Increased sensitivity to nicotine-induced seizures in mice heterozygous for the L250T mutation in the alpha7 nicotinic acetylcholine receptor.
alpha7 Nicotinic acetylcholine receptors (nAChRs) are sparsely distributed throughout the peripheral and central nervous systems. Several studies have suggested that central alpha7 nicotinic receptors may influence sensitivity to nicotine-induced seizures in mice. In order to investigate the effect of alpha7 nAChRs on seizure sensitivity, we tested heterozygous mice with a threonine for leucine substitution at position 250 (L250T) within the channel domain, which is known to increase current amplitude and decreases desensitization of the channel. We show that administration of low doses of nicotine to these mutant mice increased the sensitivity to nicotine-induced seizures and the mortality rate. EEG recordings showed high amplitude rhythmic activity during tonic-clonic seizures. Pretreatment with the alpha7 nicotinic receptor antagonist methyllycaconitine inhibited the seizures induced by nicotine. These findings further suggest an important role for alpha7 nAChRs in the nicotine-induced seizures model of epilepsy.
Gil
Ziv
Z
Department of Otolaryngology Head and Neck Surgery , Tel-Aviv Sourasky Medical Center, Sackler Medical School, Tel-Aviv University, Israel.
Sack
Ram A
RA
Kedmi
Merav
M
Harmelin
Alon
A
Orr-Urtreger
Avi
A
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D004569:Electroencephalography; D005731:Ganglionic Stimulants / Q000494:pharmacology / Q000506:poisoning; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D051379:Mice; D008810:Mice, Inbred C57BL; D009026:Mortality; D009154:Mutation / Q000502:physiology*; D009538:Nicotine / Q000494:pharmacology / Q000506:poisoning; D011978:Receptors, Nicotinic / Q000235:genetics*; D012016:Reference Values; D012640:Seizures / Q000139:chemically induced* / Q000235:genetics* / Q000503:physiopathology; D064569:alpha7 Nicotinic Acetylcholine Receptor
C579166:Chrna7 protein, mouse; D005731:Ganglionic Stimulants; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine