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

Gunter, Barak W.; Jones, Sherman A.; Paul, Ian A.; Platt, Donna M.; Rowlett, James K.

doi:10.1007/s00213-016-4369-8

Cited by 13 publications

(4 citation statements)

References 43 publications

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“…MDZ is an allosteric agonist of synaptic GABA-A receptors through sites distinct from the neurosteroid binding site (Nusser et al, 1997). A previous study has shown that the combination of GX and MDZ exerts synergistic anxiolytic effects (Gunter et al, 2016). In the present study, we found that neurosteroid exerts a synergistic response with MDZ on GABA-A receptors.…”

Section: Discussionsupporting

confidence: 67%

Isobolographic Analysis of Antiseizure Activity of the GABA Type A Receptor-Modulating Synthetic Neurosteroids Brexanolone and Ganaxolone with Tiagabine and Midazolam

Chuang

Reddy

2019

J Pharmacol Exp Ther

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Epilepsy is often treated with a combination of antiepileptic drugs. Although neurosteroids are potent anticonvulsants, little is known about their combination potential for the treatment of refractory epilepsy. Here, we investigated the combination efficacy of neurosteroids allopregnanolone (AP, brexanolone) and ganaxolone (GX) with the GABA-reuptake inhibitor tiagabine (TG) or the benzodiazepine midazolam (MDZ) on tonic inhibition in dentate gyrus granule cells and seizure protection in the hippocampus kindling and 6-Hz seizure models. Isobolographic analysis indicated that combinations of GX and TG or AP and TG at three standard ratios (1:1, 3:1, and 1:3) displayed significant synergism in augmenting tonic inhibition. In pharmacological studies, GX, AP, and TG produced dose-dependent antiseizure effects in mice (ED 50 5 1.46, 4.20, and 0.20 mg/kg, respectively). The combination of GX and TG at the fixed ratio of 1:1 exerted the greatest combination index (CI 5 0.53), indicating strong synergistic interaction in seizure protection. In addition, combination regimens of AP and TG showed robust synergism for seizure protection (CI 5 0.4). Finally, combination regimens of GX and MDZ elicited synergistic (CI 5 0.6) responses for seizure protection. These results demonstrate striking synergism of neurosteroids and TG combination for seizure protection, likely because of their effects at extrasynaptic GABA type A (GABA-A) receptors from TG-induced elevation in GABA levels. Superadditive antiseizure activity of neurosteroid-MDZ combinations may stem from their actions at both synaptic and extrasynaptic GABA-A receptors. Together, these findings provide a potential mechanistic basis for combination potential of neurosteroids with TG or benzodiazepines for the management of refractory epilepsy, status epilepticus, and seizure disorders. SIGNIFICANCE STATEMENTThis paper investigates for the first time the potential synergistic interactions between two neurosteroids with anticonvulsant properties, allopregnanolone (brexanolone) and the very similar synthetic analog, ganaxolone, and two conventional antiepileptic drugs active at GABA type A receptors: the GABA-reuptake inhibitor tiagabine and a benzodiazepine, midazolam. The results demonstrate a synergistic protective effect of neurosteroidtiagabine combinations, as well as neurosteroid-midazolam regimens in seizure models.

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Section: Discussionsupporting

confidence: 67%

Isobolographic Analysis of Antiseizure Activity of the GABA Type A Receptor-Modulating Synthetic Neurosteroids Brexanolone and Ganaxolone with Tiagabine and Midazolam

Chuang

Reddy

2019

J Pharmacol Exp Ther

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“…Anesthetic steroids potentiate the actions of the intravenous anesthetics propofol and etomidate in electrophysiological 8 and behavioral assays 9 , 31 . Similarly, coapplication of neuroactive steroids enhances the anxiolytic effect of the benzodiazepine triazolam 32 , 33 and the anticonvulsant potency of diazepam against seizures induced by pentylenetetrazol 34 .…”

Section: Discussionmentioning

confidence: 99%

Enhanced GABAergic actions resulting from the coapplication of the steroid 3α-hydroxy-5α-pregnane-11,20-dione (alfaxalone) with propofol or diazepam

Cao

Montana

Germann

et al. 2018

Sci Rep

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Many GABAergic drugs are in clinical use as anesthetics, sedatives, or anxiolytics. We have investigated the actions of the combinations of the neuroactive steroid 3α-hydroxy-5α-pregnane-11,20-dione (alfaxalone) with the intravenous anesthetic propofol or the benzodiazepine diazepam. The goal of the study was to determine whether coapplication of alfaxalone reduces the effective doses and concentrations of propofol and diazepam. Behavioral effects of alfaxalone, propofol, diazepam, and the combinations of the drugs were evaluated during a 30-min activity test in mice. Functional effects of the individual drugs and drug combinations were tested by measuring the decay times of spontaneous inhibitory postsynaptic currents in rat hippocampal neurons, and peak current responses from heterologously expressed concatemeric α1β2γ2L GABAA receptors. Co-administration of alfaxalone increased the sedative actions of propofol and diazepam in mice. The combination of alfaxalone with propofol or diazepam increased the decay times of sIPSCs and shifted the concentration-response relationships for GABA-activated receptors to lower transmitter concentrations. We infer that alfaxalone acts as a co-agonist to enhance the GABAergic effects of propofol and diazepam. We propose that co-administration of alfaxalone, and possibly other neuroactive steroids, can be employed to reduce dosage requirements for propofol and diazepam.

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“…Deviation from a linear isobole of additivity, typically interpreted as synergy, has been observed in the modulation of GABA-activated a1b2g2L receptors by the combination of propofol and flurazepam (Reynolds and Maitra, 1996), the enhancement of [ 3 H]diazepam binding to cerebrocortical synaptoneurosomes by the combination of GABA and pentobarbital, the enhancement of [ 3 H]muscimol binding by pentobarbital and diazepam (DeLorey et al, 1993), and the production of loss-of-righting in rats by combinations of barbiturates and benzodiazepines (DeLorey et al, 1993). Superadditive anxiolytic effects have been found for certain concentration combinations of triazolam and pregnanolone and for clonazepam and ganaxalone in the elevated zero maze assay (Gunter et al, 2016). In patients, the combination of midazolam and propofol apparently synergistically produces a loss of response to command (McClune et al, 1992;Minto et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

The Actions of Drug Combinations on the GABA_AReceptor Manifest as Curvilinear Isoboles of Additivity

Shin¹,

Germann²,

Steinbach³

2017

Mol Pharmacol

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Drug interactions are often analyzed in terms of isobolograms. In the isobologram, the line connecting the axial points corresponding to the concentrations of two different drugs that produce an effect of the same magnitude is termed an isobole of additivity. Although the isobole of additivity can be a straight line in some special cases, previous work has proposed that it is curvilinear when the two drugs differ in their maximal effects or Hill slopes. Modulators of transmitter-gated ion channels have a wide range of maximal effects as well as Hill slopes, suggesting that the isoboles for drug actions on ion channel function are not linear. In this study, we have conducted an analysis of direct activation and potentiation of the human 122L GABA receptor to demonstrate that: 1) curvilinear isoboles of additivity are predicted by a concerted transition model where the binding of each GABAergic drug additively and independently reduces the free energy of the open receptor compared with the closed receptor; and 2) experimental data for receptor activation using the agonist pair of GABA and propofol or potentiation of responses to a low concentration of GABA by the drug pair of alfaxalone and propofol agree very well with predictions. The approach assuming independent energetic contributions from GABAergic drugs enables, at least for the drug combinations tested, a straightforward method to accurately predict functional responses to any combination of concentrations.

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

Abstract: Although drug interactions depended on the constituent drugs, the combination tested, and the behavioral endpoint; a combination was identified that would be predicted to result in supra-additive anxiolytic-like effects with predominantly additive discriminative stimulus effects.

Cited by 13 publications

References 43 publications

Isobolographic Analysis of Antiseizure Activity of the GABA Type A Receptor-Modulating Synthetic Neurosteroids Brexanolone and Ganaxolone with Tiagabine and Midazolam

Isobolographic Analysis of Antiseizure Activity of the GABA Type A Receptor-Modulating Synthetic Neurosteroids Brexanolone and Ganaxolone with Tiagabine and Midazolam

Enhanced GABAergic actions resulting from the coapplication of the steroid 3α-hydroxy-5α-pregnane-11,20-dione (alfaxalone) with propofol or diazepam

The Actions of Drug Combinations on the GABA_AReceptor Manifest as Curvilinear Isoboles of Additivity

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

Abstract: Although drug interactions depended on the constituent drugs, the combination tested, and the behavioral endpoint; a combination was identified that would be predicted to result in supra-additive anxiolytic-like effects with predominantly additive discriminative stimulus effects.

Cited by 13 publications

References 43 publications

Isobolographic Analysis of Antiseizure Activity of the GABA Type A Receptor-Modulating Synthetic Neurosteroids Brexanolone and Ganaxolone with Tiagabine and Midazolam

Isobolographic Analysis of Antiseizure Activity of the GABA Type A Receptor-Modulating Synthetic Neurosteroids Brexanolone and Ganaxolone with Tiagabine and Midazolam

Enhanced GABAergic actions resulting from the coapplication of the steroid 3α-hydroxy-5α-pregnane-11,20-dione (alfaxalone) with propofol or diazepam

The Actions of Drug Combinations on the GABAAReceptor Manifest as Curvilinear Isoboles of Additivity

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The Actions of Drug Combinations on the GABA_AReceptor Manifest as Curvilinear Isoboles of Additivity