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

• Published in: Scientific reports 2018-07, Vol.8 (1), p.10341-12, Article 10341
• Main Authors: Cao, Lily Q., Montana, Michael C., Germann, Allison L., Shin, Daniel J., Chakrabarti, Sampurna, Mennerick, Steven, Yuede, Carla M., Wozniak, David F., Evers, Alex S., Akk, Gustav
• Format: Article
• Language: English
• Subjects: 631/378/1697/1691; 631/378/2586; 64/114; 64/60; 9/74; Anesthesia; Anesthetics; Animals; Anxiolytics; Benzodiazepines; Cells, Cultured; Decay; Diazepam; Diazepam - pharmacology; Drug development; Drug dosages; Drug Synergism; Hippocampus; Humanities and Social Sciences; Inhibitory postsynaptic potentials; Inhibitory Postsynaptic Potentials - drug effects; Intravenous administration; Locomotion - drug effects; Male; Medicine; Mice; multidisciplinary; Neurons - cytology; Neurons - drug effects; Neurons - metabolism; Neurosteroids; Oocysts - drug effects; Oocysts - physiology; Patch-Clamp Techniques; Pregnanediones - pharmacology; Propofol; Propofol - pharmacology; Rats; Receptors, GABA-A - chemistry; Receptors, GABA-A - genetics; Receptors, GABA-A - metabolism; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Science; Science (multidisciplinary); Sedatives; Steroid hormones; Steroids; Transmitters; Xenopus - growth & development; γ-Aminobutyric acid A receptors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-018-28754-7

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 GABA A 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.