The TAAR1 inhibitor EPPTB suppresses neuronal excitability and seizure activity in mice.

Epilepsy is a common neurological disease. G protein-coupled receptors (GPCRs) are extensively distributed and play an important role in human health by serving as therapeutic targets for various diseases. As one of the GPCRs, trace amine-associated receptor 1 (TAAR1) has recently aroused increasing interest as a potential therapeutic target for psychiatric disorders. However, the effect of TAAR1 on epileptic seizures remains unclear. We hypothesized that TAAR1 plays an important role in epilepsy and might represent a potential therapeutic target. In this study, we analyzed a mouse epilepsy model and patients with temporal lobe epilepsy (TLE) and observed substantially increased TAAR1 expression compared with the control group. In recordings of hippocampal slices, the TAAR1-specific inhibitor N-(3-ethoxyphenyl)-4-(pyrrolidin-1-yl)-3-(trifluoromethyl) benzamide (EPPTB) suppressed the excitability of hippocampal pyramidal neurons. EPPTB also reduced seizure-like events (SLEs) and seizure activity. Our results suggest that EPPTB attenuates seizure activity and that TAAR1 might be a potential drug target for individuals with epilepsy.