Absence of alpha7-containing neuronal nicotinic acetylcholine receptors does not prevent nicotine-induced seizures.
Nicotine is the primary addictive component in tobacco, and at relatively low doses it affects cardiovascular responses, locomotor activity, thermoregulation, learning, memory, and attention. At higher doses nicotine produces seizures. The mechanisms underlying the convulsive effects of nicotine are not known, but studies conducted on a number of inbred strains of mice have indicated a positive correlation between the number of alpha-bungarotoxin (alpha-BTX) binding sites in the hippocampus and the sensitivity to nicotine-induced seizures. Because alpha7-containing neuronal nicotinic acetylcholine receptors (nAChRs) represent the major binding site for alpha-BTX, mice lacking the alpha7 nAChR subunit were predicted to be less sensitive to the convulsive effects of nicotine. To test this hypothesis, we injected nicotine intraperitoneally in alpha7 mutant mice and found that the dose-response curve for nicotine-induced seizures was similar in the alpha7 +/+, alpha7 +/- and alpha7 -/- mice. The retained sensitivity to the convulsant effects of nicotine could not be explained by the presence of cholinergic compensatory mechanisms such as increases in mRNA levels for other nAChR subunits, or changes in binding levels or affinity for nicotinic ligands such as epibatidine and nicotine. These findings indicate that alpha7 may not be necessary for the mechanisms underlying nicotine-induced seizures.
Franceschini
Davide
D
Division of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Paylor
Richard
R
Broide
Ron
R
Salas
Ramiro
R
Bassetto
Laura
L
Gotti
Cecilia
C
De Biasi
Mariella
M
D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000378:metabolism; D002038:Bungarotoxins / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D007274:Injections, Intraperitoneal; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009538:Nicotine / Q000008:administration & dosage / Q000633:toxicity*; D021122:Protein Subunits; D011725:Pyridines / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000172:deficiency / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D012640:Seizures / Q000139:chemically induced* / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor
D019086:Bridged Bicyclo Compounds, Heterocyclic; D002038:Bungarotoxins; C579166:Chrna7 protein, mouse; D008024:Ligands; D021122:Protein Subunits; D011725:Pyridines; D012333:RNA, Messenger; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine; C082748:epibatidine