Medroxy‐progesterone acetate (MPA) treatment increases pentobarbital resistance in neurons within the pre‐Botzinger complex (PBC), consistent with increased epsilon subunit expression in GABAA receptors (GABAARs)

Abstract

PBC neurons are critical for inspiratory rhythm generation and naturally increase epsilon subunit expression in GABAARs during pregnancy. Since epsilon subunits confer resistance to positive allosteric modulators (allopregnanolone and pentobarbital) that enhance chloride ion influx, epsilon expression may protect breathing during pregnancy when central allopregnanolone levels increase 3‐fold. We hypothesize that increased epsilon subunit expression increases when central neurosteroid concentrations are increased. Thus, we tested whether MPA treatment (progesterone analogue, 10 mg/kg, SQ, 7 days) increases epsilon subunit expression in the PBC. Multichannel electrodes were used to record spontaneous action potentials of PBC‐region neurons in medullary slices from control (n=7) and MPA‐treated (n=4) P30 rats before bath‐application of 300 μM pentobarbital. In neurons (n=68 cells) from control rats, the mean neuronal firing rate decreased to 44 ± 5% of baseline; 13% of cells were pentobarbital resistant. In neurons (n=31) from MPA‐treated rats, the mean neuronal firing rate was 91 ± 12% of baseline; 52% of cells were pentobarbital resistant. These data suggest that increased central neurosteroid levels are sufficient to increase epsilon expression in PBC‐region neurons, and thereby protect inspiratory motor output from excessive inhibition. Supported by NIH T32 HL07654.