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Discriminative stimulus effects of positive GABAA modulators and other anxiolytics, sedatives, and anticonvulsants in untreated and diazepam-treated monkeys.
J Pharmacol Exp Ther. 2003 Jan; 304(1):109-20.JP

Abstract

Positive GABAA modulators and other sedatives, anxiolytics, and anticonvulsants were used to evaluate mechanisms underlying the discriminative stimulus effects of midazolam in untreated monkeys and of flumazenil in monkeys treated with diazepam (5.6 mg/kg/day). Positive GABAA modulators at benzodiazepine (e.g., flunitrazepam and abecarnil) and neuroactive steroid sites (e.g., androsterone) substituted for midazolam in all monkeys; the neuroactive steroids dihydroandrosterone and epipregnanolone substituted for midazolam in two of three monkeys. All positive GABAA modulators attenuated flumazenil in diazepam-treated monkeys; doses of flunitrazepam and abecarnil larger than doses substituting for midazolam were required to attenuate flumazenil, whereas doses of neuroactive steroids smaller than doses substituting for midazolam attenuated flumazenil. Drugs with mechanisms that do not predominantly involve allosteric modulation of GABA (e.g., buspirone, ketamine, valproic acid, and diphenhydramine) did not substitute for midazolam or flumazenil. However, valproic acid enhanced the midazolam discriminative stimulus and attenuated the flumazenil discriminative stimulus; diphenhydramine attenuated the midazolam discriminative stimulus. These results suggest that drugs not sharing a mechanism of action with benzodiazepines can modulate the behavioral effects of benzodiazepines. In addition, this study demonstrates that endogenous ligands, presumably by acting at neuroactive steroid sites on the GABAA receptor complex, share discriminative stimulus effects with benzodiazepines. This study also suggests that positive GABAA-modulating neuroactive steroids are especially potent in attenuating behavioral effects that are related to diazepam withdrawal.

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 available

Pub Type(s)

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

Language

eng

PubMed ID

12490581

Citation

McMahon, Lance R., and Charles P. France. "Discriminative Stimulus Effects of Positive GABAA Modulators and Other Anxiolytics, Sedatives, and Anticonvulsants in Untreated and Diazepam-treated Monkeys." The Journal of Pharmacology and Experimental Therapeutics, vol. 304, no. 1, 2003, pp. 109-20.
McMahon LR, France CP. Discriminative stimulus effects of positive GABAA modulators and other anxiolytics, sedatives, and anticonvulsants in untreated and diazepam-treated monkeys. J Pharmacol Exp Ther. 2003;304(1):109-20.
McMahon, L. R., & France, C. P. (2003). Discriminative stimulus effects of positive GABAA modulators and other anxiolytics, sedatives, and anticonvulsants in untreated and diazepam-treated monkeys. The Journal of Pharmacology and Experimental Therapeutics, 304(1), 109-20.
McMahon LR, France CP. Discriminative Stimulus Effects of Positive GABAA Modulators and Other Anxiolytics, Sedatives, and Anticonvulsants in Untreated and Diazepam-treated Monkeys. J Pharmacol Exp Ther. 2003;304(1):109-20. PubMed PMID: 12490581.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Discriminative stimulus effects of positive GABAA modulators and other anxiolytics, sedatives, and anticonvulsants in untreated and diazepam-treated monkeys. AU - McMahon,Lance R, AU - France,Charles P, PY - 2002/12/20/pubmed PY - 2003/1/24/medline PY - 2002/12/20/entrez SP - 109 EP - 20 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 304 IS - 1 N2 - Positive GABAA modulators and other sedatives, anxiolytics, and anticonvulsants were used to evaluate mechanisms underlying the discriminative stimulus effects of midazolam in untreated monkeys and of flumazenil in monkeys treated with diazepam (5.6 mg/kg/day). Positive GABAA modulators at benzodiazepine (e.g., flunitrazepam and abecarnil) and neuroactive steroid sites (e.g., androsterone) substituted for midazolam in all monkeys; the neuroactive steroids dihydroandrosterone and epipregnanolone substituted for midazolam in two of three monkeys. All positive GABAA modulators attenuated flumazenil in diazepam-treated monkeys; doses of flunitrazepam and abecarnil larger than doses substituting for midazolam were required to attenuate flumazenil, whereas doses of neuroactive steroids smaller than doses substituting for midazolam attenuated flumazenil. Drugs with mechanisms that do not predominantly involve allosteric modulation of GABA (e.g., buspirone, ketamine, valproic acid, and diphenhydramine) did not substitute for midazolam or flumazenil. However, valproic acid enhanced the midazolam discriminative stimulus and attenuated the flumazenil discriminative stimulus; diphenhydramine attenuated the midazolam discriminative stimulus. These results suggest that drugs not sharing a mechanism of action with benzodiazepines can modulate the behavioral effects of benzodiazepines. In addition, this study demonstrates that endogenous ligands, presumably by acting at neuroactive steroid sites on the GABAA receptor complex, share discriminative stimulus effects with benzodiazepines. This study also suggests that positive GABAA-modulating neuroactive steroids are especially potent in attenuating behavioral effects that are related to diazepam withdrawal. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/12490581/Discriminative_stimulus_effects_of_positive_GABAA_modulators_and_other_anxiolytics_sedatives_and_anticonvulsants_in_untreated_and_diazepam_treated_monkeys_ L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=12490581 DB - PRIME DP - Unbound Medicine ER -