Stimulation of α2-Adrenoceptors Suppresses Excitatory Synaptic Transmission in the Medial Prefrontal Cortex of Rat

Abstract

Stimulation of a 2 -, especially a 2A -adrenoceptor (AR), in the prefrontal cortex (PFC) produces a beneficial effect on cognitive functions such as working memory. a 2 -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 of a 2 -ARs in the PFC are poorly understood. In the present study, we recorded field excitatory post-synaptic potential (fEPSP) and evoked excitatory post-synaptic current (eEPSC) in the medial prefrontal cortex (mPFC) of rats, using in vivo field-potential recording and in vitro whole-cell patch-clamp recording techniques, and examined the effects of the a 2 -AR agonist clonidine and the selective a 2A -AR agonist guanfacine on fEPSP and eEPSC. Systemic or intra-mPFC application of clonidine or guanfacine significantly reduced fEPSP in the mPFC, 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 the a 2 -AR antagonist yohimbine or the G i 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 of a 2A -AR inhibits excitatory synaptic transmission in the mPFC through a post-synaptic mechanism.

Prefrontal cortical α2A-adrenoceptors and a possible primate model of attention deficit and hyperactivity disorder

“…Our work suggested that under normal physiological conditions, the α 2A -adrenoceptors in pyramidal cells can be activated through Gi-cAMP-HCN signaling [78] . On the other hand, 230 under stress, activation of α 2A -adrenoceptors to protect PFC functions might occur via the Gi-cAMP-PKA-CaMKII-AMPAR signaling pathway [76] .…”

Blockade of α2-adrenoceptors induces Arc gene expression in rat brain in a glutamate receptor-dependent manner: A combined qPCR, in situ hybridisation and immunocytochemistry study

“…Formal proof that a 2 -adrenoceptor antagonists evoke the release of glutamate release remains to be acquired (cf. Ji et al, 2008b).…”

“…Furthermore, though drugs that target brain monoamine neurotransmitters are currently the mainstay of psychotropic medications, an emerging view is that the therapeutic effects of such medications may be underpinned by monoamineeglutamate interactions (see above citations). The points of interaction between monoamines and glutamate are likely to be many, and range from glutamatergic modulation of the activity of midbrain monoaminergic neurones (Tao and Auerbach, 2000) to cross-talk between postsynaptic monoaminergic and glutamate receptor-mediated signalling (Marek et al, 2000;Svenningsson et al, 2007;Gonzalez-Maeso et al, 2008) to monoamine receptor-mediated modulation of glutamate release in the cerebral cortex (Marcus et al, 2005;Millan, 2006;Ji et al, 2008aJi et al, , 2008b.…”

Modulating Action of an α2Adrenoreceptor Agonist, Clonidine, on Neuronal Activity and Synaptic Transmission in the Rat Prefrontal Cortex

“…From this aspect, results of our experiments agree with findings of other authors who observed inhibitory effects of applications of clonidine on background discharges and responsiveness of neurons of the basolateral amygdalar nucleus [4,5], postsynaptic Footnote. ** P < 0.01; *** P < 0.001. currents in cells of the rat prefrontal cortex [6], and neuronal activity in the ventral anterior (VA) and ventral lateral (VL) nuclei of the thalamus [7]. The inhibitory influence of clonidine applied in mild doses can be related to the fact that moderate excitation of presynaptic α2 adrenoreceptors mimics the inhibitory effect of noradrenaline on neuronal networks in the FRA.…”