Metaphit-induced audiogenic seizures in mice: I. Pharmacologic characterization.
Metaphit [an analogue of phencyclidine (PCP) with an acylating isothiocyanate group] induced audiogenic clonic to clonic-tonic seizures in mice exposed to audio stimulation 24 h after metaphit administration. The incidence of seizures was reduced by treatment 30 min before audio stimulation with specific PCP-like compounds [5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate (MK-801), and PCP itself], competitive N-methyl-D-aspartate antagonists 2-amino-5-phosphonopentanoic acid (AP-5 and NPC-12626), antiepileptic drugs [phenobarbital (PB), phenytoin (PHT)], and gamma-aminobutyric acid (GABA) agonists (muscimol and diazepam). In contrast, when given in conjunction with metaphit, most of these drugs were ineffective in protecting animals from audiogenic seizures 24 h later. Only compounds with long half-lives (t1/2) such as MK-801, PB, and PHT had a protective effect. High-performance liquid chromatography (HPLC) determination of [3H]MK-801 showed its long-term presence in the brain after intraperitoneal (i.p.) administration of [3H]MK-801. Audiogenic seizures observed 24 h after metaphit administration were potentiated by administration of the GABA antagonist picrotoxin 15 min before audio stimulation, and picrotoxin-induced spontaneous seizures were enhanced by pretreatment (24 h earlier) with a dose of metaphit that in itself did not produce spontaneous seizures at the time of the picrotoxin test. Similar observations were made with N-methyl D-aspartic acid (NMDA) instead of picrotoxin. Thus, an interplay exists between excitatory glutaminergic and inhibitory GABAergic circuitries in the metaphit seizure model.
Division of Neurochemistry, Nathan S. Kline Institute, Orangeburg, New York.
E A
EA
Debler
M N
MN
Lipovac
A
A
Lajtha
B V
BV
Zlokovic
D S
DS
Dunlop
A E
AE
Jacobson
K C
KC
Rice
B
B
de Costa
M E
ME
Reith
D000161:Acoustic Stimulation; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D016291:Dizocilpine Maleate / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D008297:Male; D051379:Mice; D016202:N-Methylaspartate / Q000494:pharmacology; D010622:Phencyclidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010634:Phenobarbital / Q000494:pharmacology; D010852:Picrotoxin / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D017478:Receptors, Phencyclidine / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced / Q000209:etiology* / Q000517:prevention & control
D016291:Dizocilpine Maleate; D016202:N-Methylaspartate; D010622:Phencyclidine; D010634:Phenobarbital; D010852:Picrotoxin; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D017478:Receptors, Phencyclidine; C044705:metaphit