GABA-a Receptor - Changes in the Expression of Messenger RNAs Encoding for Receptor Subunits Associated with Development of Tolerance and Dependence on Benzodiazepines
Abstract
Benzodiazepines (BZs) - widely used as anxiolytics, sedative-hypnotics and anticonvulsants, bind to specific recognition sites in the g-aminobutyric acid A receptor and act to modulate GABA neurotransmission by altering the frequency of opening of GABA - dependent chloride channels. A large variety of experimental and clinical studies have indicated, that prolonged exposure to benzodiazepines results in functional tolerance and physical dependence, associated with symptoms of withdrawal after abrupt discontinuation of treatment.
Primary underlying factors of these side effects are rapid drug elimination, high receptor-binding affinity, and/or triazolo structure. The molecular basis of tolerance and dependence on benzodiazepines has yet to be established.
One of the possible mechanisms may be a switch in the subunit composition of GABA-A receptor subtypes. Recent studies have measured changes in the content of specific subunit messenger RNAs of GABA-A receptor after the prolonged administration of benzodiazepine drugs.
Rats receiving the long-term treatment with classical full BZ agonists (diazepam) developed tolerance, and showed a reversible decrease in the expression of messenger RNAs encoding for a1 (or g 2S , g 2L respectively) GABA-A receptor subunits in certain brain areas - the fronto-parietal motor cortex and the hippocampus. In contrast, no changes in the content of messenger RNAs encoding for GABA-A receptor subunits were found in rats undergoing long-term treatment with partial NZ agonists (imidazenil).
Changes in the GABA-A receptor subunit gene expression, that occur in selected brain areas during prolonged treatment with full BZ agonists, can represent a molecular basis for behavioral tolerance and physical depend- ence on these drugs.