title: Inhibition of evoked glutamate release by neurosteroid allopregnanolone via inhibition of L-type calcium channels in rat medial prefrontal cortex.
abstract: 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. In the study of the upstream mechanism of the PKA inhibition by allopregnanolone, we found that allopregnanolone inhibited extracellular calcium influx-evoked PKA activation, but had no effects on intracellular calcium store release-evoked PKA activation; L-type calcium channel antagonists, but not N- and P/Q-type calcium channel antagonist, blocked the effect of allopregnanolone; allopregnanolone inhibited L-type calcium channel agonist-evoked increase in the PKA activity, intrasynaptosomal calcium concentration and frequency of sEPSCs. These results suggest that allopregnanolone inhibits evoked glutamate release via the inhibition of L-type calcium channels in the medial prefrontal cortex, but does not in the striatum.
authors.affiliation: State Key Laboratory of Medical Neurobiology, Fudan University Shanghai Medical College, Shanghai, People's Republic of China.
authors.forename: Ai-Qun
authors.initials: AQ
authors.lastname: Hu
authors.forename: Ze-Min
authors.initials: ZM
authors.lastname: Wang
authors.forename: Dan-Mei
authors.initials: DM
authors.lastname: Lan
authors.forename: Ying-Mei
authors.initials: YM
authors.lastname: Fu
authors.forename: Yan-Hua
authors.initials: YH
authors.lastname: Zhu
authors.forename: Yi
authors.initials: Y
authors.lastname: Dong
authors.forename: Ping
authors.initials: P
authors.lastname: Zheng
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000378:metabolism* / Q000494:pharmacology; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism*; D009924:Organ Culture Techniques; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism*; D011280:Pregnanolone / Q000378:metabolism* / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D013574:Synaptosomes / Q000378:metabolism; D014701:Veratridine / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D018698:Glutamic Acid; D014701:Veratridine; D011280:Pregnanolone; D017868:Cyclic AMP-Dependent Protein Kinases