Metaphit-induced audiogenic seizures in mice: II. Studies on N-methyl-D-aspartic acid, GABA, and sodium channel receptors and on the disposition of metaphit in the brain.
We previously demonstrated that metaphit (a phencyclidine analogue with an acylating isothiocyanate group) induces occurrence of audiogenic seizures in mice exposed to audio stimulation 24 h after metaphit administration. We have studied various receptor systems associated with excitatory and inhibitory networks: sites for competitive and noncompetitive antagonists of the N-methyl D-aspartic acid (NMDA) receptor complex, for [3H]muscimol on the gamma-aminobutyric acid (GABA) receptor complex, and for [3H]batrachotoxinin A20-alpha-benzoate on the voltage-dependent sodium channel. Mice were examined for neurochemical changes at 24 h after pretreatment with metaphit, when susceptibility to audiogenic seizures is greatest. Ex vivo receptor binding studies detected no changes; in vivo labeling of the phencyclidine site in the NMDA receptor complex was reduced by 20% in cortical and midbrain regions. A separate group of experiments was aimed at measuring brain levels of metaphit. One minute after retroorbital administration of [3H]metaphit at a dose sufficient to produce susceptibility to audiogenic seizures 24 h later, the brain level of [3H]metaphit (determined by high-performance liquid chromatography, HPLC) was 49 pmol/mg tissue; at 1, 4, and 24 h, the level was 12, 6, and 1.4 pmol/mg tissue or microM if metaphit was evenly distributed throughout the brain. Although the observed metaphit concentrations during the first 4 h are high enough to acylate receptors, no firm evidence for acylation was found for most of the examined receptors. Finally, the time course of the brain level of metaphit showing a continuous decrease is entirely different from that of development of the seizure susceptibility, which peaks at 18-24 h.
Lipovac
M N
MN
Division of Neurochemistry, Nathan S. Kline Institute, Orangeburg, New York.
Debler
E A
EA
Zlokovic
B V
BV
Jacobson
A E
AE
Rice
K C
KC
de Costa
B
B
Selmeci
G
G
Chi
L
L
Reith
M E
ME
D000161:Acoustic Stimulation; D000818:Animals; D001496:Batrachotoxins / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects; D002540:Cerebral Cortex / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D006624:Hippocampus / Q000378:metabolism; D008297:Male; D051379:Mice; D009118:Muscimol / Q000378:metabolism; D010622:Phencyclidine / Q000031:analogs & derivatives* / Q000032:analysis / 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 / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000209:etiology* / Q000378:metabolism; D015222:Sodium Channels / Q000737:chemistry / Q000187:drug effects
D001496:Batrachotoxins; D011963:Receptors, GABA-A; D016194:Receptors, N-Methyl-D-Aspartate; D017478:Receptors, Phencyclidine; D015222:Sodium Channels; D009118:Muscimol; D016291:Dizocilpine Maleate; C031775:batrachotoxinin A 20-alpha-benzoate; C044705:metaphit; D010622:Phencyclidine