α7 Nicotinic acetylcholine receptor knockout selectively enhances ethanol-, but not β-amyloid-induced neurotoxicity

Abstract

The α7 subtype of nicotinic acetylcholine receptor (nAChR) has been implicated as a potential site of action for two neurotoxins, ethanol and the Alzheimer's disease related peptide, β-amyloid. Here, we utilized primary neuronal cultures of cerebral cortex from α7 nAChR null mutant mice to examine the role of this receptor in modulating the neurotoxic properties of subchronic, “binge” ethanol and β-amyloid. Knockout of the α7 nAChR gene selectively enhanced ethanol-induced neurotoxicity in a gene dosage-related fashion. Susceptibility of cultures to β-amyloid induced toxicity, however, was unaffected by α7 nAChR gene null mutation. Further, β-amyloid did not inhibit the binding of the highly α7-selective radioligand, [ 125I]α-bungarotoxin. On the other hand, in studies in Xenopus oocytes ethanol efficaciously inhibited α7 nAChR function. These data suggest that α7 nAChRs modulate the neurotoxic effects of binge ethanol, but not the neurotoxicity produced by β-amyloid. It is hypothesized that inhibition of α7 nAChRs by ethanol provides partial protection against the neurotoxic properties of subchronic ethanol.