Increase in expression of the GABA(A) receptor alpha(4) subunit gene induced by withdrawal of, but not by long-term treatment with, benzodiazepine full or partial agonists.
The effects of long-term exposure to, and subsequent withdrawal of, diazepam or imidazenil (full and partial agonists of the benzodiazepine receptor, respectively) on the abundance of GABA(A) receptor subunit mRNAs and peptides were investigated in rat cerebellar granule cells in culture. Exposure of cells to 10 microM diazepam for 5 days significantly reduced the amounts of alpha(1) and gamma(2) subunit mRNAs, and had no effect on the amount of alpha(4) mRNA. These effects were accompanied by a decrease in the levels of alpha(1) and gamma(2) protein and by a reduction in the efficacy of diazepam with regard to potentiation of GABA-evoked Cl- current. Similar long-term treatment with 10 microM imidazenil significantly reduced the abundance of only the gamma(2)S subunit mRNA and had no effect on GABA(A) receptor function. Withdrawal of diazepam or imidazenil induced a marked increase in the amount of alpha(4) mRNA; withdrawal of imidazenil also reduced the amounts of alpha(1) and gamma(2) mRNAs. In addition, withdrawal of diazepam or imidazenil was associated with a reduced ability of diazepam to potentiate GABA action. These data give new insights into the different molecular events related to GABA(A) receptor gene expression and function produced by chronic treatment and withdrawal of benzodiazepines with full or partial agonist properties.
Follesa
P
P
Department of Experimental Biology Bernardo Loddo, CNR, Center of Neuropharmacology, University of Cagliari, 09123 Cagliari, Italy. follesa@vaxca1.unica.it
Cagetti
E
E
Mancuso
L
L
Biggio
F
F
Manca
A
A
Maciocco
E
E
Massa
F
F
Desole
M S
MS
Carta
M
M
Busonero
F
F
Sanna
E
E
Biggio
G
G
D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001569:Benzodiazepines / Q000008:administration & dosage / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018118:Chloride Channels / Q000187:drug effects / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism; D003975:Diazepam / Q000008:administration & dosage / Q000494:pharmacology*; D004361:Drug Tolerance / Q000235:genetics / Q000502:physiology; D005260:Female; D005442:Flumazenil / Q000008:administration & dosage / Q000494:pharmacology; D018755:GABA Agonists / Q000008:administration & dosage / Q000494:pharmacology*; D018756:GABA Antagonists / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D007093:Imidazoles / Q000008:administration & dosage / Q000494:pharmacology*; D017136:Ion Transport / Q000187:drug effects; D008564:Membrane Potentials / Q000187:drug effects; D008845:Microinjections; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000096:biosynthesis* / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009865:Oocytes; D021122:Protein Subunits; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011963:Receptors, GABA-A / Q000096:biosynthesis* / Q000235:genetics; D013375:Substance Withdrawal Syndrome / Q000235:genetics / Q000378:metabolism; D019966:Substance-Related Disorders / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*; D014982:Xenopus laevis
D014151:Anti-Anxiety Agents; D018118:Chloride Channels; D002712:Chlorides; D018755:GABA Agonists; D018756:GABA Antagonists; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D007093:Imidazoles; D009419:Nerve Tissue Proteins; D021122:Protein Subunits; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005442:Flumazenil; C082661:imidazenil; D003975:Diazepam