Abstract
Dopamine D3 receptor (D3R)-selective compounds may be useful medications for cocaine dependence. In this study, we identified two novel arylamide phenylpiperazines, OS-3-106 and WW-III-55, as partial agonists at the D3R in the adenylyl cyclase inhibition assay. OS-3-106 and WW-III-55 have 115- and 862-fold D3R:D2 receptor (D2R) binding selectivity, respectively. We investigated their effects (0, 3, 5.6, or 10 mg/kg) on operant responding by using a multiple variable-interval (VI) 60-second schedule that alternated components with sucrose reinforcement and components with intravenous cocaine reinforcement (0.375 mg/kg). Additionally, we evaluated the effect of OS-3-106 (10 mg/kg) on the dose-response function of cocaine self-administration and the effect of WW-III-55 (0–5.6 mg/kg) on a progressive ratio schedule with either cocaine or sucrose reinforcement. Both compounds were also examined for effects on locomotion and yawning induced by a D3R agonist. OS-3-106 decreased cocaine and sucrose reinforcement rates, increased latency to first response for cocaine but not sucrose, and downshifted the cocaine self-administration dose-response function. WW-III-55 did not affect cocaine self-administration on the multiple-variable interval schedule, but it reduced cocaine and sucrose intake on the progressive ratio schedule. Both compounds reduced locomotion at doses that reduced responding, and both compounds attenuated yawning induced by low doses of 7-OH-DPAT (a D3R-mediated behavior), but neither affected yawning on the descending limb of the 7-OH-DPAT dose-response function (a D2R-mediated behavior). Therefore, both compounds blocked a D3R-mediated behavior. However, OS-3-106 was more effective in reducing cocaine self-administration. These findings support D3Rs, and possibly D2Rs, as targets for medications aimed at reducing the motivation to seek cocaine.
Footnotes
- Received January 3, 2013.
- Accepted August 1, 2013.
↵1 Current affiliation: University of Maryland, Baltimore, Maryland.
This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grant DA023957]. K.C.N. was supported by the School of Life Sciences Undergraduate Research Program from the Arizona State University.
Portions of this work were previously presented at the following conference: Cheung THC, Weber SM, Chandler KN, Lenz JD, Fahl R, Mach RH, Luedtke RR, Neisewander JL (2012) Attenuation of cocaine self-administration by two D3 receptor-selective novel phenylpiperazine derivatives. Annual Meeting of the Society for Neuroscience; 2012, Oct 13–17, New Orleans, LA.
↵This article has supplemental material available at jpet.aspetjournals.org.
- Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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