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Acute tolerance to chlordiazepoxide qualitatively changes the interaction between flumazenil and pregnanolone and not the interaction between flumazenil and midazolam in rhesus monkeys discriminating midazolam.
Eur J Pharmacol. 2013 Jan 30; 700(1-3):159-64.EJ

Abstract

Benzodiazepines and neuroactive steroids act at distinct binding sites on γ-aminobutyric acid(A) (GABA(A)) receptors where they positively modulate GABA, resulting in similar acute behavioral effects. Tolerance to benzodiazepines can develop with repeated treatment; however, cross tolerance to neuroactive steroids does not develop, perhaps due to conformational changes in benzodiazepine, and not neuroactive steroid, binding sites. Three monkeys discriminated 0.178 mg/kg midazolam while responding under a fixed-ratio 10 schedule of stimulus-shock termination. On separate occasions, dose-effect curves for midazolam and pregnanolone were determined when monkeys had not received chlordiazepoxide and when they received 10 mg/kg chlordiazepoxide 46 hours earlier; for some tests, flumazenil was given before determination of dose-effect curves. Midazolam and pregnanolone produced ≥80% midazolam-lever responding. When administered 46 h before sessions, chlordiazepoxide did not produce pregnanolone-lever responding; under those treatment conditions, midazolam dose-effect curves were shifted 2.8-fold rightward and pregnanolone dose-effect curves were not changed. Flumazenil antagonized midazolam; Schild (linear) analyses yielded slopes that were not different from unity and pA(2) values of 7.46 when monkeys had not received chlordiazepoxide and 7.44 when they received chlordiazepoxide 46 h earlier. Flumazenil did not alter the effects of pregnanolone in chlordiazepoxide-treated monkeys. Thus, interactions between flumazenil and midazolam were not qualitatively or quantitatively changed in monkeys acutely tolerant to chlordiazepoxide, suggesting that mechanisms other than alterations of benzodiazepine binding sites account for the development of acute tolerance.

Authors+Show Affiliations

Department of Pharmacology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr.-mail code 7764, San Antonio, TX 78229-3900, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

23305839

Citation

Zanettini, Claudio, et al. "Acute Tolerance to Chlordiazepoxide Qualitatively Changes the Interaction Between Flumazenil and Pregnanolone and Not the Interaction Between Flumazenil and Midazolam in Rhesus Monkeys Discriminating Midazolam." European Journal of Pharmacology, vol. 700, no. 1-3, 2013, pp. 159-64.
Zanettini C, Yoon SS, France CP, et al. Acute tolerance to chlordiazepoxide qualitatively changes the interaction between flumazenil and pregnanolone and not the interaction between flumazenil and midazolam in rhesus monkeys discriminating midazolam. Eur J Pharmacol. 2013;700(1-3):159-64.
Zanettini, C., Yoon, S. S., France, C. P., & Gerak, L. R. (2013). Acute tolerance to chlordiazepoxide qualitatively changes the interaction between flumazenil and pregnanolone and not the interaction between flumazenil and midazolam in rhesus monkeys discriminating midazolam. European Journal of Pharmacology, 700(1-3), 159-64. https://doi.org/10.1016/j.ejphar.2012.12.028
Zanettini C, et al. Acute Tolerance to Chlordiazepoxide Qualitatively Changes the Interaction Between Flumazenil and Pregnanolone and Not the Interaction Between Flumazenil and Midazolam in Rhesus Monkeys Discriminating Midazolam. Eur J Pharmacol. 2013 Jan 30;700(1-3):159-64. PubMed PMID: 23305839.
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TY - JOUR T1 - Acute tolerance to chlordiazepoxide qualitatively changes the interaction between flumazenil and pregnanolone and not the interaction between flumazenil and midazolam in rhesus monkeys discriminating midazolam. AU - Zanettini,Claudio, AU - Yoon,Seong Shoon, AU - France,Charles P, AU - Gerak,Lisa R, Y1 - 2013/01/07/ PY - 2012/09/04/received PY - 2012/12/08/revised PY - 2012/12/18/accepted PY - 2013/1/12/entrez PY - 2013/1/12/pubmed PY - 2013/8/6/medline SP - 159 EP - 64 JF - European journal of pharmacology JO - Eur J Pharmacol VL - 700 IS - 1-3 N2 - Benzodiazepines and neuroactive steroids act at distinct binding sites on γ-aminobutyric acid(A) (GABA(A)) receptors where they positively modulate GABA, resulting in similar acute behavioral effects. Tolerance to benzodiazepines can develop with repeated treatment; however, cross tolerance to neuroactive steroids does not develop, perhaps due to conformational changes in benzodiazepine, and not neuroactive steroid, binding sites. Three monkeys discriminated 0.178 mg/kg midazolam while responding under a fixed-ratio 10 schedule of stimulus-shock termination. On separate occasions, dose-effect curves for midazolam and pregnanolone were determined when monkeys had not received chlordiazepoxide and when they received 10 mg/kg chlordiazepoxide 46 hours earlier; for some tests, flumazenil was given before determination of dose-effect curves. Midazolam and pregnanolone produced ≥80% midazolam-lever responding. When administered 46 h before sessions, chlordiazepoxide did not produce pregnanolone-lever responding; under those treatment conditions, midazolam dose-effect curves were shifted 2.8-fold rightward and pregnanolone dose-effect curves were not changed. Flumazenil antagonized midazolam; Schild (linear) analyses yielded slopes that were not different from unity and pA(2) values of 7.46 when monkeys had not received chlordiazepoxide and 7.44 when they received chlordiazepoxide 46 h earlier. Flumazenil did not alter the effects of pregnanolone in chlordiazepoxide-treated monkeys. Thus, interactions between flumazenil and midazolam were not qualitatively or quantitatively changed in monkeys acutely tolerant to chlordiazepoxide, suggesting that mechanisms other than alterations of benzodiazepine binding sites account for the development of acute tolerance. SN - 1879-0712 UR - https://www.unboundmedicine.com/medline/citation/23305839/Acute_tolerance_to_chlordiazepoxide_qualitatively_changes_the_interaction_between_flumazenil_and_pregnanolone_and_not_the_interaction_between_flumazenil_and_midazolam_in_rhesus_monkeys_discriminating_midazolam_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(13)00003-4 DB - PRIME DP - Unbound Medicine ER -