The Long-Acting D3 Partial Agonist MC-25-41 Attenuates Motivation for Cocaine in Sprague-Dawley Rats
| Autor: | Janet L. Neisewander, Rachel Mendoza, Robert R. Luetdke, Mark D. Namba, John Paul Bonadonna, Benjamin E. Blass, Annika Vannan, Andrew K. Carlson, Gregory L. Powell, Peng Jen Chen |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
lcsh:QR1-502 cocaine behavioral economics Pharmacology Biochemistry Partial agonist Article lcsh:Microbiology Rats Sprague-Dawley Cocaine-Related Disorders 03 medical and health sciences 0302 clinical medicine motivation Dopamine receptor D3 On demand Drug Discovery Sprague dawley rats Animals Medicine Reinforcement Molecular Biology 030304 developmental biology reinforcement 0303 health sciences business.industry Receptors Dopamine D3 Long acting Dopamine Agonists Progressive ratio dopamine D3 receptors Self-administration business self-administration Locomotion 030217 neurology & neurosurgery |
| Zdroj: | Biomolecules, Vol 10, Iss 1076, p 1076 (2020) Biomolecules Volume 10 Issue 7 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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