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Potency of positive gamma-aminobutyric acid(A) modulators to substitute for a midazolam discriminative stimulus in untreated monkeys does not predict potency to attenuate a flumazenil discriminative stimulus in diazepam-treated monkeys.
J Pharmacol Exp Ther. 2001 Sep; 298(3):1227-35.JP

Abstract

In monkeys discriminating midazolam (0.56 mg/kg s.c.) from saline, substitution for midazolam was elicited by various positive gamma-aminobutyric acid(A) (GABA(A)) modulators, including the benzodiazepines (BZs) triazolam, midazolam, and diazepam; the BZ(1)-selective ligands zaleplon and zolpidem; the barbiturates amobarbital and pentobarbital; and the neuroactive steroid pregnanolone. In another group of diazepam (5.6 mg/kg/day p.o.)-treated monkeys discriminating flumazenil (0.32 mg/kg s.c.) from vehicle, these positive GABA(A) modulators shifted the flumazenil dose-effect function to the right, i.e., attenuated diazepam withdrawal. The potency of positive GABA(A) modulators to substitute for midazolam in untreated monkeys did not predict their potency to attenuate the flumazenil stimulus in diazepam-treated monkeys. For instance, larger doses of BZs and BZ(1)-selective ligands were required to attenuate the flumazenil stimulus than to substitute for midazolam. The opposite relationship was revealed for non-BZ ligands, i.e., smaller doses of barbiturates and a neuroactive steroid were required to attenuate the flumazenil stimulus than to substitute for midazolam. The greater potency of non-BZ site ligands to attenuate diazepam withdrawal might be due to actions at a subtype of GABA(A) receptor not modulated by BZ site ligands, to the development of BZ tolerance without cross-tolerance to non-BZ site ligands, or to noncompetitive interactions at the GABA(A) receptor complex. Thus, interactions among GABA(A) modulators in BZ-dependent subjects are not predicted by their acute actions in nondependent subjects. It is not clear whether attenuation of BZ withdrawal is determined by subunit specificity or site of action on the GABA(A) receptor complex.

Authors+Show Affiliations

Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229-3900, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11504825

Citation

McMahon, L R., et al. "Potency of Positive Gamma-aminobutyric acid(A) Modulators to Substitute for a Midazolam Discriminative Stimulus in Untreated Monkeys Does Not Predict Potency to Attenuate a Flumazenil Discriminative Stimulus in Diazepam-treated Monkeys." The Journal of Pharmacology and Experimental Therapeutics, vol. 298, no. 3, 2001, pp. 1227-35.
McMahon LR, Gerak LR, France CP. Potency of positive gamma-aminobutyric acid(A) modulators to substitute for a midazolam discriminative stimulus in untreated monkeys does not predict potency to attenuate a flumazenil discriminative stimulus in diazepam-treated monkeys. J Pharmacol Exp Ther. 2001;298(3):1227-35.
McMahon, L. R., Gerak, L. R., & France, C. P. (2001). Potency of positive gamma-aminobutyric acid(A) modulators to substitute for a midazolam discriminative stimulus in untreated monkeys does not predict potency to attenuate a flumazenil discriminative stimulus in diazepam-treated monkeys. The Journal of Pharmacology and Experimental Therapeutics, 298(3), 1227-35.
McMahon LR, Gerak LR, France CP. Potency of Positive Gamma-aminobutyric acid(A) Modulators to Substitute for a Midazolam Discriminative Stimulus in Untreated Monkeys Does Not Predict Potency to Attenuate a Flumazenil Discriminative Stimulus in Diazepam-treated Monkeys. J Pharmacol Exp Ther. 2001;298(3):1227-35. PubMed PMID: 11504825.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Potency of positive gamma-aminobutyric acid(A) modulators to substitute for a midazolam discriminative stimulus in untreated monkeys does not predict potency to attenuate a flumazenil discriminative stimulus in diazepam-treated monkeys. AU - McMahon,L R, AU - Gerak,L R, AU - France,C P, PY - 2001/8/16/pubmed PY - 2001/9/14/medline PY - 2001/8/16/entrez SP - 1227 EP - 35 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 298 IS - 3 N2 - In monkeys discriminating midazolam (0.56 mg/kg s.c.) from saline, substitution for midazolam was elicited by various positive gamma-aminobutyric acid(A) (GABA(A)) modulators, including the benzodiazepines (BZs) triazolam, midazolam, and diazepam; the BZ(1)-selective ligands zaleplon and zolpidem; the barbiturates amobarbital and pentobarbital; and the neuroactive steroid pregnanolone. In another group of diazepam (5.6 mg/kg/day p.o.)-treated monkeys discriminating flumazenil (0.32 mg/kg s.c.) from vehicle, these positive GABA(A) modulators shifted the flumazenil dose-effect function to the right, i.e., attenuated diazepam withdrawal. The potency of positive GABA(A) modulators to substitute for midazolam in untreated monkeys did not predict their potency to attenuate the flumazenil stimulus in diazepam-treated monkeys. For instance, larger doses of BZs and BZ(1)-selective ligands were required to attenuate the flumazenil stimulus than to substitute for midazolam. The opposite relationship was revealed for non-BZ ligands, i.e., smaller doses of barbiturates and a neuroactive steroid were required to attenuate the flumazenil stimulus than to substitute for midazolam. The greater potency of non-BZ site ligands to attenuate diazepam withdrawal might be due to actions at a subtype of GABA(A) receptor not modulated by BZ site ligands, to the development of BZ tolerance without cross-tolerance to non-BZ site ligands, or to noncompetitive interactions at the GABA(A) receptor complex. Thus, interactions among GABA(A) modulators in BZ-dependent subjects are not predicted by their acute actions in nondependent subjects. It is not clear whether attenuation of BZ withdrawal is determined by subunit specificity or site of action on the GABA(A) receptor complex. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/11504825/Potency_of_positive_gamma_aminobutyric_acid_A__modulators_to_substitute_for_a_midazolam_discriminative_stimulus_in_untreated_monkeys_does_not_predict_potency_to_attenuate_a_flumazenil_discriminative_stimulus_in_diazepam_treated_monkeys_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=11504825 DB - PRIME DP - Unbound Medicine ER -