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Combined discriminative stimulus effects of midazolam with other positive GABAA modulators and GABAA receptor agonists in rhesus monkeys.
Psychopharmacology (Berl). 2005 Apr; 178(4):400-9.P

Abstract

RATIONALE

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).

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 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+Show Affiliations

Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.No affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15765255

Citation

McMahon, Lance R., and Charles P. France. "Combined Discriminative Stimulus Effects of Midazolam With Other Positive GABAA Modulators and GABAA Receptor Agonists in Rhesus Monkeys." Psychopharmacology, vol. 178, no. 4, 2005, pp. 400-9.
McMahon LR, France CP. Combined discriminative stimulus effects of midazolam with other positive GABAA modulators and GABAA receptor agonists in rhesus monkeys. Psychopharmacology (Berl). 2005;178(4):400-9.
McMahon, L. R., & France, C. P. (2005). Combined discriminative stimulus effects of midazolam with other positive GABAA modulators and GABAA receptor agonists in rhesus monkeys. Psychopharmacology, 178(4), 400-9.
McMahon LR, France CP. Combined Discriminative Stimulus Effects of Midazolam With Other Positive GABAA Modulators and GABAA Receptor Agonists in Rhesus Monkeys. Psychopharmacology (Berl). 2005;178(4):400-9. PubMed PMID: 15765255.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Combined discriminative stimulus effects of midazolam with other positive GABAA modulators and GABAA receptor agonists in rhesus monkeys. AU - McMahon,Lance R, AU - France,Charles P, Y1 - 2004/10/14/ PY - 2004/02/12/received PY - 2004/08/24/accepted PY - 2005/3/15/pubmed PY - 2005/10/21/medline PY - 2005/3/15/entrez SP - 400 EP - 9 JF - Psychopharmacology JO - Psychopharmacology (Berl) VL - 178 IS - 4 N2 - RATIONALE: 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). 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 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. SN - 0033-3158 UR - https://www.unboundmedicine.com/medline/citation/15765255/Combined_discriminative_stimulus_effects_of_midazolam_with_other_positive_GABAA_modulators_and_GABAA_receptor_agonists_in_rhesus_monkeys_ L2 - https://dx.doi.org/10.1007/s00213-004-2022-4 DB - PRIME DP - Unbound Medicine ER -