Chronic administration of NMDA glycine partial agonists induces tolerance in the Porsolt swim test

The Porsolt swim test (PST) was used to assess behavioral effects following acute or chronic treatment with two N-methyl-D-aspartate (NMDA) glycine partial agonists, 1-aminocyclopropanecarboxylic acid (ACPC), and D-cycloserine (DCS). Consistent with previous findings in mice, single intravenous doses of ACPC in rats produced a significant, dose-dependent reduction in immobility in the PST compared to saline. Single dose DCS also elicited significant dose-dependent reductions in PST immobility times. Single-dose ACPC or DCS (200 mg/kg) reduced immobility (p < 0.05) by 26 or 30%, respectively, compared to saline. However, multiple dosing with either ACPC or DCS (6 daily doses, 200 mg/kg) produced an apparent behavioral adaptation, as the immobility data were indistinguishable from chronic saline administration. Moreover, pretreatment with a 5-day course of ACPC or DCS promoted the development of a behavioral cross-tolerance following a sixth dose of DCS or ACPC, respectively. The development of a behavioral tolerance in the PST following chronic therapy of these drugs appears to be a general feature of glycine partial agonists. In toto, these findings support the hypothesis that chronic administration of NMDA glycine partial agonists produces a behavioral tolerance putatively through an adaptation of the NMDA receptor complex.