INVESTIGATION OF THE INVOLVEMENT OF THE N-METHYL-D-ASPARTATE RECEPTORMACROCOMPLEX IN THE DEVELOPMENT OF SPERMINE-INDUCED CNS EXCITATION IN-VIVO

1 The involvement of the N-methy-D-asparate (NMDA) receptor macrocompl ex in the development of spermine-induced CNS excitation in vivo was i nvestigated. 2 Injection of 100 mu g of spermine into the left lateral cerebral ventricle of female Laca mice (20-25 g) resulted in the deve lopment of two distinct phases of CNS excitatory effects which were qu antified by a scoring system. 3 The first phase effects occurred withi n minutes of injection and generally lasted for about 1 h. Most mice s howed scratching of the upper body, frequent face washing and some mic e developed clonic convulsions. By about 2 h after injection, the seco nd phase of effects began to develop in the form of body tremor which worsened with time and culminated in fatal tonic convulsions, generall y within 8 h of injection. 4 Pretreatment of the mice with dizocilpine (0.3 mg kg(-1), i.p.) resulted in antagonism of the first phase of sp ermine-induced effects, but a higher dose (0.3 mg kg(-1), (x 2), i.p.) was necessary to inhibit the second phase effects.5 Whereas the gluta mate antagonist, 3-((R)-2-carboxypiperazin-4-yl) propyl-1-phosphonic a cid (D-CPP) (10, 20 mg kg(-1), i.p.), the glycine antagonist 7-chlorok ynurenate (10, 30, 50 nmol, i.c.v.), or the polyamine antagonist ifenp rodil (30, 60 mg kg(-1), i.p.) antagonized the first phase of effects produced by spermine, these agents given as monotherapy, were ineffect ive against the development of the second phase of effects. 6 Co-admin istration of ifenprodil with either D-CPP or 7-chlorokynurenate result ed in a dose-dependent antagonism of the development of the second pha se of spermine-induced effects. 7 It is concluded that the development of the two temporally distinct phases of spermine-induced effects may be mediated by pharmacologically distinct mechanisms, although the re sults suggest that the NMDA receptor macrocomplex may be involved in b oth phases of effects. Furthermore, a moderate dose of D-CPP or 7-chlo rokynurenate appears to enhance the inhibitory potential of ifenprodil in vivo.