Nicotine exposure reduces N-methyl-D-aspartate toxicity in the hippocampus: relation to distribution of the alpha7 nicotinic acetylcholine receptor subunit.
BACKGROUND
Exposure to nicotine has been shown to promote neuronal survival after excitotoxic insult to the brain. The role of specific nicotinic acetylcholine receptors (nAChRs) subtypes in mediating this effect is not well understood, however. Examination of distinct receptor subtypes in promoting neuronal survival is of importance not only in understanding the regulation of necrotic cell death but potentially in the development of novel pharmacological therapies that may reduce this form of neurodegeneration.


METHODS
The present studies examined the relationship between distribution of alpha7 subunit-bearing nAChRs, using autoradiographic imaging of [125I]alpha-bungarotoxin binding, and protective effects of nicotine against excitotoxic damage. Organotypic cultures of rat hippocampus were exposed to N-methyl-D-aspartate (NMDA; 200 microM) for 1 hour with or without (-)-nicotine (0.1-10 microM) and the alpha7 nAChR antagonist methyllycaconitine (MLA; 100 nM). Neuronal damage was assayed 24 hours later by observation of uptake of the non-vital fluorescent marker propidium iodide.


RESULTS
NMDA exposure produced significant neurotoxicity, particularly in pyramidal cell layers of CA3 and CA1, that was prevented by co-exposure to MK-801 (10 microM). Localization of the alpha7 subunit was varied with no binding observed in the dentate gyrus, low density in the CA3 and CA1 regions, and dense binding in the hilus. In all regions, co-exposure to (-)-nicotine (0.1-10.0 microM) significantly reduced (>30%) the cytotoxic consequences of NMDA insult. This protective effect was inhibited by co-exposure to MLA in the dentate and CA3, and to a lesser extent, CA1 regions.


CONCLUSIONS
The neuroprotective effect of nicotine against excitotoxicity, then, is not directly related to alpha7 subunit localization in the hippocampus.
Prendergast
M A
MA
Department of Psychology, University of Kentucky, Lexington, Kentucky 40506-0044, USA.
Harris
B R
BR
Mayer
S
S
Holley
R C
RC
Pauly
J R
JR
Littleton
J M
JM
D000818:Animals; D001345:Autoradiography; D002038:Bungarotoxins / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D016202:N-Methylaspartate / Q000633:toxicity*; D009538:Nicotine / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism*; D064569:alpha7 Nicotinic Acetylcholine Receptor
D002038:Bungarotoxins; C579165:Chrna7 protein, rat; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D009538:Nicotine