Pharmacology of tolerance to benzodiazepine receptor ligands.
State of the art of pharmacology of tolerance to and dependence on benzodiazepine receptor ligands is shortly summarized. Firstly, the inadequacies of animal models of drug-dependency are underlined. Then, some elements of molecular biology of the GABA-A receptor complex are described to give a theoretical background for discussing pharmacological profiles of action of the selective type 1 (e.g. zolpidem), and partial benzodiazepine receptor agonists (e.g. bretazenil). These groups of benzodiazepine receptor ligands are considered to exhibit low tolerance and dependence liability. The evidence from behavioral and electrophysiological experiments so far favors the concept that the gradually developing hypofunction of the brain GABA system is the basis for tolerance to benzodiazepines, and the cause of abstinence symptoms. Receptor binding studies on adaptive changes in the GABA-A and benzodiazepine receptors after chronic benzodiazepine administration, insofar gave negative or contradictory results. The available up to now data on the long-term processes occurring in the subunits of the GABA-A receptor complex are also not homogenous, and it is difficult to discuss them. Likewise, the contribution of neurosteroids and specific ligands of the peripheral type of benzodiazepine receptor to the discussed phenomenona, is a matter of controversy. In conclusion, it should be stressed that the selective type 1 benzodiazepine receptor agonists, and partial benzodiazepine receptor agonists, either due to excitation of a smaller fraction of receptors, or lower efficacy, do not entirely readjust the function of the GABA-A receptor complex, thus leaving the place for action of the endogenous neurotransmitter. Such profile of central activity should prevent the development of strong tolerance and abstinence symptoms.
Płaźnik
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Department of Pharmacology and Physiology of the Nervous System, Institute of Psychiatry and Neurology, Warszawa, Poland.
D000818:Animals; D004361:Drug Tolerance; D006801:Humans; D008024:Ligands; D011963:Receptors, GABA-A / Q000187:drug effects*
D008024:Ligands; D011963:Receptors, GABA-A