Effect of a neuroactive steroid infused into the cerebral ventricles of fetal sheep in utero using small infusion volumes.

Placental progesterone metabolites may influence fetal behaviour during late gestation. We have investigated the effect of the neuroactive metabolite, pregnanolone, on the sleep/awake behaviour of fetal sheep. These studies can only be effectively performed in unanesthetized animals with chronically implanted leads and catheters. The relatively large internal volumes of these catheters raises problems for cerebroventriclear infusions. Therefore, we developed a device with negligible deadspace ( approximately 10 microl) consisting of a ventricular cannula attached to a small cap which allowed the instillation of microl volumes of neuroactive steroids into a cerebral ventricle of fetal sheep in utero. Two catheters attached to the cap allow it to be filled in a push-pull configuration. The smaller internal diameter of the ventricular cannular prevents the solution entering the ventricle until the outflow catheter is occluded and solution is forced through the probe. Using this device, the infusion of 5beta-pregnane-3alpha-ol-20-one (pregnanolone, 1 mg), in 35% hydroxypropyl-beta-cyclodextrin, resulted in a marked suppression of fetal behaviour parameters indicative of arousal, while vehicle alone did not affect these parameters. We conclude that neuroactive steroids can be infused into the cerebroventricular system of chronically catheterised fetal sheep in small volumes and that pregnanolone may act directly to influence fetal behaviour.