TY - JOUR
T1 - Dopamine D3 receptor partial agonist LS-3-134 attenuates cocaine-motivated behaviors
AU - Powell, Gregory L.
AU - Bonadonna, John Paul
AU - Vannan, Annika
AU - Xu, Kuiying
AU - Mach, Robert H.
AU - Luedtke, Robert R.
AU - Neisewander, Janet
N1 - Funding Information:
This work was supported by the National Institute on Drug Abuse [Grant DA023957 ]. The authors acknowledge Andrew K. Carlson, Taleen Der-Ghazarian, Raul Garcia, Samantha Scott, Broc A. Pagni, Jennifer Hesterman, Trisha Chaudhury, Austin R. Cotter, Ryan M. Bastle, Ph.D., and Natalie Peartree, Ph.D., for their technical assistance with the experiments.
PY - 2018/12
Y1 - 2018/12
N2 - Aims: The dopamine D3 receptor (D3R) is a pharmacotherapeutic target for drug dependence. We have successfully imaged human D3Rs using radiolabeled LS-3-134, an arylamide phenylpiperazine with moderate selectivity for the D3R over D2R and low efficacy at the D2 and D3R. In this study, we screened for effects of LS-3-134 as a potential anti-cocaine therapeutic. Methods: Male rats were pretreated with LS-3-134 (0, 1.0, 3.2, or 5.6 mg/kg, IP) 15 min prior to tests for its effects on spontaneous and cocaine-induced locomotion. We next investigated the effects of LS-3-134 (0, 1.0, 3.2, 5.6, or 10.0 mg/kg, IP) on operant responding on a multiple variable-interval (VI) 60-second schedule with alternating cocaine (0.375 mg/kg, IV) and sucrose (45 mg) reinforcer components. Additionally, we tested LS-3-134 (5.6 mg/kg, IP) effects on a progressive ratio (PR) schedule of cocaine reinforcement, on extinction of cocaine-seeking behavior, and on reinstatement of extinguished cocaine-seeking behavior by cocaine-associated light/tone cues. Results: LS-3-134 did not alter spontaneous locomotion, but reduced cocaine-induced locomotion, break points on the high-effort progressive ratio schedule of reinforcement, and responding during extinction and cue reinstatement. In contrast, LS-3-134 did not alter cocaine or sucrose reinforcement on the low-effort multiple VI 60-second schedule. Conclusions: The effects of LS-3-134 are similar to other dopamine D3 low efficacy partial agonists and antagonists in attenuating cocaine intake under high effort schedules of reinforcement and in attenuating cocaine-seeking behavior elicited by cocaine-associated cues. These findings are consistent with the anti-craving profile of other dopamine D3 drugs.
AB - Aims: The dopamine D3 receptor (D3R) is a pharmacotherapeutic target for drug dependence. We have successfully imaged human D3Rs using radiolabeled LS-3-134, an arylamide phenylpiperazine with moderate selectivity for the D3R over D2R and low efficacy at the D2 and D3R. In this study, we screened for effects of LS-3-134 as a potential anti-cocaine therapeutic. Methods: Male rats were pretreated with LS-3-134 (0, 1.0, 3.2, or 5.6 mg/kg, IP) 15 min prior to tests for its effects on spontaneous and cocaine-induced locomotion. We next investigated the effects of LS-3-134 (0, 1.0, 3.2, 5.6, or 10.0 mg/kg, IP) on operant responding on a multiple variable-interval (VI) 60-second schedule with alternating cocaine (0.375 mg/kg, IV) and sucrose (45 mg) reinforcer components. Additionally, we tested LS-3-134 (5.6 mg/kg, IP) effects on a progressive ratio (PR) schedule of cocaine reinforcement, on extinction of cocaine-seeking behavior, and on reinstatement of extinguished cocaine-seeking behavior by cocaine-associated light/tone cues. Results: LS-3-134 did not alter spontaneous locomotion, but reduced cocaine-induced locomotion, break points on the high-effort progressive ratio schedule of reinforcement, and responding during extinction and cue reinstatement. In contrast, LS-3-134 did not alter cocaine or sucrose reinforcement on the low-effort multiple VI 60-second schedule. Conclusions: The effects of LS-3-134 are similar to other dopamine D3 low efficacy partial agonists and antagonists in attenuating cocaine intake under high effort schedules of reinforcement and in attenuating cocaine-seeking behavior elicited by cocaine-associated cues. These findings are consistent with the anti-craving profile of other dopamine D3 drugs.
KW - Cocaine-seeking behavior
KW - Extinction
KW - Phenylpiperazine
KW - Progressive ratio
KW - Reinforcement (psychology)
KW - Reinstatement
KW - Substance use disorders
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U2 - 10.1016/j.pbb.2018.10.002
DO - 10.1016/j.pbb.2018.10.002
M3 - Article
C2 - 30308214
AN - SCOPUS:85055052496
SN - 0091-3057
VL - 175
SP - 123
EP - 129
JO - Pharmacology Biochemistry and Behavior
JF - Pharmacology Biochemistry and Behavior
ER -