GABAergic modulation of lindane (gamma-hexachlorocyclohexane)-induced seizures.
The main objective of this work was to study the role of the GABAergic system on the convulsions elicited by the organochlorine insecticide lindane. The concentration of lindane in rat brain at the onset of the first tonic convulsion was taken as the endpoint for the neurotoxic action of the insecticide administered by intravenous infusion. Pretreatment with the GABA agonists muscimol and progabide, the GABA uptake blocker SK&F 89976-A, the GABA transaminase inhibitor gamma-acetylenic GABA, and the GABA indirect agonist phenobarbital significantly increased the threshold concentration of lindane in brain required to induce convulsions. The GABA agonist THIP, the GABA competitive antagonist bicuculline, and the prodrug cetyl-GABA had no effect on the brain level of lindane required to induce seizures. The noncompetitive GABA antagonists, picrotoxinin and pentylenetetrazol, significantly decreased the brain concentration of lindane needed to elicit convulsions. The concentration of GABA in the brain of lindane-treated rats was only modified by the significant increase produced after gamma-acetylenic GABA pretreatment. These results show that the convulsions elicited by lindane can be facilitated by some GABA antagonists and antagonized by GABA mimetics, especially those that enhance GABA functionality. The present data are consistent with the proposed in vitro competition of lindane for the picrotoxinin binding site associated with the Cl- ionophore of the GABAA receptor, and suggest that lindane may also interact in vivo with this site.
Suñol
C
C
Department of Neurochemistry, Consejo Superior de Investigaciones Científicas, Barcelona, Spain.
Tusell
J M
JM
Gelpí
E
E
Rodríguez-Farré
E
E
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D018756:GABA Antagonists; D001556:Hexachlorocyclohexane / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000633:toxicity*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011963:Receptors, GABA-A / Q000187:drug effects*; D012640:Seizures / Q000139:chemically induced* / Q000517:prevention & control; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D018756:GABA Antagonists; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; D001556:Hexachlorocyclohexane