We studied knock-in mice with a gain of function Leu9’Ser mutation in the M2 region of the nicotinic acetylcholine receptor (nAChR) α4 subunit. We previously showed that heterozygous L9’S mice (hets) are ~ 10 times more sensitive to nicotine-induced seizures than their wild type littermates (WT) (Fonck et al, SFN, 2001). Seizure studies on α4-mutated mice may be interesting for epilepsy research because all known mutations responsible for autosomal dominant nocturnal frontal lobe epilepsy occur in the M2 region of the α4 or β2 subunits. Hets and WT received a single injection of either: a) the nicotinic agonist epibatidine, b) the cholinesterase inhibitor and nicotinic modulator galanthamine or c) the cholinesterase inhibitor tacrine. Hets were significantly more sensitive than WT to epibatidine, galanthamine and tacrine as assessed by latency to seizure and Straub tail. Epibatidine (2 to 10 μg/kg), galanthamine (5 to 20 mg/kg) and tacrine (5 to 20 mg/kg) induced seizures and Straub tail in hets in a dose ...