LAUSR

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 5.6mg/kg, IP) 15min 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 10.0mg/kg, IP) on operant responding on a multiple variable‐interval (VI) 60‐second schedule with alternating cocaine (0.375mg/kg, IV) and sucrose (45mg) reinforcer components. Additionally, we tested LS‐3–134 (5.6mg/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.