N-Phenylpropyl-N'-(3-methoxyphenethyl)piperazine (YZ-185) Attenuates the Conditioned-Rewarding Properties of Cocaine in Mice.

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  μ mol/kg) dose and dose-dependently attenuated cocaine-induced hyperactivity at higher (3.16-31.6  μ mol/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  μ mol/kg) did not have intrinsic activity to produce conditioned place preference or aversion. A higher (31.6  μ mol/kg) YZ-185 dose, but not lower (0.1-3.16  μ mol/kg) YZ-185 doses, prevented the development of place preference to cocaine (66  μ mol/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  μ mol/kg dose and demonstrate that sigma receptors can mediate the development of the conditioned-rewarding properties of cocaine.