Whereas the entorhinal cortex (EC) receives noradrenergic innervations from the locus coeruleus of the pons and expresses adrenergic receptors, the function of norepinephrine (NE) in the EC is still elusive. We examined the effects of NE on GABA_A receptor-mediated synaptic transmission in the superficial layers of the EC. Application of NE dose-dependently increased the frequency and amplitude of spontaneous IPSCs recorded from the principal neurons in layer II/III via activation of ₁ adrenergic receptors. NE increased the frequency not the amplitude of miniature IPSCs (mIPSCs) recorded in the presence of tetrodotoxin suggesting that NE increases presynaptic GABA release with no effects on postsynaptic GABA_A receptors. Application of Ca²⁺ channel blockers (Cd²⁺ and Ni²⁺), omission of Ca²⁺ in the extracellular solution or replacement of extracellular Na⁺ with NMDG failed to alter NE-induced increase in mIPSC frequency suggesting that Ca²⁺ influx via voltage-gated Ca²⁺ or other cationic channels is not required. Application of BAPTA-AM, thapsigargin and ryanodine did not change NE-induced increase in mIPSC frequency suggesting that Ca²⁺ release from intracellular stores is not necessary for NE-induced increase in GABA release. Whereas ¹ receptors are coupled to G_q/11 resulting in activation of phospholipase C (PLC) pathway, NE-mediated facilitation of GABAergic transmission was independent of PLC, protein kinase C and tyrosine kinase activities. Our results suggest that NE-mediated facilitation of GABAergic function contributes to its antiepileptic effects in the EC.