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-aspartate (NMDA) receptor macrocomplex in the development of spermine-induced CNS excitation in vivo was investigated. 2. Injection of 100 micrograms 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.
Doyle
K M
KM
Department of Pharmacology, School of Pharmacy, Trinity College, Dublin, Ireland.
Shaw
G G
GG
D000818:Animals; D001921:Brain / Q000187:drug effects*; D002552:Cerebral Ventricles / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000494:pharmacology; D005260:Female; D007736:Kynurenic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D018696:Neuroprotective Agents / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D012640:Seizures / Q000139:chemically induced; D013096:Spermine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D014202:Tremor / Q000139:chemically induced
D018696:Neuroprotective Agents; D010879:Piperazines; D010880:Piperidines; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D013096:Spermine; D016291:Dizocilpine Maleate; C050592:3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid; D007736:Kynurenic Acid; C010739:ifenprodil; C057013:7-chlorokynurenic acid