Noradrenergic stimulation of α1 adrenoceptors in the medial prefrontal cortex mediates acute stress-induced facilitation of seizures in mice

Abstract

Stress is one of the critical facilitators for seizure induction in patients with epilepsy. However, the neural mechanisms underlying this facilitation remain poorly understood. Here, we investigated whether noradrenaline (NA) transmission enhanced by stress exposure facilitates the induction of medial prefrontal cortex (mPFC)-originated seizures. In mPFC slices, whole-cell current-clamp recordings revealed that bath application of picrotoxin induced sporadic epileptiform activities (EAs), which consisted of depolarization with bursts of action potentials in layer 5 pyramidal cells. Addition of NA dramatically shortened the latency and increased the number of EAs. Simultaneous whole-cell and field potential recordings revealed that the EAs are synchronous in the mPFC local circuit. Terazosin, but not atipamezole or timolol, inhibited EA facilitation, indicating the involvement of α1 adrenoceptors. Intra-mPFC picrotoxin infusion induced seizures in mice in vivo. Addition of NA substantially shortened the seizure latency, while co-infusion of terazosin into the mPFC inhibited the effect of NA. Finally, acute restraint stress shortened the latency of intra-mPFC picrotoxin infusion-induced seizures, whereas prior infusion of terazosin reversed this stress-induced shortening of seizure latency. Our findings suggest that stress facilitates the induction of mPFC-originated seizures via NA stimulation of α1 adrenoceptors.

Adrenergic receptor system as a pharmacological target in the treatment of epilepsy (Review)

“…Furthermore, new pyrrolidin-2-one derivatives with affinity for α 1 -ARs cause a decrease in seizure susceptibility by exhibiting GABAergic activity ( 77 ). In addition, it has been shown that seizures originating from the medial prefrontal cortex and caused by acute stress are induced by NE stimulation of α 1 -ARs ( 65 ). Electrophysiological recordings have revealed that NE promotes epileptiform activity induction through α 1- AR stimulation in medial prefrontal cortex pyramidal cells.…”

“…α 1 -ARs frequently increase the activity of GABAergic interneurons, and GABA released from interneurons plays a key role in the inhibitory effects of these receptors (59,60). By contrast, the overactivity of α 1B -AR causes spontaneous epileptic seizures in mice overexpressing α 1B -AR (61), while a deficiency in α 1B -AR results in the reduction of pilocarpine-induced seizures (31) (Table I) (30,31,(62)(63)(64)(65)(66)(67)(68)(69)(70)(71)(72)(73).…”