Premium
Chronic Benzodiazepine Administration: From the Patient to the Gene
Author(s) -
Miller Lawrence G.
Publication year - 1991
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/j.1552-4604.1991.tb03725.x
Subject(s) - benzodiazepine , flumazenil , inverse agonist , clonazepam , gabaa receptor , pharmacology , lorazepam , agonist , downregulation and upregulation , receptor , alprazolam , diazepam , antagonist , medicine , endocrinology , chemistry , anesthesia , biochemistry , anxiety , psychiatry , gene
Chronic benzodiazepine administration is associated with the development of tolerance and dependence. To evaluate the cellular mechanisms for these phenomena the authors developed a mouse model of chronic benzodiazepine exposure. The benzodiazepine agonists lorazepam, alprazolam, and clonazepam produced tolerance in this system, which was associated in each case with benzodiazepine and GABA A receptor downregulation. After discontinuation, a syndrome that included increased motor activity and receptor upregulation occurred with each of these compounds. A benzodiazepine antagonist, flumazenil, and an inverse agonist, FG 7142, were associated with receptor upregulation and increased activity during chronic administration. In contrast, a partial agonist (Ro16–6028) did not produce tolerance or receptor changes. Similar results were obtained in a culture system for clonazepam, flumazenil, and FG 7142. The increase in receptor binding after lorazepam discontinuation may be due to enhanced receptor synthesis. Changes in gene expression for GABA A receptor subunits also occur with chronic lorazepam administration, and they follow alterations in binding.