Different kinetics of tolerance to behavioral and electroencephalographic effects of chlordiazepoxide in the rat

Eur J Pharmacol. 1995 Jan 24;273(1-2):35-45. doi: 10.1016/0014-2999(94)00665-t.

Abstract

The daily oral administration of chlordiazepoxide (40 mg/kg) over 9 weeks in rats elicited full tolerance to muscle relaxant effects within 7 weeks, as revealed by twice weekly evaluations of abdominal tone myorelaxation and decreased grip strength. No full tolerance was achieved, however, during the 9 weeks of treatment in terms of ataxia. Electroencephalographic (EEG) studies showed that this tolerance to the behavioural effects was accompanied by a progressive decrease in mean power spectra, associated with a progressive decrease in the beta band, but in this case, full tolerance was reached within 4 weeks. Once weekly evaluations of the ability of chlordiazepoxide to protect the animals against pentylenetetrazole seizures revealed a similar pattern. Treatment with flumazenil (50 mg/kg p.o.) 24 h after the last chlordiazepoxide administration induced a clear withdrawal syndrome associated with EEG changes which consisted of an increase in total power spectra associated with an increase in the delta band (in comparison with chlordiazepoxide-dependent rats not given the antagonist). These findings suggest that the different kinetics of the tolerance to anticonvulsant and EEG effects in comparison to myorelaxant effects can be attributed to a different involvement of benzodiazepine receptor subtypes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticonvulsants / pharmacology
  • Behavior, Animal / drug effects*
  • Body Weight / drug effects
  • Chlordiazepoxide / pharmacology*
  • Drug Tolerance
  • Electroencephalography / drug effects*
  • Kinetics
  • Male
  • Muscle Relaxation / drug effects
  • Rats
  • Rats, Wistar
  • Substance Withdrawal Syndrome / physiopathology

Substances

  • Anticonvulsants
  • Chlordiazepoxide