Chronic benzodiazepine administration. II. Discontinuation syndrome is associated with upregulation of gamma-aminobutyric acidA receptor complex binding and function.

Article date: 1988/7/1

PubMed ID: 2455789

Journal name: The Journal of pharmacology and experimental therapeutics (ISSN: 0022-3565)


A “withdrawal” or “rebound” syndrome may follow the abrupt discontinuation of chronic treatment with benzodiazepines. To assess the neurochemical basis of this syndrome, mice were treated with lorazepam, 2 mg/kg/day for 7 days, a course which produces tolerance and downregulation of receptor binding and function. Behavioral studies indicated that open-field activity in lorazepam-treated mice was similar to controls at 1 day postlorazepam. Activity was increased at 4 days postlorazepam, and had returned to control levels by day 7. Benzodiazepine receptor binding as measured by specific uptake of [3H]Ro15-1788 in several brain regions returned to control levels by day 2 postbrazepam but had increased above controls at day 4 postlorazepam. Binding returned to control levels by day 7. Similar results were observed using [3H]flunitrazepam in membrane preparations. A similar time course was also observed for the maximum binding of the chloride channel ligand t-[35S]butylbicyclophosphorothionate during this period. The IC50 value for muscimol inhibition of t-butylbicyclophosphorothionate binding was decreased at day 4, suggesting increased coupling between gamma-aminobutyric acid and the chloride channel. Muscimol-stimulated [36Cl-] up-take in cortical synaptoneurosomes was increased at day 4 postlorazepam. These results indicate that the benzodiazepine discontinuation syndrome is associated with upregulation of receptor binding and function at the gamma-aminobutyric acidA receptor complex.

Author List: Miller L G, Greenblatt D J, Roy R B, Summer W R, Shader R I

Publication Types: Journal Article; Research Support, U.S. Gov't, P.H.S.

Substances mentioned in the article: Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Chlorides; Ion Channels; Receptors, GABA-A; Muscimol; Flumazenil; Flunitrazepam; tert-butylbicyclophosphorothionate; Lorazepam;

Mesh terms: Animals; Binding Sites; Brain/metabolism; Bridged Bicyclo Compounds/metabolism; Bridged Bicyclo Compounds, Heterocyclic; Cerebral Cortex/drug effects; Chlorides/metabolism; Drug Tolerance; Flumazenil/metabolism; Flunitrazepam/metabolism; Ion Channels/metabolism; Lorazepam/pharmacokinetics; Male; Mice; Motor Activity/drug effects; Muscimol/pharmacology; Receptors, GABA-A/metabolism; Time Factors;

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