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

Lisa R Gerak, Charles P France

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

Benzodiazepines and neuroactive steroids are positive c-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 diazepamtreated 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 flumazenillever 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.

Original languageEnglish (US)
Pages (from-to)49-57
Number of pages9
JournalBehavioural Pharmacology
Volume22
Issue number1
DOIs
StatePublished - Feb 2011

Fingerprint

GABA Modulators
Flumazenil
Pentylenetetrazole
Benzodiazepines
Haplorhini
Midazolam
Pregnanolone
Steroids
Binding Sites
Diazepam
GABA-A Receptors

Keywords

  • γ-aminobutyric acid modulators
  • Diazepam
  • Drug discrimination
  • Flumazenil
  • Monkey
  • Neuroactive steroids
  • Pentylenetetrazole
  • Pregnanolone

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

Cite this

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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 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 diazepamtreated 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 flumazenillever 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.",
keywords = "γ-aminobutyric acid modulators, Diazepam, Drug discrimination, Flumazenil, Monkey, Neuroactive steroids, Pentylenetetrazole, Pregnanolone",
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