title: Combined discriminative stimulus effects of midazolam with other positive GABAA modulators and GABAA receptor agonists in rhesus monkeys.
abstract: BACKGROUND
  Interactions among compounds at GABA(A) receptors might have important implications for the therapeutic and other effects of positive GABA(A) modulators (e.g. benzodiazepines).
  
  
  OBJECTIVE
  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 GABA(A) receptor agonists (e.g. muscimol and gaboxadol), an indirect-acting GABA(A) 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 GABA(A) receptor agonists are qualitatively different from positive GABA(A) modulators in rhesus monkeys trained to discriminate midazolam. Although GABA(A) receptor agonists and modulators can enhance the actions of benzodiazepines at the GABA(A) 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 GABA(A) 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.
authors.affiliation: Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
authors.forename: Lance R
authors.initials: LR
authors.lastname: McMahon
authors.forename: Charles P
authors.initials: CP
authors.lastname: France
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D003216:Conditioning, Operant / Q000187:drug effects; D004193:Discrimination Learning / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D000431:Ethanol / Q000494:pharmacology; D018757:GABA Modulators / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D058785:GABA-A Receptor Agonists; D007279:Injections, Subcutaneous; D007555:Isoxazoles / Q000494:pharmacology; D008253:Macaca mulatta; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010424:Pentobarbital / Q000494:pharmacology; D011280:Pregnanolone / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000008:administration & dosage*; D013997:Time Factors; D014229:Triazolam / Q000494:pharmacology; D014930:Women; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D018757:GABA Modulators; D058785:GABA-A Receptor Agonists; D007555:Isoxazoles; D011963:Receptors, GABA-A; D014229:Triazolam; C017985:progabide; D000431:Ethanol; D005680:gamma-Aminobutyric Acid; D011280:Pregnanolone; D010424:Pentobarbital; C015542:gaboxadol; D008874:Midazolam