Chronic treatment with 1-aminocyclopropanecarboxylic acid (ACPC) but not with dizocilpine or imipramine produces desensitization to the behavioral response in ACPC challenge in the forced swim test (forced swim test). The mechanism by which ACPC produces this effect is unclear and may depend upon either its functional antagonist or its agonist properties at the NMDA receptor. We now report that chronic treatment with glycine or ACPC desensitizes the behavioral effect of challenge with ACPC in the forced swim test. The desensitization of the acute effects of ACPC cannot be explained by the presence of residual glycine because 24 h after the last of 14 daily glycine injections (i.e. the time of forced swim test) cortical and hippocampal glycine concentrations were unchanged. Likewise, the affinity of glycine to displace specific [3H]5,7-DCKA binding to glycine sites of the NMDA receptor complex was unchanged by chronic glycine administration. These results support the hypothesis that antidepressants produce adaptation of the NMDA receptor complex by mechanisms other than simply increasing synaptic glycine concentrations. Moreover, these results indicate that the behavioral adaptation in the forced swim test induced by chronic treatment with ACPC results from its agonist properties.