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Metaphit‐Induced Audiogenic Seizures in Mice: I. Pharmacologic Characterization
Author(s) -
Debler E. A.,
Lipovac M. N.,
Lajtha A.,
Zlokovic B. V.,
Dunlop D. S.,
Jacobson A. E.,
Rice K. C.,
Costa B.,
Reith M. E. A.
Publication year - 1993
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/j.1528-1157.1993.tb02400.x
Subject(s) - picrotoxin , chemistry , phencyclidine , pharmacology , nmda receptor , stimulation , epilepsy , antagonist , endocrinology , psychology , medicine , neuroscience , biochemistry , receptor
Summary: Metaphit [an analogue of phencyclidine (PCP) with an acylating isothiocyanate group] induced audiogenie 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, ll‐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 γ‐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 (t½) such as MK‐801, PB, and PHT had a protective effect. High‐performance liquid chromatography (HPLC) determination of [ 3 H]MK‐801 showed its long‐term presence in the brain after intraperitoneal (i.p.) administration of [ 3 H]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.