The Long-Acting D3 Partial Agonist MC-25-41 Attenuates Motivation for Cocaine in Sprague-Dawley Rats

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.

Neuronal Dopamine D3 Receptors: Translational Implications for Preclinical Research and CNS Disorders

“…Among N-(4-(4-phenyl piperazin-1-yl)butyl)-4-(thiophen-3-yl)benzamides [ 157 ], MC-25-41 (D3R Ki: 0.5 nM, 1,486-fold selectivity over D2Rs) has been identified as potent and long acting partial agonist for the D3R. MC-25-41 has been found to reduce motivation for cocaine in rats and the long half-life of the drug may render it useful in the treatment of cocaine abuse [ 158 ].…”

An approach for prioritizing candidate genes from RNA-seq using preclinical cocaine self-administration datasets as a test case

“…a) Brain specificity, as measured by log2 FC of expression in CNS tissues vs all other tissues, of Candidate genes (orange) compared to all other genes (gray) in GTEx V8. Select genes are labeled, including several established genes in clinical SUDs and/or preclinical models of substance abuse— CREB1 ( Carlezon et al 1998 ; McClung and Nestler 2003 ), C1QL2 ( Gelernter et al 2014 ; Huggett and Stallings 2020 ), DRD3 ( Neisewander et al 2014 ; Powell et al 2018 ; Powell, Namba, et al 2020 ), and FAM53B ( Gelernter et al 2014 ). * indicates significant difference ( P < 0.05) for Candidate genes in a given dataset compared to all other genes not in any dataset with Mann–Whitney U test.…”

Dopamine D3 Receptor: Contemporary Views of Its Function and Pharmacology for Neuropsychiatric Diseases

“…Partial agonists at D3Rs also have a strong interest in the treatment of cocaine addiction. Powell et al proposed pharmacological characterization of the selective D3R partial agonist MC-25-41 against cocaine addiction [ 5 ]. They confirmed using this specific compound that D3R partial agonism opposes cocaine consumption in rats in a progressive fixed-ratio schedule or in a variable interval of multiple schedules.…”