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Pharmacol Biochem Behav. 2018 Dec;175:123-129. doi: 10.1016/j.pbb.2018.10.002. Epub 2018 Oct 8.

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

Author information

1
School of Life Sciences, Arizona State University, Tempe, AZ, United States of America.
2
Department of Radiology, University of Pennsylvania School of Medicine, Philadelphia, PA, United States of America.
3
University of North Texas Health Science Center, the Department of Pharmacology and Neuroscience, Fort Worth, TX, United States of America.
4
School of Life Sciences, Arizona State University, Tempe, AZ, United States of America. Electronic address: janet.neisewander@asu.edu.

Abstract

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.

KEYWORDS:

Cocaine-seeking behavior; Extinction; Phenylpiperazine; Progressive ratio; Reinforcement (psychology); Reinstatement; Substance use disorders

PMID:
30308214
DOI:
10.1016/j.pbb.2018.10.002
[Indexed for MEDLINE]

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