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 foll owing acute or chronic treatment with two N-methyl-D-aspartate (NMDA) glycine partial agonists, 1-aminocyclopropanecarboxylic acid (ACPC), a nd D-cycloserine (DCS). Consistent with previous findings in mice, sin gle intravenous doses of ACPC in rats produced a significant, dose-dep endent reduction in immobility in the PST compared to saline. Single d ose DCS also elicited significant dose-dependent reductions in PST imm obility times. Single-dose ACPC or DCS (200 mg/kg) reduced immobility (p < 0.05) by 26 or 30%, respectively, compared to saline. However, mu ltiple dosing with either ACPC or DCS (6 daily doses, 200 mg/kg) produ ced an apparent behavioral adaptation, as the immobility data were ind istinguishable from chronic saline administration. Moreover, pretreatm ent with a 5-day course of ACPC or DCS promoted the development of a b ehavioral cross-tolerance following a sixth dose of DCS or ACPC, respe ctively. The development of a behavioral tolerance in the PST followin g chronic therapy of these drugs appears to be a general feature of gl ycine partial agonists. In tote, these findings support the hypothesis that chronic administration of NMDA glycine partial agonists produces a behavioral tolerance putatively through an adaptation of the NMDA r eceptor complex. (C) 1997 Elsevier Science Inc.