Stimulation of α2-adrenoceptors suppresses excitatory synaptic transmission in the medial prefrontal cortex of rat

Stimulation of alpha(2)-, especially alpha(2A)- adrenoceptor (AR), in the prefrontal cortex (PFC) produces a beneficial effect on cognitive functions such as working memory. alpha(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 alpha(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 alpha(2)-AR agonist clonidine and the selective alpha(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 alpha(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 alpha(2A)-AR inhibits excitatory synaptic transmission in the mPFC through a post-synaptic mechanism.