Effects of ethanol or rimcazole on dizocilpine maleate–induced behaviors in male and female rats☆

Abstract 

The current investigation was undertaken to explore further the interactions between ethanol and the phencyclidine analog dizocilpine maleate (MK-801) on behaviors in male and female rats. It was previously found that ethanol dependence conferred cross-tolerance to the behaviorally activating effects of dizocilpine. The current set of studies was designed to assay the interactions between dizocilpine and ethanol in ethanol-naive animals by measuring open field behaviors. I also tested interactions between dizocilpine and rimcazole, a sigma receptor antagonist. In agreement with previous reports, I found significant effects of dizocilpine on several open field behaviors. In general, female rats displayed a lower level of hyperlocomotion and higher level of stereotypies than did male rats. Co-administration of ethanol delayed time to peak hyperlocomotion in male rats. It reduced locomotion in female rats compared with findings for administration of dizocilpine alone. Co-administration of ethanol with dizocilpine increased stereotypies in both sexes. Administration of ethanol increased locomotion to a greater degree in female than in male rats. In contrast, co-administration of rimcazole with dizocilpine had little effect on hyperlocomotion in male rats while increasing levels in female rats. Rimcazole increased dizocilpine-induced stereotypies to a greater extent in male than in female rats. Results of receptor-binding studies revealed small differences for cerebral cortical sigma receptors between male and female rats. Dizocilpine was unable to compete for sigma receptor-binding sites. This is in contrast to phencyclidine, which acts at both N-methyl-d-aspartate (NMDA) and sigma receptors. These findings extend previous evidence of interactions between ethanol and dizocilpine, but highlight that responses vary by measure, sex, and length of ethanol exposure. In addition, findings from the current study uncovered sex-selective interactions between dizocilpine and a sigma receptor ligand, providing further evidence for complex actions and interactions of this noncompetitive NMDA receptor antagonist with multiple sites in brain.

Keywords:  Dizocilpine, Ethanol, Rimcazole, Sex, NMDA receptors, Sigma receptors