial agonists, MC-25-41 reduces motivation for cocaine under conditions of high cost but has the added advantage of a long half-life (>10 h). These findings suggest that MC-25-41 may be a suitable pre-clinical lead compound for development of medications to treat CUDs.

Original languageEnglish (US)
Article number1076
Pages (from-to)1-16
Number of pages16
JournalBiomolecules
Volume10
Issue number7
DOIs
StatePublished - Jul 2020

Keywords

  • Behavioral economics
  • Cocaine
  • Dopamine D3 receptors
  • Motivation
  • Reinforcement
  • Self-administration

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology

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    Powell, G. L., Namba, M. D., Vannan, A., Bonadonna, J. P., Carlson, A., Mendoza, R., Chen, P. J., Luetdke, R. R., Blass, B. E., & Neisewander, J. L. (2020). The long-acting D3 partial agonist MC-25-41 attenuates motivation for cocaine in sprague-dawley rats. Biomolecules, 10(7), 1-16. [1076]. https://doi.org/10.3390/biom10071076