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Tolerance to the behavioral effects of chlordiazepoxide: pharmacological and biochemical selectivity.
J Pharmacol Exp Ther. 1993 Dec; 267(3):1311-20.JP

Abstract

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-beta-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 FG7142 and neither group showed a significant change in sensitivity to any of the other drugs. Biochemical studies of gamma-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.

Authors+Show Affiliations

Behavioral Pharmacology and Genetics Section, National Institute on Drug Abuse, Baltimore, Maryland.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

8263795

Citation

Sannerud, C A., et al. "Tolerance to the Behavioral Effects of Chlordiazepoxide: Pharmacological and Biochemical Selectivity." The Journal of Pharmacology and Experimental Therapeutics, vol. 267, no. 3, 1993, pp. 1311-20.
Sannerud CA, Marley RJ, Serdikoff SL, et al. Tolerance to the behavioral effects of chlordiazepoxide: pharmacological and biochemical selectivity. J Pharmacol Exp Ther. 1993;267(3):1311-20.
Sannerud, C. A., Marley, R. J., Serdikoff, S. L., Alastra, A. J., Cohen, C., & Goldberg, S. R. (1993). Tolerance to the behavioral effects of chlordiazepoxide: pharmacological and biochemical selectivity. The Journal of Pharmacology and Experimental Therapeutics, 267(3), 1311-20.
Sannerud CA, et al. Tolerance to the Behavioral Effects of Chlordiazepoxide: Pharmacological and Biochemical Selectivity. J Pharmacol Exp Ther. 1993;267(3):1311-20. PubMed PMID: 8263795.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tolerance to the behavioral effects of chlordiazepoxide: pharmacological and biochemical selectivity. AU - Sannerud,C A, AU - Marley,R J, AU - Serdikoff,S L, AU - Alastra,A J, AU - Cohen,C, AU - Goldberg,S R, PY - 1993/12/1/pubmed PY - 1993/12/1/medline PY - 1993/12/1/entrez SP - 1311 EP - 20 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 267 IS - 3 N2 - 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-beta-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 FG7142 and neither group showed a significant change in sensitivity to any of the other drugs. Biochemical studies of gamma-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. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/8263795/Tolerance_to_the_behavioral_effects_of_chlordiazepoxide:_pharmacological_and_biochemical_selectivity_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=8263795 DB - PRIME DP - Unbound Medicine ER -