Investigation of the involvement of the N‐methyl‐D‐aspartate receptor macrocomplex in the development of spermine‐induced CNS excitation in vivo

1 The involvement of the N‐methyl‐D‐asparate (NMDA) receptor macrocomplex in the development of spermine‐induced CNS excitation in vivo was investigated. 2 Injection of 100 μg of spermine into the left lateral cerebral ventricle of female Laca mice (20–25 g) resulted in the development of two distinct phases of CNS excitatory effects which were quantified by a scoring system. 3 The first phase effects occurred within minutes of injection and generally lasted for about 1 h. Most mice showed scratching of the upper body, frequent face washing and some mice developed clonic convulsions. By about 2 h after injection, the second phase of effects began to develop in the form of body tremor which worsened with time and culminated in fatal tonic convulsions, generally 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 spermine‐induced effects, but a higher dose (0.3 mg kg−1, (x2), i.p.) was necessary to inhibit the second phase effects. 5 Whereas the glutamate antagonist, 3‐((R)‐2‐carboxypiperazin‐4‐yl) propyl‐1‐phosphonic acid (D‐CPP) (10, 20 mg kg−1, i.p.), the glycine antagonist 7‐chlorokynurenate (10, 30, 50 nmol, i.c.v.), or the polyamine antagonist ifenprodil (30, 60 mg kg−1, i.p.) antagonized the first phase of effects produced by spermine, these agents given as monotherapy, were ineffective against the development of the second phase of effects. 6 Co‐administration of ifenprodil with either D‐CPP or 7‐chlorokynurenate resulted in a dose‐dependent antagonism of the development of the second phase 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 results suggest that the NMDA receptor macrocomplex may be involved in both phases of effects. Furthermore, a moderate dose of D‐CPP or 7‐chlorokynurenate appears to enhance the inhibitory potential of ifenprodil in vivo.