TY - JOUR
T1 - The long-acting D3 partial agonist MC-25-41 attenuates motivation for cocaine in sprague-dawley rats
AU - Powell, Gregory L.
AU - Namba, Mark D.
AU - Vannan, Annika
AU - Bonadonna, John Paul
AU - Carlson, Andrew
AU - Mendoza, Rachel
AU - Chen, Peng Jen
AU - Luetdke, Robert R.
AU - Blass, Benjamin E.
AU - Neisewander, Janet L.
N1 - Funding Information:
Funding: This research was funded by the National Institute on Drug Abuse (#DA023957).
Funding Information:
This research was funded by the National Institute on Drug Abuse (#DA023957). We would like to thank Jennifer Hesterman, Sophia M. Doyle, and Ashley Adams for their assistance running behavioral experiments. Additionally, we would like to thank Raul Garcia, Samantha Scott, andTaleenDer-Ghazarianfortheirassistancewithcatheterimplantationsurgeries. Additionally,MC-25-41o?site binding data was provided by the National Institute of Mental Health Psychoactive Drug Screening Program [23].
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/7
Y1 - 2020/7
N2 - 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.
AB - 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.
KW - Behavioral economics
KW - Cocaine
KW - Dopamine D3 receptors
KW - Motivation
KW - Reinforcement
KW - Self-administration
UR - http://www.scopus.com/inward/record.url?scp=85088163044&partnerID=8YFLogxK
U2 - 10.3390/biom10071076
DO - 10.3390/biom10071076
M3 - Article
C2 - 32708461
AN - SCOPUS:85088163044
SN - 2218-273X
VL - 10
SP - 1
EP - 16
JO - Biomolecules
JF - Biomolecules
IS - 7
M1 - 1076
ER -