Audiogenic seizure susceptibility is induced by termination of continuous infusion of gamma-aminobutyric acid or an N-methyl-D-aspartic acid Antagonist into the inferior colliculus.
The inferior colliculus (IC) is strongly implicated in seizure initiation in a genetic form of audiogenic seizures (AGS) and in AGS observed during ethanol withdrawal (ETX). Ethanol is known to block the actions of excitatory amino acids (EAA) and enhance the actions of gamma-aminobutyric acid (GABA) in several brain areas, including the IC. The present study investigated the effects on susceptibility to AGS following withdrawal from continuous blockade of N-methyl-D-aspartic acid (NMDA) receptors or continuous activation of GABA receptors in the IC. This involved infusion of GABA (1 M) or a competitive NMDA antagonist, DL-2-amino-7-phosphonoheptanoic acid (AP7, 1 mM), at 0.25 microl/h for 7 days using an Alzet osmotic minipump. Following abrupt termination of the infusion, AGS susceptibility began at 30 min. The incidence of AGS was 38.9 and 56.3% following GABA and AP7 withdrawal, respectively. The AGS behaviors observed during withdrawal, which included wild running and bouncing clonus, were very similar to those evoked by acoustic stimuli during ETX. AGS susceptibility lasted for several hours and in 13% of animals persisted for up to 6 months. The current results support diminished GABAergic and elevated glutamatergic function in the IC as the critical mechanisms and sites for AGS initiation. The present study, coupled with previous evidence that chronic ethanol exposure reduced GABA-mediated inhibition and enhanced EAA-mediated excitation, suggests that these amino acid receptor-mediated alterations in the IC are key elements in initiating AGS during ethanol withdrawal.
Yang
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Department of Pharmacology, Southern Illinois University School of Medicine, Springfield, Illinois 62794-9629, USA.
Long
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Faingold
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D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives; D000161:Acoustic Stimulation / Q000009:adverse effects; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002404:Catheterization; D004198:Disease Susceptibility / Q000139:chemically induced* / Q000150:complications; D004333:Drug Administration Routes; D020195:Epilepsy, Reflex / Q000139:chemically induced* / Q000150:complications / Q000503:physiopathology; D018691:Excitatory Amino Acid Antagonists; D007245:Inferior Colliculi / Q000187:drug effects* / Q000503:physiopathology; D015918:Infusion Pumps, Implantable; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects; D013997:Time Factors; D005680:gamma-Aminobutyric Acid
D018691:Excitatory Amino Acid Antagonists; D005680:gamma-Aminobutyric Acid; D015763:2-Amino-5-phosphonovalerate; C031231:2-amino-7-phosphonoheptanoic acid