Diazepam-induced adaptive plasticity revealed by alpha1 GABAA receptor-specific expression profiling.
Benzodiazepines are in wide clinical use for their sedative and tranquilizing actions, the former being mediated via alpha1-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 alpha1(H101R) mice, in which the alpha1 GABAA receptor subunit had been rendered insensitive to diazepam. In wild-type animals, diazepam reduced the expression levels of the alpha 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 alpha1(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 CaMKIIalpha 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.
Institute of Pharmacology and Toxicology, University of Zürich, Zürich, Switzerland.
Laura
L
Huopaniemi
Ruth
R
Keist
Ann
A
Randolph
Ulrich
U
Certa
Uwe
U
Rudolph
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics; D018797:Cell Cycle Proteins; D003975:Diazepam / Q000494:pharmacology*; D004351:Drug Resistance / Q000235:genetics; D054638:Dual Specificity Phosphatase 1; D018757:GABA Modulators / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D017874:Immediate-Early Proteins / Q000235:genetics; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010749:Phosphoprotein Phosphatases; D016133:Polymerase Chain Reaction; D054645:Protein Phosphatase 1; D021122:Protein Subunits / Q000235:genetics; D017027:Protein Tyrosine Phosphatases / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D011963:Receptors, GABA-A / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics
D019208:Brain-Derived Neurotrophic Factor; D018797:Cell Cycle Proteins; D018757:GABA Modulators; D017874:Immediate-Early Proteins; D021122:Protein Subunits; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D014157:Transcription Factors; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D010749:Phosphoprotein Phosphatases; D054645:Protein Phosphatase 1; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse; D017027:Protein Tyrosine Phosphatases; D003975:Diazepam