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-Amyloid Peptide Activates Non-7 Nicotinic Acetylcholine Receptors in Rat Basal Forebrain Neurons

Division of Neurology, Department of Medicine, Centre for Alzheimer and Neurodegenerative Research, University of Alberta, Edmonton, Alberta T6G 2S2, Canada

Submitted 27 June 2003; accepted in final form 25 July 2003

Alzheimer's disease (AD) is a progressive neurodegenerative condition characterized by profound deficits in memory and cognitive function. Neuropathological hallmarks of the disease include a loss of basal forebrain cholinergic neurons and the deposition of -amyloid peptide (A) in neuritic plaques. At a cellular level, considerable attention has focused on a study of A interactions with the neuronal nicotinic acetylcholine receptor (nAChR) subtypes. In this study, using cell-attached and outside-out single channel recordings from acutely dissociated rat basal forebrain neurons, we report that A and nicotine activate nAChRs with two distinct levels of single-channel conductance. Whole cell recordings from these neurons reveal A and nicotine, in a concentration-dependent and reversible manner, evoke brisk depolarizing responses and an inward current. The effects of A on both single channel and whole cell are blocked by the noncompetitive nAChR antagonist mecamylamine and competitive nAChR antagonist dihydro-beta-erythroidine, but not the specific 7-selective nAChR antagonist methyllycaconitine, indicating that A activated non-7 nAChRs on basal forebrain neurons. In addition, the non-7 nAChR agonists UB-165, epibatidine, and cytisine, but not the selective 7 agonist AR-R17779, induced similar responses as A and nicotine. Thus non-7 nAChRs may also represent a novel target in mediating the effects of A in AD.

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