Phenylephrine enhances glutamate release in the medial prefrontal cortex through interaction with N-type Ca2+ channels and release machinery

alpha(1)-adrenoceptors ((1)-ARs) stimulation has been found to enhance excitatory processes in many brain regions. A recent study in our laboratory showed that (1)-ARs stimulation enhances glutamatergic transmission via both pre- and post-synaptic mechanisms in layer V/VI pyramidal cells of the rat medial prefrontal cortex (mPFC). However, a number of pre-synaptic mechanisms may contribute to (1)-ARs-induced enhancement of glutamate release. In this study, we blocked the possible post-synaptic action mediated by (1)-ARs to investigate how (1)-ARs activation regulates pre-synaptic glutamate release in layer V/VI pyramidal neurons of mPFC. We found that the (1)-ARs agonist phenylephrine (Phe) induced a significant enhancement of glutamatergic transmission. The Phe-induced potentiation was mediated by enhancing pre-synaptic glutamate release probability and increasing the number of release vesicles via a protein kinase C-dependent pathway. The mechanisms of Phe-induced potentiation included interaction with both glutamate release machinery and N-type Ca2+ channels, probably via a pre-synaptic G(q)/phospholipase C/protein kinase C pathway. Our results may provide a cellular and molecular mechanism that helps explain (1)-ARs-mediated influence on PFC cognitive functions.