Combined discriminative stimulus effects of midazolam with other positive GABAA modulators and GABAA receptor agonists in rhesus monkeys

Lance R. McMahon, Charles P France

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Rationale: Interactions among compounds at GABAA receptors might have important implications for the therapeutic and other effects of positive GABAA modulators (e.g. benzodiazepines). Objectives: This study examined whether a midazolam discriminative stimulus is modified by GABA A agonists that act at sites other than benzodiazepine sites. Methods: Rhesus monkeys discriminating midazolam (0.32 mg/kg SC) received direct-acting GABAA receptor agonists (e.g. muscimol and gaboxadol), an indirect-acting GABAA receptor agonist (progabide), ethanol, another benzodiazepine (triazolam), a barbiturate (pentobarbital), or a neuroactive steroid (pregnanolone) alone and in combination with midazolam. Results: When administered alone, triazolam (0.1 mg/kg), pentobarbital (17.8 mg/kg) and pregnanolone (5.6 mg/kg) occasioned high levels of midazolam lever responding, ethanol (1-3 g/kg) occasioned intermediate levels of midazolam lever responding, and muscimol (0.32-1 mg/kg), gaboxadol (3.2-10 mg/kg) and progabide (10-32 mg/kg) occasioned low levels of midazolam lever responding. When combined with less-than-fully effective doses of midazolam, progabide (32 mg/kg) and ethanol (1 g/kg), but not muscimol and gaboxadol, enhanced the midazolam discriminative stimulus. Triazolam, pregnanolone and pentobarbital increased the potency of midazolam to occasion midazolam lever responding and the effects of these combinations were additive. Conclusions: Direct-acting GABAA receptor agonists are qualitatively different from positive GABAA modulators in rhesus monkeys trained to discriminate midazolam. Although GABAA receptor agonists and modulators can enhance the actions of benzodiazepines at the GABAA receptor complex, the same drugs do not necessarily modify the discriminative stimulus effects of benzodiazepines. These results underscore the importance of the mechanism by which drugs alter Cl - flux at the GABAA receptor complex as a determinant not only of drug action but also of drug interaction and whether any particular drug enhances the behavioral effects of a benzodiazepine.

Original languageEnglish (US)
Pages (from-to)400-409
Number of pages10
JournalPsychopharmacology
Volume178
Issue number4
DOIs
StatePublished - Apr 2005

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GABA-A Receptor Agonists
Midazolam
Macaca mulatta
Benzodiazepines
Pregnanolone
Triazolam
Muscimol
Pentobarbital
GABA-A Receptors
Ethanol
Pharmaceutical Preparations
Therapeutic Uses
Drug Interactions

Keywords

  • Additive
  • Barbiturate
  • Benzodiazepine
  • Drug discrimination
  • GABA
  • Interaction
  • Muscimol
  • Neuroactive steroid
  • Progabide
  • Rhesus monkey

ASJC Scopus subject areas

  • Pharmacology

Cite this

Combined discriminative stimulus effects of midazolam with other positive GABAA modulators and GABAA receptor agonists in rhesus monkeys. / McMahon, Lance R.; France, Charles P.

In: Psychopharmacology, Vol. 178, No. 4, 04.2005, p. 400-409.

Research output: Contribution to journalArticle

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abstract = "Rationale: Interactions among compounds at GABAA receptors might have important implications for the therapeutic and other effects of positive GABAA modulators (e.g. benzodiazepines). Objectives: This study examined whether a midazolam discriminative stimulus is modified by GABA A agonists that act at sites other than benzodiazepine sites. Methods: Rhesus monkeys discriminating midazolam (0.32 mg/kg SC) received direct-acting GABAA receptor agonists (e.g. muscimol and gaboxadol), an indirect-acting GABAA receptor agonist (progabide), ethanol, another benzodiazepine (triazolam), a barbiturate (pentobarbital), or a neuroactive steroid (pregnanolone) alone and in combination with midazolam. Results: When administered alone, triazolam (0.1 mg/kg), pentobarbital (17.8 mg/kg) and pregnanolone (5.6 mg/kg) occasioned high levels of midazolam lever responding, ethanol (1-3 g/kg) occasioned intermediate levels of midazolam lever responding, and muscimol (0.32-1 mg/kg), gaboxadol (3.2-10 mg/kg) and progabide (10-32 mg/kg) occasioned low levels of midazolam lever responding. When combined with less-than-fully effective doses of midazolam, progabide (32 mg/kg) and ethanol (1 g/kg), but not muscimol and gaboxadol, enhanced the midazolam discriminative stimulus. Triazolam, pregnanolone and pentobarbital increased the potency of midazolam to occasion midazolam lever responding and the effects of these combinations were additive. Conclusions: Direct-acting GABAA receptor agonists are qualitatively different from positive GABAA modulators in rhesus monkeys trained to discriminate midazolam. Although GABAA receptor agonists and modulators can enhance the actions of benzodiazepines at the GABAA receptor complex, the same drugs do not necessarily modify the discriminative stimulus effects of benzodiazepines. These results underscore the importance of the mechanism by which drugs alter Cl - flux at the GABAA receptor complex as a determinant not only of drug action but also of drug interaction and whether any particular drug enhances the behavioral effects of a benzodiazepine.",
keywords = "Additive, Barbiturate, Benzodiazepine, Drug discrimination, GABA, Interaction, Muscimol, Neuroactive steroid, Progabide, Rhesus monkey",
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AU - France, Charles P

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N2 - Rationale: Interactions among compounds at GABAA receptors might have important implications for the therapeutic and other effects of positive GABAA modulators (e.g. benzodiazepines). Objectives: This study examined whether a midazolam discriminative stimulus is modified by GABA A agonists that act at sites other than benzodiazepine sites. Methods: Rhesus monkeys discriminating midazolam (0.32 mg/kg SC) received direct-acting GABAA receptor agonists (e.g. muscimol and gaboxadol), an indirect-acting GABAA receptor agonist (progabide), ethanol, another benzodiazepine (triazolam), a barbiturate (pentobarbital), or a neuroactive steroid (pregnanolone) alone and in combination with midazolam. Results: When administered alone, triazolam (0.1 mg/kg), pentobarbital (17.8 mg/kg) and pregnanolone (5.6 mg/kg) occasioned high levels of midazolam lever responding, ethanol (1-3 g/kg) occasioned intermediate levels of midazolam lever responding, and muscimol (0.32-1 mg/kg), gaboxadol (3.2-10 mg/kg) and progabide (10-32 mg/kg) occasioned low levels of midazolam lever responding. When combined with less-than-fully effective doses of midazolam, progabide (32 mg/kg) and ethanol (1 g/kg), but not muscimol and gaboxadol, enhanced the midazolam discriminative stimulus. Triazolam, pregnanolone and pentobarbital increased the potency of midazolam to occasion midazolam lever responding and the effects of these combinations were additive. Conclusions: Direct-acting GABAA receptor agonists are qualitatively different from positive GABAA modulators in rhesus monkeys trained to discriminate midazolam. Although GABAA receptor agonists and modulators can enhance the actions of benzodiazepines at the GABAA receptor complex, the same drugs do not necessarily modify the discriminative stimulus effects of benzodiazepines. These results underscore the importance of the mechanism by which drugs alter Cl - flux at the GABAA receptor complex as a determinant not only of drug action but also of drug interaction and whether any particular drug enhances the behavioral effects of a benzodiazepine.

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KW - Additive

KW - Barbiturate

KW - Benzodiazepine

KW - Drug discrimination

KW - GABA

KW - Interaction

KW - Muscimol

KW - Neuroactive steroid

KW - Progabide

KW - Rhesus monkey

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