Anxiolytic effects of ethanol and phenobarbital are abolished in test-experienced rats submitted to the elevated plus maze.

Prior test experience compromises the anxiolytic efficacy of benzodiazepines (BZs) either in rats or mice, a phenomenon not exclusive to the elevated plus-maze (EPM) animal model of anxiety, which is referred to as "one-trial tolerance." However, it remains to be determined whether a similar event occurs when testing other drugs that also possess binding-sites on the GABA(A) receptor, such as ethanol and barbiturates. In the present study, we have addressed this issue using maze-naive and maze-experienced (free exploration of the EPM 48 h earlier for 5 min) rats pretreated with ethanol (1.0-1.4 g/kg) or phenobarbital (20-60 mg/kg) and submitted to the EPM. The results confirmed the anxiolytic profile of both drugs, represented by increased open arm exploration and decreased risk assessment behavior, in maze-naive rats. However, in maze-experienced rats, neither ethanol nor phenobarbital anxiolytic effects were observed, suggesting that prior maze experience compromised the drugs' anxiolytic activity. Thus, the "one-trial tolerance" phenomenon might also be extended to other drugs that bind to the GABA(A) receptor complex.