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Status epilepticus alters zolpidem sensitivity of [H-3]flunitrazepam binding in the developing rat brain
Tekijät: Lauren HB, Lopez-Picon FR, Kukko-Lukjanov TK, Uusi-Oukari M, Holopainen IE
Kustantaja: PERGAMON-ELSEVIER SCIENCE LTD
Julkaisuvuosi: 2007
Journal: Neuroscience
Tietokannassa oleva lehden nimi: NEUROSCIENCE
Lehden akronyymi: NEUROSCIENCE
Vuosikerta: 146
Numero: 2
Aloitussivu: 802
Lopetussivu: 811
Sivujen määrä: 10
ISSN: 0306-4522
DOI: https://doi.org/10.1016/j.neuroscience.2007.01.064
Tiivistelmä
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 [H-3]flunitrazepam binding by zolpidem, a ligand selective for the alpha beta 2 gamma 2 receptor subtype. Regional changes in the binding properties were further corroborated at the cellular level by immunocytochernistry. The results revealed that status epilepticus significantly decreased displacement of [H-3]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 GABAA receptors in the immature rat brain. A part of these changes could be due to alterations in the cell surface expression of receptor subtypes. (C) 2007 IBRO. Published by Elsevier Ltd. All rights reserved.
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 [H-3]flunitrazepam binding by zolpidem, a ligand selective for the alpha beta 2 gamma 2 receptor subtype. Regional changes in the binding properties were further corroborated at the cellular level by immunocytochernistry. The results revealed that status epilepticus significantly decreased displacement of [H-3]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 GABAA receptors in the immature rat brain. A part of these changes could be due to alterations in the cell surface expression of receptor subtypes. (C) 2007 IBRO. Published by Elsevier Ltd. All rights reserved.
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