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Pilocarpine, given intraperitoneally to rats, reproduces the neuropathological sequelae of temporal lobe epilepsy and provides a relevant animal model for studying mechanisms of buildup of convulsive activity and pathways operative in the generalization and propagation of seizures within the forebrain. In the present study, the effects of manipulating the activity of the gamma-aminobutyric acid (GABA)-mediated synaptic inhibition within the substantia nigra on seizures produced by pilocarpine in rats, were investigated. In animals pretreated with microinjections of isoniazid, 150 micrograms, an inhibitor of activity of the GABA-synthesizing enzyme, L-glutamic acid decarboxylase, into the substantia nigra pars reticulata (SNR), bilaterally, non-convulsant doses of pilocarpine, 100 and 200 mg/kg, resulted in severe motor limbic seizures and status epilepticus. Electroencephalographic and behavioral monitoring revealed a profound reduction of the threshold for pilocarpine-induced convulsions. Morphological analysis of frontal forebrain sections with light microscopy revealed seizure-related damage to the hippocampal formation, thalamus, amygdala, olfactory cortex, substantia nigra and neocortex, which is typically observed with pilocarpine in doses exceeding 350 mg/kg. Bilateral intrastriatal injections of isoniazid did not augment seizures produced by pilocarpine, 200 mg/kg. Application of an irreversible inhibitor of GABA transaminase, gamma-vinyl-GABA (D,L-4-amino-hex-5-enoic acid), 5 micrograms, into the SNR, bilaterally, suppressed the appearance of electrographic and behavioral seizures produced by pilocarpine, 380 mg/kg. This treatment was also sufficient to protect animals from the occurrence of brain damage. Microinjections of gamma-vinyl-GABA, 5 micrograms, into the dorsal striatum, bilaterally, failed to prevent the development of convulsions produced by pilocarpine, 380 mg/kg. The results demonstrate that the threshold for pilocarpine-induced seizures in rats is subjected to the regulation of the GABA-mediated synaptic inhibition within the substantia nigra.
L Turski, and
E A Cavalheiro, and
M Schwarz, and
W A Turski, and
L E De Moraes Mello, and
Z A Bortolotto, and
T Klockgether, and
K H Sontag
March 1983,
Neuroscience letters,
L Turski, and
E A Cavalheiro, and
M Schwarz, and
W A Turski, and
L E De Moraes Mello, and
Z A Bortolotto, and
T Klockgether, and
K H Sontag
December 1983,
The Journal of pharmacology and experimental therapeutics,
L Turski, and
E A Cavalheiro, and
M Schwarz, and
W A Turski, and
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Z A Bortolotto, and
T Klockgether, and
K H Sontag
March 1987,
Experimental neurology,
L Turski, and
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Z A Bortolotto, and
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K H Sontag
December 1991,
Brain research,
L Turski, and
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K H Sontag
September 1985,
Brain research,
L Turski, and
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January 1990,
Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas,
L Turski, and
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May 1989,
Brain research,
L Turski, and
E A Cavalheiro, and
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K H Sontag
September 1992,
Brain research,
L Turski, and
E A Cavalheiro, and
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July 1992,
Brain research,
L Turski, and
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K H Sontag
July 1979,
Life sciences,
