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

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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 GABAA 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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Acknowledgements

The authors wish to thank C. Cruz, A. Gaylor, R. Jimenez, and K. Stone for providing technical assistance. This study was supported by US Public Health Service Grant DA05018.

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Authors and Affiliations

  1. Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, Tex., USA

    Lance R. McMahon & Charles P. France

  2. Department of Psychiatry, The University of Texas Health Science Center at San Antonio, San Antonio, Tex., USA

    Charles P. France

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  1. Lance R. McMahon
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  2. Charles P. France
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Correspondence to Charles P. France.

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McMahon, L.R., France, C.P. Combined discriminative stimulus effects of midazolam with other positive GABAA modulators and GABAA receptor agonists in rhesus monkeys. Psychopharmacology 178, 400–409 (2005). https://doi.org/10.1007/s00213-004-2022-4

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  • DOI: https://doi.org/10.1007/s00213-004-2022-4

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