Diazepam-induced adaptive plasticity revealed by α1 GABAA receptor-specific expression profiling

Laura Huopaniemi, Ruth Keist, Ann Randolph, Ulrich Certa, Uwe Rudolph

Research output: Contribution to journalArticlepeer-review

Abstract

Benzodiazepines are in wide clinical use for their sedative and tranquilizing actions, the former being mediated via α1-containing GABAA receptors. The signal transduction pathways elicited beyond the receptor are only poorly understood. Changes of transcript levels in cerebral cortex induced by acute diazepam administration were therefore compared by microarray analysis between wild-type and point mutated α1(H101R) mice, in which the α1 GABAA receptor subunit had been rendered insensitive to diazepam. In wild-type animals, diazepam reduced the expression levels of the α subunit of the calcium/calmodulin-dependent protein kinase II, as well as brain-derived neurotrophic factor, MAP kinase phosphatase, transcription factor GIF, c-fos and nerve growth factor induced gene-A. None of these transcripts was changed in the α1(H101R) mice after treatment with diazepam. Thus, the sedative action of diazepam is correlated with a selective down-regulation of transcripts involved in the regulation of neuronal plasticity and neurotrophic responses. Most transcript changes were transient except for the decrease of the CaMKIIα transcript which persisted even 40 h after the single dose of diazepam. This long-term alteration is likely to contribute to the resetting of the neuronal responsiveness, which may be involved in rebound phenomena and, under chronic treatment, in the development of tolerance and dependence.

Original languageEnglish (US)
Pages (from-to)1059-1067
Number of pages9
JournalJournal of Neurochemistry
Volume88
Issue number5
DOIs
StatePublished - Mar 2004
Externally publishedYes

Keywords

  • Diazepam
  • GABA receptor
  • Gene expression
  • Microarray
  • Plasticity

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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