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

Abstract

a 1 -adrenoceptors (a 1 -ARs) stimulation has been found to enhance excitatory processes in many brain regions. A recent study in our laboratory showed that a 1 -ARs stimulation enhances glutamatergic transmission via both pre-and postsynaptic mechanisms in layer V/VI pyramidal cells of the rat medial prefrontal cortex (mPFC). However, a number of presynaptic mechanisms may contribute to a 1 -ARs-induced enhancement of glutamate release. In this study, we blocked the possible post-synaptic action mediated by a 1 -ARs to investigate how a 1 -ARs activation regulates pre-synaptic glutamate release in layer V/VI pyramidal neurons of mPFC. We found that the a 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 Ca 2+ channels, probably via a presynaptic G q /phospholipase C/protein kinase C pathway. Our results may provide a cellular and molecular mechanism that helps explain a 1 -ARs-mediated influence on PFC cognitive functions.

Norepinephrine regulates cocaine-primed reinstatement via α1-adrenergic receptors in the medial prefrontal cortex

“…Because cocaine does not act on glutamate directly, a monoamine must mediate cocaine-induced activation of mPFC pyramidal neurons, and our results implicate NE- α1AR transmission. We have shown that α1ARs are expressed on both presynaptic and postsynaptic glutamatergic elements in the mPFC (Mitrano et al, 2012), and previous studies indicate that activation of these receptors increases local glutamate transmission and excitation of pyramidal neurons (Luo et al, 2014, 2015; Marek and Aghajanian, 1999). Thus, we propose that a cocaine prime blocks NE reuptake in the mPFC, which acts on presynaptic α1ARs to facilitate local glutamate release that, together with direct α1AR-mediated depolarization of pyramidal neurons, drives glutamate transmission in the NAc.…”

Locus Ceruleus Norepinephrine Release: A Central Regulator of CNS Spatio-Temporal Activation?

“…For instance, α 1 R activation improves working memory deficit induced by applications of the GABA A R agonist muscimol (Hvoslef-Eide et al, 2015), while α 1 R block disrupts the “ go ” performance in a “ go-no-go ” task (Bari and Robbins, 2013). At the synaptic basis of these effects could lay an enhancement in glutamatergic function (Luo et al, 2014b, 2015a), which may, in turn, yield a general increase in firing frequency in the PFC (Zhang Z. et al, 2013). Other cellular and synaptic effects of α 1 R activation in the PFC, like an increase in inhibitory drive (Luo et al, 2015b) or a specific decrease in NMDAR-mediated response are not necessarily prone to similarly straightforward interpretations.…”

The α2A‐adrenoceptor suppresses excitatory synaptic transmission to both excitatory and inhibitory neurons in layer 4 barrel cortex

“…However, other studies reported that an activation of presynaptic α 1 ‐receptors rather causes an increase of glutamate release in the medial prefrontal cortex (Luo et al . , ). Concerning the physiological function of α 2A ‐subtype of α 2 ‐adrenergic receptors (α 2A ‐ARs), only a few studies indicated that the activation of α 2A ‐ARs causes suppression of the transmitter release from presynaptic sites in sympathetic preganglionic neurons (Miyazaki et al .…”