RT Journal Article
SR Electronic
T1 Increased Sensitivity to Nicotine-Induced Seizures in Mice Expressing the L250T α7 Nicotinic Acetylcholine Receptor Mutation
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 695
OP 705
DO 10.1124/mol.61.3.695
VO 61
IS 3
A1 Ron S. Broide
A1 Ramiro Salas
A1 Daoyun Ji
A1 Richard Paylor
A1 James W. Patrick
A1 John A. Dani
A1 Mariella De Biasi
YR 2002
UL http://molpharm.aspetjournals.org/content/61/3/695.abstract
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.