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

P Follesa; E Cagetti; L Mancuso; F Biggio; A Manca; E Maciocco; F Massa; M S Desole; M Carta; F Busonero; E Sanna; G Biggio

doi:10.1016/s0169-328x(01)00164-4

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

Brain Res Mol Brain Res. 2001 Aug 15;92(1-2):138-48. doi: 10.1016/s0169-328x(01)00164-4.

Authors

P Follesa¹, E Cagetti, L Mancuso, F Biggio, A Manca, E Maciocco, F Massa, M S Desole, M Carta, F Busonero, E Sanna, G Biggio

Affiliation

¹ Department of Experimental Biology Bernardo Loddo, CNR, Center of Neuropharmacology, University of Cagliari, 09123 Cagliari, Italy. [email protected]

PMID: 11483250
DOI: 10.1016/s0169-328x(01)00164-4

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anti-Anxiety Agents / administration & dosage
Anti-Anxiety Agents / pharmacology*
Benzodiazepines / administration & dosage
Benzodiazepines / pharmacology*
Cell Membrane / drug effects
Cells, Cultured
Cerebellum / cytology
Cerebellum / drug effects
Cerebellum / metabolism
Chloride Channels / drug effects
Chloride Channels / metabolism
Chlorides / metabolism
Diazepam / administration & dosage
Diazepam / pharmacology*
Drug Tolerance / genetics
Drug Tolerance / physiology
Female
Flumazenil / administration & dosage
Flumazenil / pharmacology
GABA Agonists / administration & dosage
GABA Agonists / pharmacology*
GABA Antagonists / pharmacology
GABA-A Receptor Agonists
GABA-A Receptor Antagonists
Imidazoles / administration & dosage
Imidazoles / pharmacology*
Ion Transport / drug effects
Membrane Potentials / drug effects
Microinjections
Nerve Tissue Proteins / agonists
Nerve Tissue Proteins / biosynthesis*
Nerve Tissue Proteins / genetics
Neurons / drug effects
Neurons / metabolism
Oocytes
Protein Subunits
RNA, Messenger / biosynthesis
Rats
Receptors, GABA-A / biosynthesis*
Receptors, GABA-A / genetics
Substance Withdrawal Syndrome / genetics
Substance Withdrawal Syndrome / metabolism
Substance-Related Disorders / genetics
Substance-Related Disorders / metabolism
Up-Regulation / drug effects*
Xenopus laevis

Substances

Anti-Anxiety Agents
Chloride Channels
Chlorides
GABA Agonists
GABA Antagonists
GABA-A Receptor Agonists
GABA-A Receptor Antagonists
Imidazoles
Nerve Tissue Proteins
Protein Subunits
RNA, Messenger
Receptors, GABA-A
Benzodiazepines
Flumazenil
imidazenil
Diazepam