β-Phenylethylamine Inhibits K⁺ Currents in Neocortical Neurons of the Rat: A Possible Mechanism of β-phenylethylamine-induced Seizures

Abstract

β-Phenylethylamine (β-PEA), an endogenous amine synthesized in the brain, serves as a neuromodulator and is involved in the pathophysiology of various neurological disorders such as depression, schizophrenia, and attention-deficit hyperactivity disorder. β-PEA fully exerts the physiological effects within the nanomolar concentration range via the trace amine receptors, but β-PEA also causes convulsions at much higher concentrations via an as yet unknown mechanism. To investigate the electrophysiological mechanism by which β-PEA induces convulsions, we examined the effect of β-PEA on ionic currents passing through the cell membrane of dissociated rat cerebral cortical neurons, using a patch-clamp technique. The external application of β-PEA suppressed ionic currents which continuously flowed when the membrane potential was held at −25 mV. The suppression was in a concentration-dependent manner and a half-maximal effective concentration was 540 μM. These currents suppressed by β-PEA consisted of two K⁺ currents: a time- and voltage-dependent K⁺ current (M-current) and a leakage K⁺ current. The suppression of the M-current reduces the efficacy of the current in limiting excessive neuronal firing, and the suppression of the leakage K⁺ current can cause membrane depolarization and thus promote neuronal excitation. Reducing both of these currents in concert may produce neuronal seizing activity, which could conceivably underlie the convulsions induced by high-dose β-PEA.