Acute cross tolerance to midazolam, and not pentobarbital and pregnanolone, after a single dose of chlordiazepoxide in monkeys discriminating midazolam

Lisa R. Gerak, Lance R. McMahon, Charles P. France

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Although cross tolerance can develop among positive γ-aminobutyric acidA (GABAA) modulators acting at the same modulatory site, cross tolerance does not always develop to drugs acting at sites that are different from the sue of action of the drug administered chronically. To examine the relationship between cross tolerance and site of action, four rhesus monkeys discriminated midazolam and, on separate occasions, received 32 mg/kg of chlordiazepoxide 24 h before dose-effect determinations for drugs acting at different sites. Midazolam, pentobarbital, and pregnanolone produced >80% midazolam-lever responding. Although monkeys responded on the midazolam lever 2-4 h after 32 mg/kg of chlordiazepoxide, they responded on the saline lever 24 h later. Twenty-four hours after an acute Injection of 32 mg/kg of chlordiazepoxide, mldazolam dose-effect curves were shifted 4.6-fold to the right, whereas pregnanolone dose-effect curves were shifted three-fold to the left Sensitivity to pentobarbital increased in one monkey and decreased in others 24 h after chlordiazepoxide administration. Decreased sensitivity to midazolam shows that acute cross tolerance develops after chlordiazepoxide administration, although it does not develop to drugs acting at other sites on GABAA receptors. These differences among positive GABAA modulators suggest that even short-term benzodiazepine administration changes GABAA receptors, and those changes impact modulatory sites differently.

Original languageEnglish (US)
Pages (from-to)796-804
Number of pages9
JournalBehavioural pharmacology
Volume19
Issue number8
DOIs
StatePublished - Dec 2008

Keywords

  • Acute cross tolerance
  • Chlordiazepoxide
  • Drug discrimination
  • Monkey
  • Neuroactive steroids
  • Pentoberbital
  • Pregnanolone

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

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