TY - JOUR T1 - Increased Sensitivity to Nicotine-Induced Seizures in Mice Expressing the L250T α7 Nicotinic Acetylcholine Receptor Mutation JF - Molecular Pharmacology JO - Mol Pharmacol SP - 695 LP - 705 DO - 10.1124/mol.61.3.695 VL - 61 IS - 3 AU - Ron S. Broide AU - Ramiro Salas AU - Daoyun Ji AU - Richard Paylor AU - James W. Patrick AU - John A. Dani AU - Mariella De Biasi Y1 - 2002/03/01 UR - http://molpharm.aspetjournals.org/content/61/3/695.abstract N2 - High doses of nicotine, the addictive component of tobacco, induce clonic-tonic seizures in animals. Pharmacological and biochemical data have suggested that α7-containing neuronal nicotinic receptors (nAChRs) contribute to these seizures. To study potential α7 contributions, we examined α7 subunits with a Leu250-to-Thr substitution in the channel domain, which creates a gain-of-function mutation. Previous studies have shown that mice homozygous for the α7 L250T mutation (T/T) die shortly after birth, but animals heterozygous for the mutation (+/T) are viable and grow to adulthood. Hippocampal neurons from the +/T mice exhibited altered α7-type currents with increased amplitudes and slower desensitization kinetics, confirming a partial gain of function for the α7 nAChR. We found that +/T mice were more sensitive to the convulsant effects of nicotine compared with their wild-type (+/+) littermates. Furthermore, although their behavior was normal in basal conditions, +/T mice showed a unique nicotine-induced phenotype, consisting of head-bobbing and paw-tapping movements. Increased sensitivity to nicotine-induced seizures occurred despite a 60% decline in brain α7 nAChR protein levels. There were no changes in the levels of α4, α5, α6, α7, β2, and β4 mRNA, or in [125I]epibatidine and [3H]nicotine binding between +/T and +/+ mice. Recent data from our laboratory show that α7-null mice maintain normal sensitivity to nicotine-induced seizures. Hence, these present findings suggest that alterations in the properties rather than absence of α7 nAChRs might affect the mechanisms underlying the convulsive properties of nicotine. ER -