The discriminative stimulus effects of bretazenil and lorazepam in rats trained to discriminate pentobarbital from saline

Abstract

Low‐efficacy positive modulators of the GABAA receptor, such as bretazenil, could potentially treat anxiety disorders with less liability for abuse and dependence than traditional benzodiazepines. For this reason, bretazenil was compared with pentobarbital and lorazepam (high‐efficacy positive modulators) in rats trained to discriminate 10 mg/kg of pentobarbital from saline under a fixed‐ratio 20 schedule of food reinforcement. To establish a dose‐response curve in a single session, a cumulative‐dosing procedure was used in which subjects received increasing doses prior to each of four test components. Full substitution was defined as greater than 80% of total lever presses occurring on the pentobarbital‐associated lever. When increasing doses of pentobarbital were administered, pentobarbital‐lever responding increased up to doses that decreased response rate. Unlike pentobarbital, lorazepam only substituted for pentobarbital at doses that decreased response rate. Bretazenil fully substituted in each subject tested. Furthermore, ineffective doses of bretazenil were able to shift the lorazepam dose‐response curve upward and to the left. Together, these data indicate that bretazenil produces pentobarbital‐like discriminative stimulus effects and enhances the effects of lorazepam, indicating that this combination could be clinically useful for long‐term treatment of anxiety disorders.This work supported by an NIH grant from the National Institute on Alcohol Abuse and Alcoholism AA019848‐01