Status epilepticus alters zolpidem sensitivity of [3H]flunitrazepam binding in the developing rat brain.
GABA, the main inhibitory neurotransmitter in the adult brain, exerts its effects through multiple GABA(A) receptor subtypes with different pharmacological profiles, the alpha subunit variant mainly determining the binding properties of benzodiazepine site on the receptor protein. In adult experimental epileptic animals and in humans with epilepsy, increased excitation, i.e. seizures, alters GABA(A) receptor subunit expression leading to changes in the receptor structure, function, and pharmacology. Whether this also occurs in the developing brain, in which GABA has a trophic, excitatory effect, is not known. We have now applied autoradiography to study properties of GABA(A)/benzodiazepine receptors in 9-day-old rats acutely (6 h) and sub-acutely (7 days) after kainic acid-induced status epilepticus by analyzing displacement of [(3)H]flunitrazepam binding by zolpidem, a ligand selective for the alpha1beta2gamma2 receptor subtype. Regional changes in the binding properties were further corroborated at the cellular level by immunocytochemistry. The results revealed that status epilepticus significantly decreased displacement of [(3)H]flunitrazepam binding by zolpidem 6 h after the kainic acid-treatment in the dentate gyrus of the hippocampus, parietal cortex, and thalamus, and in the hippocampal CA3 and CA1 cell layers 1 week after the treatment. Our results suggest that status epilepticus modifies region-specifically the pharmacological properties of GABA(A) receptors, and may thus disturb the normal, strictly developmentally-regulated maturation of zolpidem-sensitive GABA(A) receptors in the immature rat brain. A part of these changes could be due to alterations in the cell surface expression of receptor subtypes.
Laurén
H B
HB
Department of Pharmacology, Drug Development, and Therapeutics, Institute of Biomedicine, University of Turku, Itäinen Pitkäkatu 4, Turku, FIN-20014, Finland.
Lopez-Picon
F R
FR
Kukko-Lukjanov
T-K
TK
Uusi-Oukari
M
M
Holopainen
I E
IE
D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001345:Autoradiography / Q000379:methods; D001921:Brain / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005445:Flunitrazepam / Q000493:pharmacokinetics*; D018755:GABA Agonists / Q000494:pharmacology*; D018757:GABA Modulators / Q000493:pharmacokinetics*; D007608:Kainic Acid; D011485:Protein Binding / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism; D013226:Status Epilepticus / Q000139:chemically induced / Q000473:pathology*; D000077334:Zolpidem
D018755:GABA Agonists; D018757:GABA Modulators; D011725:Pyridines; D011963:Receptors, GABA-A; D005445:Flunitrazepam; D000077334:Zolpidem; D007608:Kainic Acid