TY - JOUR
T1 - Tolerance to the behavioral effects of chlordiazepoxide
T2 - Pharmacological and biochemical selectivity
AU - Sannerud, C. A.
AU - Marley, R. J.
AU - Serdikoff, S. L.
AU - Alastra, A. J.G.
AU - Cohen, C.
AU - Goldberg, S. R.
PY - 1993/12/1
Y1 - 1993/12/1
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-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.
AB - 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.
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M3 - Article
C2 - 8263795
AN - SCOPUS:0027757165
SN - 0022-3565
VL - 267
SP - 1311
EP - 1320
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 3
ER -