Effects of the selective sigma receptor ligand, 1-(2-phenethyl)piperidine oxalate (AC927), on the behavioral and toxic effects of cocaine

Background: Sigma receptors represent a unique structural class of proteins and they have become increasingly studied as viable medication development targets for neurological and psychiatric disorders, including drug abuse. Earlier studies have shown that cocaine and many other abused substances interact with sigma receptors and that antagonism of these proteins can mitigate their actions. Methods: In the present study, AC927 (1-(2-phenethyl)piperidine oxalate), a selective sigma receptor ligand, was tested against the behavioral and toxic effects of cocaine in laboratory animals. Results: Acute administration of AC927 in male, Swiss Webster mice significantly attenuated cocaine-induced convulsions, lethality, and locomotor activity, at doses that alone had no significant effects on behavior. Subchronic administration of AC927 also attenuated cocaine-induced conditioned place preference in mice, at doses that alone had no effects on place conditioning. In drug discrimination studies in male, Sprague-Dawley rats, AC927 partially substituted for the discriminative stimulus effects of cocaine. When it was administered with cocaine, AC927 shifted the cocaine dose-response curve to the left, suggesting an enhancement of the discriminative stimulus effects of cocaine. In non-human primates, AC927 was self-administered, maintaining responding that was intermediate between contingent saline and a maintenance dose of cocaine. Conclusion: The ability of AC927 to elicit some cocaine-like appetitive properties and to also reduce many cocaine-induced behaviors suggests that it is a promising lead for the development of a medication to treat cocaine abuse. (C) 2011 Elsevier Ireland Ltd. All rights reserved.