Tolerance to the behavioral effects of chlordiazepoxide: Pharmacological and biochemical selectivity

C. A. Sannerud, R. J. Marley, S. L. Serdikoff, A. J.G. Alastra, C. Cohen, S. R. Goldberg

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There is a dynamic interaction between a drug's pharmacological effects and the behavioral context in which it is administered. The present study evaluated the influence of behavioral processes on the development of tolerance and cross-tolerance to the rate-decreasing effects of chlordiazepoxide in rats. Sprague-Dawley rats responded under a fixed-ratio 30 schedule of food delivery. Different groups of rats received 18 mg/kg/day of chlordiazepoxide either before (PRE, n = 8) or after (POST, n = 10) daily experimental sessions for 8 weeks. Cumulative dose-response curves for chlordiazepoxide were obtained before and during chronic chlordiazepoxide administration and during chronic saline administration. Cumulative dose- response curves for midazolam, FG 7142 (N-methyl-β-carboline-3-carboxamide) flumazenil, pentobarbital, caffeine, morphine and d-amphetamine were determined before, during and 4.5 to 5 months after chronic chlordiazepoxide administration. Group PRE developed tolerance to chlordiazepoxide, whereas group POST did not develop tolerance. Although cross-tolerance developed to midazolam in both groups, it was greater in group PRE. Both groups showed comparable sensitization to FG 7142 and neither group showed a significant change in sensitivity to any of the other drugs. Biochemical studies of γ- aminobutyric acid (GABA)-related functioning in groups of rats that received chronic chlordiazepoxide administration either before (BIO-PRE, n = 6) or after (BIO-POST, n = 6) daily sessions found that GABA-stimulated 36Cl- uptake increased in both cortical and cerebellar preparations. However, GABA sensitivity in cerebellar tissue was significantly lower in group BIO-PRE compared with group BIO-POST. Thus, behavioral tolerance to chlordiazepoxide was associated with both pharmacological and biochemical effects, which suggests a relationship between behavioral tolerance to benzodiazepines and changes in the functional state of the GABA-benzodiazepine receptor complex.

Original languageEnglish (US)
Pages (from-to)1311-1320
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number3
StatePublished - Dec 1 1993

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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    Sannerud, C. A., Marley, R. J., Serdikoff, S. L., Alastra, A. J. G., Cohen, C., & Goldberg, S. R. (1993). Tolerance to the behavioral effects of chlordiazepoxide: Pharmacological and biochemical selectivity. Journal of Pharmacology and Experimental Therapeutics, 267(3), 1311-1320.