Analysis of the hippocampal GABAA receptor system in kindled rats by autoradiographic and in situ hybridization techniques: contingent tolerance to carbamazepine.
Tolerance to the anticonvulsant effects of carbamazepine (CBZ) in the amygdala kindling paradigm is a contingent process, since it only develops in rats treated with CBZ before the kindling stimulation and not in those animals treated after the stimulation. The present study was designed to investigate the GABAA receptor system in CBZ contingent tolerance. Receptor autoradiography utilizing various radioligands that bind to different components of the GABAA receptor system and in situ hybridization with oligonucleotides that recognize different subunits of the GABAA receptor were performed. Kindling increased binding to benzodiazepine, picrotoxin, and GABA recognition sites selectively in the dentate gyrus of the hippocampus. Kindling also increased levels of mRNA for the alpha 4, beta 1, and beta 3 subunits but did not change alpha 1, alpha 2, or gamma 2 subunit levels. Rats tolerant to CBZ showed decreased [3H]muscimol binding, diazepam-insensitive [3H]Ro 15-4513 binding, and decreased alpha 4 subunit mRNA content compared to non-tolerant rats, whereas [3H]flunitrazepam binding, [35S]TBPS binding, and the levels of beta 1, and beta 3 subunit mRNAs remained elevated. The data suggest an indirect interaction of CBZ with the GABAA receptor system, since CBZ reportedly does not bind to this receptor system.
Biological Psychiatry Branch, National Institute of Mental Health, Bethesda, MD 20892.
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Clark
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Massenburg
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Weiss
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D000345:Affinity Labels; D000679:Amygdala / Q000502:physiology*; D000818:Animals; D001345:Autoradiography; D001386:Azides / Q000378:metabolism; D001569:Benzodiazepines / Q000378:metabolism; D001643:Bridged Bicyclo Compounds / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002220:Carbamazepine / Q000494:pharmacology*; D003292:Convulsants / Q000378:metabolism; D004361:Drug Tolerance; D004558:Electric Stimulation; D004569:Electroencephalography; D005445:Flunitrazepam / Q000378:metabolism; D007839:Functional Laterality; D015870:Gene Expression / Q000187:drug effects; D006624:Hippocampus / Q000378:metabolism*; D017403:In Situ Hybridization; D007696:Kindling, Neurologic; D046911:Macromolecular Substances; D009118:Muscimol / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D017966:Pyramidal Cells / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000032:analysis / Q000096:biosynthesis* / Q000378:metabolism; D012640:Seizures / Q000378:metabolism; D014316:Tritium
D000345:Affinity Labels; D001386:Azides; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003292:Convulsants; D046911:Macromolecular Substances; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D014316:Tritium; D001569:Benzodiazepines; D009118:Muscimol; D002220:Carbamazepine; D005445:Flunitrazepam; C037476:tert-butylbicyclophosphorothionate; C042957:Ro 15-4513