TOLERANCE TO THE BEHAVIORAL-EFFECTS OF CHLORDIAZEPOXIDE - PHARMACOLOGICAL AND BIOCHEMICAL SELECTIVITY

There is a dynamic interaction between a drug's pharmacological effect s and the behavioral context in which it is administered. The present study evaluated the influence of behavioral processes on the developme nt 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 admi nistration. Cumulative dose-response curves for midazolam, FG 7142 (N- methyl-beta-carboline-3-carboxamide) flumazenil, pentobarbital, caffei ne, morphine and d-amphetamine were determined before, during and 4.5 to 5 months after chronic chlordiazepoxide administration. Group PRE d eveloped tolerance to chlordiazepoxide, whereas group POST did not dev elop tolerance. Although cross-tolerance developed to midazolam in bot h groups, it was greater in group PRE. Both groups showed comparable s ensitization to FG 71 42 and neither group showed a significant change in sensitivity to any of the other drugs. Biochemical studies of gamm a-aminobutyric acid (GABA)-related functioning in groups of rats that received chronic chlordiazepoxide administration either before (BIO-PR E, n = 6) or after (BIO-POST, n = 6) daily sessions found that GABA-st imulated Cl-36- uptake increased in both cortical and cerebellar prepa rations. However, GABA sensitivity in cerebellar tissue was significan tly lower in group BIO-PRE compared with group BIO-POST. Thus, behavio ral tolerance to chlordiazepoxide was associated with both pharmacolog ical and biochemical effects, which suggests a relationship between be havioral tolerance to benzodiazepines and changes in the functional st ate of the GABA-benzodiazepine receptor complex.