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Acute cross tolerance to midazolam, and not pentobarbital and pregnanolone, after a single dose of chlordiazepoxide in monkeys discriminating midazolam.
Behav Pharmacol. 2008 Dec; 19(8):796-804.BP

Abstract

Although cross tolerance can develop among positive gamma-aminobutyric acidA (GABAA) modulators acting at the same modulatory site, cross tolerance does not always develop to drugs acting at sites that are different from the site of action of the drug administered chronically. To examine the relationship between cross tolerance and site of action, four rhesus monkeys discriminated midazolam and, on separate occasions, received 32 mg/kg of chlordiazepoxide 24 h before dose-effect determinations for drugs acting at different sites. Midazolam, pentobarbital, and pregnanolone produced >80% midazolam-lever responding. Although monkeys responded on the midazolam lever 2-4 h after 32 mg/kg of chlordiazepoxide, they responded on the saline lever 24 h later. Twenty-four hours after an acute injection of 32 mg/kg of chlordiazepoxide, midazolam dose-effect curves were shifted 4.6-fold to the right, whereas pregnanolone dose-effect curves were shifted three-fold to the left. Sensitivity to pentobarbital increased in one monkey and decreased in others 24 h after chlordiazepoxide administration. Decreased sensitivity to midazolam shows that acute cross tolerance develops after chlordiazepoxide administration, although it does not develop to drugs acting at other sites on GABAA receptors. These differences among positive GABAA modulators suggest that even short-term benzodiazepine administration changes GABAA receptors, and those changes impact modulatory sites differently.

Authors+Show Affiliations

Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900, USA. gerak@uthscsa.eduNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

19020414

Citation

Gerak, Lisa R., et al. "Acute Cross Tolerance to Midazolam, and Not Pentobarbital and Pregnanolone, After a Single Dose of Chlordiazepoxide in Monkeys Discriminating Midazolam." Behavioural Pharmacology, vol. 19, no. 8, 2008, pp. 796-804.
Gerak LR, McMahon LR, France CP. Acute cross tolerance to midazolam, and not pentobarbital and pregnanolone, after a single dose of chlordiazepoxide in monkeys discriminating midazolam. Behav Pharmacol. 2008;19(8):796-804.
Gerak, L. R., McMahon, L. R., & France, C. P. (2008). Acute cross tolerance to midazolam, and not pentobarbital and pregnanolone, after a single dose of chlordiazepoxide in monkeys discriminating midazolam. Behavioural Pharmacology, 19(8), 796-804. https://doi.org/10.1097/FBP.0b013e32831c3b40
Gerak LR, McMahon LR, France CP. Acute Cross Tolerance to Midazolam, and Not Pentobarbital and Pregnanolone, After a Single Dose of Chlordiazepoxide in Monkeys Discriminating Midazolam. Behav Pharmacol. 2008;19(8):796-804. PubMed PMID: 19020414.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Acute cross tolerance to midazolam, and not pentobarbital and pregnanolone, after a single dose of chlordiazepoxide in monkeys discriminating midazolam. AU - Gerak,Lisa R, AU - McMahon,Lance R, AU - France,Charles P, PY - 2008/11/21/pubmed PY - 2009/4/9/medline PY - 2008/11/21/entrez SP - 796 EP - 804 JF - Behavioural pharmacology JO - Behav Pharmacol VL - 19 IS - 8 N2 - Although cross tolerance can develop among positive gamma-aminobutyric acidA (GABAA) modulators acting at the same modulatory site, cross tolerance does not always develop to drugs acting at sites that are different from the site of action of the drug administered chronically. To examine the relationship between cross tolerance and site of action, four rhesus monkeys discriminated midazolam and, on separate occasions, received 32 mg/kg of chlordiazepoxide 24 h before dose-effect determinations for drugs acting at different sites. Midazolam, pentobarbital, and pregnanolone produced >80% midazolam-lever responding. Although monkeys responded on the midazolam lever 2-4 h after 32 mg/kg of chlordiazepoxide, they responded on the saline lever 24 h later. Twenty-four hours after an acute injection of 32 mg/kg of chlordiazepoxide, midazolam dose-effect curves were shifted 4.6-fold to the right, whereas pregnanolone dose-effect curves were shifted three-fold to the left. Sensitivity to pentobarbital increased in one monkey and decreased in others 24 h after chlordiazepoxide administration. Decreased sensitivity to midazolam shows that acute cross tolerance develops after chlordiazepoxide administration, although it does not develop to drugs acting at other sites on GABAA receptors. These differences among positive GABAA modulators suggest that even short-term benzodiazepine administration changes GABAA receptors, and those changes impact modulatory sites differently. SN - 1473-5849 UR - https://www.unboundmedicine.com/medline/citation/19020414/Acute_cross_tolerance_to_midazolam_and_not_pentobarbital_and_pregnanolone_after_a_single_dose_of_chlordiazepoxide_in_monkeys_discriminating_midazolam_ L2 - https://doi.org/10.1097/FBP.0b013e32831c3b40 DB - PRIME DP - Unbound Medicine ER -