PT  - JOURNAL ARTICLE
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
TI  - Increased Sensitivity to Nicotine-Induced Seizures in Mice Expressing the L250T α7 Nicotinic Acetylcholine Receptor Mutation
AID  - 10.1124/mol.61.3.695
DP  - 2002 Mar 01
TA  - Molecular Pharmacology
PG  - 695--705
VI  - 61
IP  - 3
4099  - http://molpharm.aspetjournals.org/content/61/3/695.short
4100  - http://molpharm.aspetjournals.org/content/61/3/695.full
SO  - Mol Pharmacol2002 Mar 01; 61
AB  - 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.