Noradrenaline and Seizures: A Perspective on the Role of Adrenergic Receptors in Limbic Seizures

Background: Noradrenergic fibers originating from the locus coeruleus densely innervate limbic structures, including the piriform cortex, which is the limbic structure with the lowest seizure threshold. Noradrenaline (NA) modulates limbic seizures while stimulating autophagy through beta(2)-adrenergic receptors (AR). Since autophagy is related to seizure threshold, this perspective questions whether modulating beta(2)-AR focally within the anterior piriform cortex affects limbic seizures. Objective: In this perspective, we analyzed a potential role for beta(2)-AR as an anticonvulsant target within the anterior piriform cortex, area tempestas (AT). Methods: We developed this perspective based on current literature on the role of NA in limbic seizures and autophagy. The perspective is also grounded on preliminary data obtained by micro-infusing within AT either a beta(2)-AR agonist (salbutamol) or a beta(2)-AR antagonist (butoxamine) 5 minutes before bicuculline. Results: beta(2)-AR stimulation fully prevents limbic seizures induced by bicuculline micro-infusion in AT. Conversely, antagonism at beta(2)-AR worsens bicuculline-induced seizure severity and prolongs seizure duration, leading to self-sustaining status epilepticus. These data indicate a specific role for beta(2)-AR as an anticonvulsant in AT. Conclusion: NA counteracts limbic seizures. This relies on various receptors in different brain areas. The anterior piriform cortex plays a key role in patients affected by limbic epilepsy. The anti-convulsant effects of NA through beta(2)-AR may be related to the stimulation of the autophagy pathway. Recent literature and present data draw a perspective where beta(2)-AR stimulation while stimulating autophagy mitigates limbic seizures, focally within AT. The mechanism linking beta(2)-AR to autophagy and seizure modulation should be extensively investigated.