Combined Discriminative Stimulus Effects of Midazolam with Other Positive GABAA Modulators and GABAA Receptor Agonists in Rhesus Monkeys

Overview

Journal Psychopharmacology (Berl)

Specialty Pharmacology

Date 2005 Mar 15

PMID 15765255

Citations 20

Authors

Lance R McMahon

Charles P France

Affiliations

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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.

Citing Articles

Behavioral effects of triazolam and pregnanolone combinations: reinforcing and sedative-motor effects in female rhesus monkeys.

Cook J, Platt D, Ruedi-Bettschen D, Rowlett J Front Psychiatry. 2023; 14:1142531.

PMID: 37252149 PMC: 10213563. DOI: 10.3389/fpsyt.2023.1142531.

Humulone Modulation of GABA Receptors and Its Role in Hops Sleep-Promoting Activity.

Benkherouf A, Eerola K, Soini S, Uusi-Oukari M Front Neurosci. 2020; 14:594708.

PMID: 33177986 PMC: 7591795. DOI: 10.3389/fnins.2020.594708.

Discriminative Stimulus Effects and Metabolism of Ethanol in Rhesus Monkeys.

Allen D, Grant K Alcohol Clin Exp Res. 2019; 43(9):1909-1917.

PMID: 31237691 PMC: 6721990. DOI: 10.1111/acer.14142.

Cross-Species Translational Findings in the Discriminative Stimulus Effects of Ethanol.

Allen D, Ford M, Grant K Curr Top Behav Neurosci. 2017; 39:95-111.

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Benzodiazepine and neuroactive steroid combinations in rats: anxiolytic-like and discriminative stimulus effects.

Gunter B, Jones S, Paul I, Platt D, Rowlett J Psychopharmacology (Berl). 2016; 233(17):3237-47.

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