Effects of N-phenylpropyl-N′-substituted piperazine sigma receptor ligands on cocaine-induced hyperactivity in mice

The present study examined N-phenylpropyl-N′-substituted piperazine sigma receptor ligands on cocaine-induced changes in locomotor activity in mice. Previous reports indicate that N-phenylpropyl-N′-(4-methoxybenzyl)piperazine (Nahas-3h), N-phenylpropyl-N′-(4-methoxyphenethyl)piperazine (YZ-067), and N-phenylpropyl-N′-(3-methoxyphenethyl)piperazine (YZ-185) bind with high affinity (Ki values ≈ 1 nM) to σ1 sigma receptors. YZ-067 and YZ-185 are known to attenuate cocaine-induced convulsions, while Nahas-3h has not been tested in behavioral studies. Nahas-3h significantly attenuated cocaine-induced hyperactivity. YZ-067 decreased the effect of cocaine in a dose-dependent manner. Interestingly, YZ-185 inhibited cocaine's effect at higher doses, but enhanced cocaine's effect at a low dose. The YZ-185 inhibition of cocaine-induced hyperactivity was not surmounted by increasing the cocaine dose. Overall, this study is consistent with previous work showing the ability of certain sigma receptor ligands to affect cocaine-induced hyperactivity. Further, subtle alterations of ligand structure and the specific dosage levels employed influence the behavioral effects observed, with a 3-methoxy substituent apparently conferring the ability of a ligand to enhance cocaine's locomotor stimulatory effects.