Sigma receptor antagonists diminish the effects of cocaine in behavioral assays, including conditioned place preference. Previous locomotor activity experiments in mice determined that the sigma receptor ligand YZ-185 (N-phenylpropyl-N′-(3-methoxyphenethyl)piperazine) enhanced cocaine-induced hyperactivity at a lower (0.1？μmol/kg) dose and dose-dependently attenuated cocaine-induced hyperactivity at higher (3.16–31.6？μmol/kg) doses. The present study investigated the effect of YZ-185 on cocaine’s conditioned-rewarding properties in mice. YZ-185 (0.1, 0.316, 3.16, and 31.6？μmol/kg) did not have intrinsic activity to produce conditioned place preference or aversion. A higher (31.6？μmol/kg) YZ-185 dose, but not lower (0.1–3.16？μmol/kg) YZ-185 doses, prevented the development of place preference to cocaine (66？μmol/kg). YZ-185 did not alter the expression of cocaine place preference. To further characterize YZ-185’s behavioral profile, its effects in the elevated zero maze and rotarod procedures were also determined; YZ-185 produced no significant change from baseline in either assay, indicating that the sigma receptors probed by YZ-185 do not regulate anxiety-like or coordinated motor skill behaviors. Overall, these results suggest that YZ-185 is a sigma receptor antagonist at the 31.6？μmol/kg dose and demonstrate that sigma receptors can mediate the development of the conditioned-rewarding properties of cocaine. 1. Introduction The conditioned place preference procedure in rodents is used to study the conditioned-rewarding properties of drugs of abuse (e.g., cocaine) that can contribute to substance abuse and dependence in humans [1, 2]. During the development of conditioned place preference, cocaine injection is paired with a distinct context, and vehicle is paired with a different context. The expression of place preference is examined in a cocaine-free state when the rodent is given free choice access to both contexts. Conditioned place preference (CPP) is defined as an increase in the amount of time spent on the drug paired side (DPS, e.g., cocaine context), relative to the amount of time spent on this same side during a preconditioning trial (CPP score = DPSpostest？？？ DPSpretest). The development and expression of cocaine-induced conditioned place preference have most frequently been attributed to the drug’s efficacy to regulate dopamine signaling in the brain; however, other neural circuits—such as those associated with memory, motor control, and anxiety—play an important role in this effect [3–5]. Sigma receptors contribute to cocaine’s behavioral
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