Effects of pregnanolone on behavioural parameters and the responses to GABA(A) receptor antagonists in the late gestation fetal sheep

Abstract

Placental progesterone metabolites may suppress fetal behaviour by interacting with GABA(A) receptors. In an initial study, the effect of 5β-pregnan-3α-ol-20-one (pregnanolone) given as a bolus (2.5 and 5.0 mg) or infused at a rate of 25 mg/h was investigated in unanaesthetized, catheterized fetal sheep, 127-135 days gestation. The incidence of fetal breathing movements (FBM) and behavioural arousal activity, defined as nuchal muscle electromyographic (EMG) activity during low voltage electrocortical (LV ECoG) activity were suppressed by pregnanolone administered as a bolus, while the pregnanolone infusion produced a significant decrease in arousal and EOG activity, and an increase in the presence of HV ECoG. The effect of pregnanolone on fetal behaviour and arousal induced by the GABA(A) antagonist picrotoxin was also investigated. Picrotoxin was given as a bolus (≃ 300 μg/kg) and pregnanolone was subsequently administered as a bolus (5.0 mg), and behavioural parameters were recorded and analysed. The incidence of arousal and FBM were 1.1 ± 1.6 min/10 min and 2.5 ± 2.3 min/10 min, respectively, before picrotoxin treatment and increased during the 10-20 and 20-30 min epochs after picrotoxin treatment (arousal: 5.0 ± 2.2 and 6.5 ± 3.6 min/10 min, respectively, n = 6, P < 0.05; FBM: 7.3 ± 3.2 and 9.3 ± 1.2 min/10 min, respectively, n = 6, P < 0.05.). The picrotoxin-induced increases in arousal and FBM were significantly suppressed (n = 6, P < 0.05) by pregnanolone treatment to 1.6 ± 1.5 min/10 min and 4.6 ± 2.3 min/10 min, respectively. We conclude that; (i) the GABA(A) active steroid pregnanolone suppresses basal and picrotoxin-induced fetal arousal and FBM; and (ii) steroid sensitive GABA(A) receptors may regulate fetal behaviour and breathing.