Chronic treatment with antidepressants affects glycine/NMDA receptor function: behavioral evidence.

Like the clinically effective benzodiazepine anxiolytic, chlordiazepoxide, the glycine/NMDA receptor antagonist L-701,324 (3, 7.5 and 10 mg/kg), produces dose-related increases in the percentage of time spent in the open arms and the percentage of entries into the open arms of an elevated plus maze in mice. Consistent with its proposed mechanism of action, these anxiolytic effects of L-701,324 (7.5 mg/kg) are reversed by pretreatment with glycine (500 and 800 mg/kg). Chronic treatment with citalopram (20 mg/kg for 21 days), imipramine (15 mg/kg for 21 days) and electroconvulsive shock (ECS, for 8 days), produced a reduction in the anxiolytic-like actions of L-701,324 (7.5 mg/kg) such that they could not be reversed by glycine. In contrast, the anxiolytic effects of L-701,324 and reversal of these effects by glycine were unaffected by acute treatment with imipramine, chronic administration with placebo or the neuroleptic chlorpromazine, or sham ECS. Further, imipramine administered for 21 days did not affect the anxiolytic effect of 5 mg/kg of chlordiazepoxide. The apparent reduction in the anxiolytic-like actions of a specific glycine/NMDA receptor antagonist following chronic treatment with a variety of antidepressants is consistent with previous neurochemical and molecular studies indicating that chronic antidepressant treatment can affect NMDA receptor function.