Tolerance to the behavioral effects of chlordiazepoxide: pharmacological and biochemical selectivity.
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.
Sannerud
C A
CA
Behavioral Pharmacology and Genetics Section, National Institute on Drug Abuse, Baltimore, Maryland.
Marley
R J
RJ
Serdikoff
S L
SL
Alastra
A J
AJ
Cohen
C
C
Goldberg
S R
SR
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002110:Caffeine / Q000494:pharmacology; D002243:Carbolines / Q000494:pharmacology; D002707:Chlordiazepoxide / Q000494:pharmacology*; D002712:Chlorides / Q000493:pharmacokinetics; D002713:Chlorine / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005442:Flumazenil / Q000494:pharmacology; D008297:Male; D008874:Midazolam / Q000494:pharmacology; D009020:Morphine / Q000494:pharmacology; D010424:Pentobarbital / Q000494:pharmacology; D011868:Radioisotopes; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism; D012680:Sensitivity and Specificity; D013268:Stimulation, Chemical; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D002243:Carbolines; D002712:Chlorides; D011868:Radioisotopes; D011963:Receptors, GABA-A; D002110:Caffeine; D005442:Flumazenil; D002713:Chlorine; D005680:gamma-Aminobutyric Acid; C035874:FG 7142; D002707:Chlordiazepoxide; D009020:Morphine; D000661:Amphetamine; D010424:Pentobarbital; D008874:Midazolam