Figure 7.

Midazolam (MDZ) in combination with allopregnanolone (ALLO) mitigates TETS-triggered SCO patterns at concentrations that are individually less effective and their combination is more potent as positive allosteric modulator. A and B, MDZ (1 μM) or ALLO (0.1-0.3 µM) applied individually do not significantly reverse tetramethylenedisulfotetramine (TETS)-triggered synchronous Ca²⁺ oscillation (SCO) dysregulation. MDZ (1 µM) in combination with ≥ 0.3 µM ALLO restored SCO to (frequency and amplitude), or above (frequency) respective measures in Vehicle control. One-way ANOVA with additional correction (Tukey) for post hoc multiple comparison was applied to determine the statistical differences. Each data point represents mean ± SEM of data from 10–15 wells. *p < .05; **p < .01; ***p < .001, and ****p < .0001. C, Effect of MDZ (3 µM), ALLO (100 nM) or of the combination of MDZ and ALLO on the gamma-aminobutyric acid (GABA) concentration response curve of α₂β₃γ₂ GABA_A receptors. GABA: EC₅₀ 7.25 µM (95% CI: 6.39–8.11 µM; n_H = 1.66); GABA + 3 µM MDZ: EC₅₀ 1.66 µM (95% CI: 1.57–1.74 µM; n_H = 1.87); GABA + 100 nM ALLO: EC₅₀ 1.12 µM (95% CI: 1.05–1.20 µM; n_H = 1.30); GABA + 3 mM MDZ + 100 nM ALLO: EC₅₀ 0.27 µM (95% CI: 0.12–0.42 µM; n_H = 1.21). D, Representative currents elicited by 1 µM of GABA in the absence and the presence of MDZ (3 µM), ALLO (100 nM) or of the combination of MDZ and ALLO are shown below the data plot. Each data point is the mean ± SD of measurements of 4–8 cells.