Adrenergic Receptor Regulation Of The Prefrontal Cortex, Excitatory Synaptic Transmission

The prefrontal cortex(PFC)plays a critical role in behaviors requiring a high level of mental integration.Norepinephrine(NE)is a neurotransmitter which is widely distributed throughout the central nervous system.Previous behavioral and physiological studies have demonstrated that NE system exerts an important influence on PFC cognitive functions.The adrenoceptors in the PFC compriseα₁-,α₂-,andβ-adrenoceptors(ARs).Previous studies focus on the role ofα₁- andα₂-adrenoceptors in the PFC,using behavioral approach, however,little is known about the role of adrenoceptors in excitatory synaptic transmission in the PFC.In the present study,we examined the modulation effects ofβ-andα₂-adrenoceptors activation on excitatory synaptic transmission in the medial PFC,using the whole-cell patch clamp recordings,field recordings in vivo and immunohistochemistry technique.Part 1:β-adrenergic activation enhances excitatory synaptic transmission in layer V/VI pyramidal neurons of the medial prefrontal cortex in ratsThe present study investigated the modulation byβ-adrenoceptor of excitatory synaptic transmission in layer V/VI pyramidal neurons of the rat medial prefrontal cortex(mPFC), using whole-cell patch clamp recording.Treatment with isoproterenol(ISO),a selectiveβ-AR agonist,induced a significant increase in the frequency of spontaneous excitatory postsynaptic currents(sEPSCs)and miniature excitatory postsynaptic currents(mEPSCs).The facilitation effect of ISO on the frequency of mEPSCs no longer existed when cadmium was pre-administered.Treatment with ISO produced a significant enhancement in the evoked excitatory postsynaptic currents(eEPSCs)mediated by non-NMDA and NMDA receptors and a marked decrease in the paired-pulse facilitation of the non-NMDA-R and NMDA-R mediated eEPSCs.ISO significantly enhanced the currents induced by pressure-delivered or bath-applied NMDA.The ISO-induced facilitation of NMDA-R eEPSC or NMDA-induced current was partly or completely blocked in the presence of Rp-cAMPS,a protein kinase A inhibitor.Immunohistochemistry staining showed thatβ₁-AR exists in both nervel terminals and neurons in the mPFC.The present study provides a strong demonstration thatβ-AR activation facilitates excitatory synaptic transmission in the mPFC through both pre- and post-synaptic mechanisms.Part 2:α₂-adrenergic activation inhibits excitatory synaptic transmission in the medial prefrontal cortex in rats in vivo and in vitroStimulation ofα₂-,especiallyα_2A-adrenoceptor(AR),in the prefrontal cortex(PFC) produces a beneficial effect on cognitive functions such as working memory.α₂-adrenergic agonists like clonidine and guanfacine have been used experimentally and clinically for treatment of psychiatric disorders such as attention-deficit/hyperactivity disorder(ADHD) and schizophrenia.However,the neurophysiological actions ofα₂-ARs in the PFC are poorly understood.Field excitatory postsynaptic potential(fEPSP),evoked excitatory post-synaptic current(eEPSC)were recorded in the medial prefrontal cortex(mPFC)of rats,using in vivo field-potential recording and in vitro whole-cell patch-clamp recording techniques.Effects of theα₂-AR agonist clonidine and the selectiveα_2A-AR agonist guanfacine on fEPSP and eEPSC were examined.Systemic or intra-mPFC application of clonidine or guanfacine significantly reduced fEPSP in the mPFC in a dose-dependent way,either in anesthetized or freely-moving rats.Consistently,bath-application of guanfacine suppressed eEPSC in layer V/VI pyramidal neurons,and this effect was blocked by theα₂-AR antagonist yohimbine or the Gi inhibitor NF023.Moreover,treatment with guanfacine had no effect on paired-pulse facilitation(PPF)of fEPSP and eEPSC.The present study provides the first electrophysiological evidence that stimulation ofα_2A-AR inhibits excitatory synaptic transmission in the mPFC through a post-synaptic mechanism.