Pregnanolone (3α-hydroxy-5α-pregnane-20-one), a progesterone metabolite, facilitates inhibition of synaptic transmission in the Schäffer collateral pathway of the guinea pig hippocampus in vitro

Pregnanolone (3α-hydroxy-5α-pregnane-20-one, a metabolite of progesterone) caused a significant depression of the amplitude of the population spike evoked in stratum pyramidale in CA1 of the guinea pig hippocampus in vitro. Local application of pregnanolone on the surface of the slice in stratum oriens depressed the population spike without effects on the presynaptic spike and the population excitatory postsynaptic potential simultaneously recorded in stratum radiatum. The depression was dose-dependent and was observed with a minimum latency of 10 s after application of a 0.5-nl droplet of 3.1 μM pregnanolone. The concentration at the recording site was computed to be 0.2 μM. The duration of the depression was 20–30 min. The depression was significantly reduced during perfusion of the slice bath with 100 μM picrotoxin in artificial cerebrospinal fluid. When pregnanolone was applied locally in stratum radiatum, the amplitudes of the presynaptic spike, the population excitatory postsynaptic potential and the population spike were depressed. The effects on the presynaptic spike and the population excitatory postsynaptic potential vanished with different time courses. It is concluded that the depression of the population spike was caused by GABA_A-mediated inhibition of the pyramidal neurones. The role of pregnanolone as a positive modulator of the GABA_A receptor and the effect of this modulation on the complex mechanisms underlying catamenial epilepsy are discussed.