Title : Increased sensitivity to nicotine-induced seizures in mice expressing the L250T alpha 7 nicotinic acetylcholine receptor mutation - Broide_2002_Mol.Pharmacol_61_695 |
Author(s) : Broide RS , Salas R , Ji D , Paylor R , Patrick JW , Dani JA , De Biasi M |
Ref : Molecular Pharmacology , 61 :695 , 2002 |
Abstract :
High doses of nicotine, the addictive component of tobacco, induce clonic-tonic seizures in animals. Pharmacological and biochemical data have suggested that alpha 7-containing neuronal nicotinic receptors (nAChRs) contribute to these seizures. To study potential alpha 7 contributions, we examined alpha 7 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 alpha 7 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 alpha 7-type currents with increased amplitudes and slower desensitization kinetics, confirming a partial gain of function for the alpha 7 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 alpha 7 nAChR protein levels. There were no changes in the levels of alpha 4, alpha 5, alpha 6, alpha 7, beta 2, and beta 4 mRNA, or in [(125)I]epibatidine and [(3)H]nicotine binding between +/T and +/+ mice. Recent data from our laboratory show that alpha 7-null mice maintain normal sensitivity to nicotine-induced seizures. Hence, these present findings suggest that alterations in the properties rather than absence of alpha 7 nAChRs might affect the mechanisms underlying the convulsive properties of nicotine. |
PubMedSearch : Broide_2002_Mol.Pharmacol_61_695 |
PubMedID: 11854451 |
Broide RS, Salas R, Ji D, Paylor R, Patrick JW, Dani JA, De Biasi M (2002)
Increased sensitivity to nicotine-induced seizures in mice expressing the L250T alpha 7 nicotinic acetylcholine receptor mutation
Molecular Pharmacology
61 :695
Broide RS, Salas R, Ji D, Paylor R, Patrick JW, Dani JA, De Biasi M (2002)
Molecular Pharmacology
61 :695