Dizocilpine prevents the development of tolerance to the sedative effects of diazepam in rats

Abstract

Acute treatment with diazepam (2 mg/kg) decreased locomotor activity, rearing, and the number of head dips made in a holeboard. After 3 days of diazepam treatment, tolerance developed to the decreases in locomotor activity and the number of head dips, and there was an emergence of an increased time spent head dipping, compared with controls. Two days of concomitant treatment with the noncompetitive NMDA receptor antagonist, dizocilpine (0.25 mg/kg) blocked the development of tolerance and the increased time spent head dipping. In some respects, the effects of dizocilpine resembled those of holeboard experience. Thus, the rats tested daily in the holeboard after diazepam treatment showed significantly less tolerance to the decrease in locomotor activity and did not show enhanced time spent head dipping after 3 days of treatment. Possible similarities between changes induced by experience and those occurring during the development of tolerance are discussed.