Molecular mechanisms of tolerance to and withdrawal of GABA(A) receptor modulators

Eur Neuropsychopharmacol. 2003 Dec;13(6):411-23. doi: 10.1016/j.euroneuro.2003.08.002.

Abstract

Here, we summarize recent data pertaining to the effects of GABA(A) receptor modulators on the receptor gene expression in order to elucidate the molecular mechanisms behind tolerance and dependence induced by these drugs. Drug selectivity and intrinsic activity seems to be important to evidence at the molecular level the GABA(A) receptor tolerance. On the contrary, we suggested that all drug tested are equally potentially prone to induce dependence. Our results demonstrate that long-lasting exposure of GABA(A) receptors to endogenous steroids, benzodiazepines and ethanol, as well as their withdrawal, induce marked effects on receptor structure and function. These results suggest the possible synergic action between endogenous steroids and these drugs in modulating the functional activity of specific neuronal populations. We report here that endogenous steroids may play a crucial role in the action of ethanol on dopaminergic neurons.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Animals, Newborn
  • Benzodiazepines / pharmacology
  • Cell Extracts / pharmacology
  • Cell Membrane
  • Cells, Cultured
  • Cerebellum / cytology
  • Cerebellum / metabolism
  • Chromatography, High Pressure Liquid
  • Dose-Response Relationship, Drug
  • Drug Interactions
  • Drug Tolerance / genetics*
  • Electrochemistry
  • Ethanol / pharmacology*
  • Gene Expression Regulation / drug effects
  • Immunoblotting
  • Male
  • Membrane Potentials / drug effects
  • Microdialysis
  • Neural Inhibition / drug effects
  • Neurons / drug effects
  • Neurons / metabolism
  • Oocytes / metabolism
  • Patch-Clamp Techniques
  • RNA, Messenger / biosynthesis
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, GABA-A / drug effects
  • Receptors, GABA-A / genetics
  • Receptors, GABA-A / metabolism*
  • Reverse Transcriptase Polymerase Chain Reaction / methods
  • Steroids / metabolism*
  • Substance Withdrawal Syndrome / metabolism*
  • Time
  • Tyrosine 3-Monooxygenase / metabolism
  • gamma-Aminobutyric Acid / pharmacology

Substances

  • Cell Extracts
  • RNA, Messenger
  • Receptors, GABA-A
  • Steroids
  • Benzodiazepines
  • Ethanol
  • gamma-Aminobutyric Acid
  • Tyrosine 3-Monooxygenase