Anxioselective profile of glycineB receptor partial agonist, d-cycloserine, in plus-maze-naïve but not plus-maze-experienced mice

Recent successes as a pharmacological adjunct to exposure therapy has focused attention on the therapeutic potential of the glycineB receptor partial agonist, d-cycloserine (DCS), in certain clinical anxiety disorders. Although widely believed to reflect a facilitation of extinction learning, previous research with DCS and other glycineB partial agonists suggests the additional possibility of intrinsic anxiolytic activity. In the present study, ethological methods were used to profile the behavioural effects of DCS (7.5–30.0 mg/kg) and the positive control chlordiazepoxide (CDP, 15 mg/kg) in mice exposed to the elevated plus-maze for the first time (plus-maze trial 1; Experiment 1) and in mice pre-exposed undrugged to the maze 24 h prior to testing (plus-maze trial 2; Experiment 2). The results show that, in test-naive animals, both CDP and DCS (15 mg/kg, but not lower or higher doses) produced significant anxioselective profiles with the effects of DCS statistically weaker than those of CDP. However, as predicted by the plus-maze retest effect, CDP was without behavioural activity in test-experienced animals, while the highest dose of DCS (30 mg/kg) induced behavioural changes more consistent with mild psychomotor stimulation than anxiolysis. Present findings therefore confirm the intrinsic anxiolytic activity of DCS in untrained animals, with the observed bell-shaped dose–response function most probably indicative of varying affinities and intrinsic activities at NMDA receptor subtypes. The contrasting and comparatively limited effects of DCS in test-experienced mice suggest that prior maze exposure radically alters the extent to which NMDA receptor-related mechanisms are involved in future behavioural responses to this test environment.