title: Chronic benzodiazepine treatment does not alter interactions  between positive GABA(A) modulators and flumazenil or  pentylenetetrazole in monkeys.
abstract: Benzodiazepines and neuroactive steroids are positive c-aminobutyric acid(A) (GABA(A)) 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 GABA(A) 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 GABA(A) 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 GABA(A) 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.
authors.affiliation: 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. gerak@uthscsa.edu
authors.forename: Lisa R
authors.initials: LR
authors.lastname: Gerak
authors.forename: Charles P
authors.initials: CP
authors.lastname: France
mesh_terms: D000818:Animals; D003975:Diazepam / Q000494:pharmacology*; D004192:Discrimination, Psychological / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D005442:Flumazenil / Q000494:pharmacology*; D018757:GABA Modulators / Q000494:pharmacology*; D008253:Macaca mulatta; D008297:Male; D008874:Midazolam / Q000494:pharmacology*; D010433:Pentylenetetrazole / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000378:metabolism
chemical_list: D018757:GABA Modulators; D011963:Receptors, GABA-A; D005442:Flumazenil; D003975:Diazepam; D008874:Midazolam; D010433:Pentylenetetrazole