Dopamine D3 receptor partial agonist LS-3-134 attenuates cocaine-motivated behaviors

Powell, Gregory L.; Bonadonna, John Paul; Vannan, Annika; Xu, Kuiying; Mach, Robert H.; Luedtke, Robert R.; Neisewander, Janet L.

doi:10.1016/j.pbb.2018.10.002

Cited by 8 publications

(10 citation statements)

References 42 publications

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“…Additional studies that employ female rats are needed as sex differences in dopamine systems are documented and will be crucial to investigate for the advancement of D3R treatment strategies [59][60][61][62][63]. Also given that other D3R partial agonists reduce cocaine-seeking behavior in the reinstatement model [11,[36][37][38][39][40], future research using this model would further support our observed MC-25-41-induced changes in behavioral economic parameters reflecting a reduction in motivation for cocaine.…”

Section: Discussionmentioning

confidence: 73%

“…As thoroughly reviewed by Sokoloff and Le Foll [9], D3R drugs reduce cocaine-motivated behaviors on high-but not low-effort schedules of reinforcement. Dopamine D3R partial agonists and antagonists are generally ineffective in altering cocaine intake on low fixed ratio schedules requiring 5 or fewer responses [10][11][12][13][14]. Similarly, we have found that cocaine intake on a low-effort variable interval (VI) 60 s schedule of reinforcement is only affected at doses of D3R partial agonists and antagonists that also affect sucrose reinforcement and cocaine-induced locomotor activity [11].…”

Section: Introductionmentioning

confidence: 73%

“…Our finding that MC-25-41 reduced cocaine intake when rats were tested on the higher-effort PR schedule is consistent with previous studies with other D3R antagonists and partial agonists. We have previously reported, for example, that a D3R-selective partial agonist phenylpiperazine, LS-3-134, successfully reduces cocaine intake on a PR schedule [11]. Several other studies have shown similar effects of D3R antagonists and partial agonists when animals are tested on a PR schedule for cocaine reinforcement [13,15,16,41].…”

Section: Discussionmentioning

confidence: 94%

“…Experimentally naïve animals were tested for effects of MC-25-41 on cocaine-induced and/or spontaneous locomotor activity following similar procedures to those previously described [11]. All animals were randomly assigned to groups that received one of three doses of MC-25-41 (1.0, 3.0, or 5.6 mg/kg IP; n = 8-12/dose) prior to tests of drug effects and they also received vehicle prior to separate control tests, with the order of drug and vehicle tests counterbalanced.…”

Section: Locomotionmentioning

confidence: 99%

“…Dopamine D3R partial agonists and antagonists are generally ineffective in altering cocaine intake on low fixed ratio schedules requiring 5 or fewer responses [10][11][12][13][14]. Similarly, we have found that cocaine intake on a low-effort variable interval (VI) 60 s schedule of reinforcement is only affected at doses of D3R partial agonists and antagonists that also affect sucrose reinforcement and cocaine-induced locomotor activity [11]. In contrast, on high-effort progressive ratio (PR) schedules that require progressively more responses for reinforcement, D3R partial agonists and antagonists selectively decrease cocaine intake [11,15].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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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.

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