Increased sensitivity to nicotine-induced seizures in mice expressing the L250T alpha 7 nicotinic acetylcholine receptor mutation.
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.
Broide
Ron S
RS
Division of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA.
Salas
Ramiro
R
Ji
Daoyun
D
Paylor
Richard
R
Patrick
James W
JW
Dani
John A
JA
De Biasi
Mariella
M
D019943:Amino Acid Substitution; D000818:Animals; D004079:Dihydro-beta-Erythroidine / Q000494:pharmacology; D004195:Disease Models, Animal; D004594:Electrophysiology; D005260:Female; D005731:Ganglionic Stimulants / Q000494:pharmacology*; D006579:Heterozygote; D006624:Hippocampus / Q000378:metabolism; D008239:Lysine / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009445:Neuroanatomy; D009538:Nicotine / Q000494:pharmacology*; D010641:Phenotype; D011978:Receptors, Nicotinic / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D012640:Seizures / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D013912:Threonine / Q000235:genetics; D064569:alpha7 Nicotinic Acetylcholine Receptor
C579166:Chrna7 protein, mouse; D005731:Ganglionic Stimulants; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D004079:Dihydro-beta-Erythroidine; D013912:Threonine; D009538:Nicotine; D008239:Lysine