Allopregnanolone is one of the most important neurosteroids in the brain.We studied the effect and mechanism of allopregnanolone on spontaneous and evoked glutamate release in the medial prefrontal cortex using electrophysiological and biochemical methods combined with pharmacological approaches.The results showed that allopregnanolone had no effects on the frequency of miniature excitatory postsynaptic current (mEPSCs),but inhibited the depolarizing agent veratridine-evoked increase in the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) and inhibited the first of the two responses evoked by a pair of electrical pulses more effectively than the second,resulting in increased paired-pulse facilitation (PPF) and thus suggesting a presynaptic inhibitory effect on electrical pulse-evoked glutamate release.A similar effect was also obtained for the effect of allopregnanolone on protein kinase A (PKA) activation,an upstream event of presynaptic glutamate release.Interestingly,allopregnanolone had none of these effects in the striatum.