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

J Pharmacol Exp Ther. 1988 Jul;246(1):177-82.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

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


  • Bridged Bicyclo Compounds
  • Bridged Bicyclo Compounds, Heterocyclic
  • Chlorides
  • Ion Channels
  • Receptors, GABA-A
  • Muscimol
  • Flumazenil
  • Flunitrazepam
  • tert-butylbicyclophosphorothionate
  • Lorazepam