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Chronic benzodiazepine treatment does not alter interactions between positive GABAA modulators and flumazenil or pentylenetetrazole in monkeys

Gerak, Lisa R.a; France, Charles P.a,b

doi: 10.1097/FBP.0b013e3283425aa0
Original Articles

Benzodiazepines and neuroactive steroids are positive γ-aminobutyric acidA (GABAA) modulators acting at distinct binding sites; during benzodiazepine treatment, tolerance develops to many behavioral effects of benzodiazepines, although cross tolerance typically does not develop to neuroactive steroids. To determine whether differential changes in binding sites contribute to these behavioral differences, interactions between GABAA modulators were studied in two groups of four monkeys: one otherwise untreated group discriminated 0.178 mg/kg of the benzodiazepine midazolam; the other received 5.6 mg/kg/day of diazepam and discriminated 0.1 mg/kg of flumazenil, which binds to benzodiazepine sites without modulating GABAA receptors. In untreated monkeys, flumazenil antagonized midazolam but not the neuroactive steroid pregnanolone, whereas pentylenetetrazole (a negative modulator acting at a third site) antagonized both positive modulators. In diazepam-treated monkeys, 0.1 mg/kg of flumazenil or 32 mg/kg of pentylenetetrazole produced flumazenil-lever responding, which was reversed by midazolam and pregnanolone. As the flumazenil dose increased, larger doses of midazolam, but not pregnanolone, were needed to reverse flumazenil-lever responding. When the pentylenetetrazole dose increased, larger doses of both positive modulators were needed. Thus, interactions between GABAA modulators were not different between diazepam-treated and untreated monkeys and do not reveal changes in binding sites that could account for reported differences between benzodiazepines and neuroactive steroids.

Departments of aPharmacology

bPsychiatry, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA

Correspondence to Lisa R. Gerak, PhD, Department of Pharmacology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, mail code 7764, San Antonio, TX 78229-3900, USA e-mail: gerak@uthscsa.edu

Received April 13, 2010

Accepted October 24, 2010

© 2011 Lippincott Williams & Wilkins, Inc.