Chemical kindling decreases GABA-activated chloride channels of mouse brain.
The repeated administration of N-methyl-beta-carboline-3-carboxamide (FG 7142) to mice leads to 'chemical kindling', i.e. the development of seizures in response to doses which were initially insufficient to produce convulsive activity. To determine if chemical kindling produced changes in the GABAA receptor/chloride channel complex, we measured the binding of [35S]t-butylbicyclophosphorothionate ([35S]TBPS) to the convulsant site of the complex by quantitative autoradiography. As a measure of chloride channel function, we studied muscimol-stimulated uptake of 36Cl- by isolated brain synaptosomes. Kindling decreased the Bmax of [35S]TBPS binding in cortex but not in cerebellum or hippocampus. Kindling did not alter binding affinities in any of these brain regions. Some mice injected with FG 7142 did not kindle despite receiving the same treatment as kindled mice. These 'injected but not kindled' mice did not display decreased receptor binding in any of these brain areas. Muscimol-stimulated 36Cl- uptake into cortical synaptosomes was also diminished by chemical kindling. These findings suggest that a decrease in functioning GABA-regulated chloride channels may be responsible for chemical kindling with FG 7142.
Lewin
E
E
Neurology Service, VA Medical Center, Denver, CO 80220.
Peris
J
J
Bleck
V
V
Zahniser
N R
NR
Harris
R A
RA
D000818:Animals; D001345:Autoradiography; D001923:Brain Chemistry / Q000187:drug effects*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002712:Chlorides / Q000378:metabolism*; D003292:Convulsants / Q000494:pharmacology; D007473:Ion Channels / Q000187:drug effects*; D007696:Kindling, Neurologic / Q000187:drug effects*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009118:Muscimol / Q000494:pharmacology; D013462:Sulfur Radioisotopes; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002712:Chlorides; D003292:Convulsants; D007473:Ion Channels; D013462:Sulfur Radioisotopes; D009118:Muscimol; D005680:gamma-Aminobutyric Acid; C037476:tert-butylbicyclophosphorothionate