Increased sensitivity to nicotine-induced seizures in mice heterozygous for the L250T mutation in the α7 nicotinic acetylcholine receptor

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Abstract
α7 Nicotinic acetylcholine receptors (nAChRs) are sparsely distributed throughout the peripheral and central nervous systems. Several studies have suggested that central α7 nicotinic receptors may influence sensitivity to nicotine-induced seizures in mice. In order to investigate the effect of α7 nAChRs on seizure sensitivity, we tested heterozygous mice with a threonine for leucine substitution at position 250 (L250T) within the channel domain, which is known to increase current amplitude and decreases desensitization of the channel. We show that administration of low doses of nicotine to these mutant mice increased the sensitivity to nicotine-induced seizures and the mortality rate. EEG recordings showed high amplitude rhythmic activity during tonic–clonic seizures. Pretreatment with the α7 nicotinic receptor antagonist methyllycaconitine inhibited the seizures induced by nicotine. These findings further suggest an important role for α7 nAChRs in the nicotine-induced seizures model of epilepsy.