Basic pharmacologic mechanisms involved in benzodiazepine tolerance and withdrawal

Benzodiazepines are widely prescribed for the treatment of anxiety and sleep disorders. Although safe, tolerance develops rapidly to their sedative activity and more slowly to their anticonvulsant activity. In animals anxiolytic tolerance has also been measured. Abrupt cessation of benzodiazepine treatment leads to symptoms of withdrawal. The mechanisms responsible for these phenomena are not known. Benzodiazepines act via GABA(A) receptors, but do not appear to produce tolerance and dependence by simple downregulation of receptor number. GABA(A) receptors are hetero-oligomers comprised of multiple subunits encoded by a multigene family. The molecular effects of long-term benzodiazepine exposure are reviewed and a model is presented that draws on results from a number of research groups working in this area.