Human amylin (hAmylin), a 37-amino acid pancreatic peptide and amyloid protein (A), a 39-43 amino acid peptide abundantly deposited in the brains of Alzheimer's patients, induce neurotoxicity in hippocampal and cortical cultures. Although the mechanism of this neurotoxicity is unknown, both peptides are capable of modulating ion channel function that may result in a disruption of cellular homeostasis. In this study we examined the effects of hAmylin on whole-cell currents in chemically identified neurons from the rat basal forebrain and the interactions of hAmylin-induced responses with those of A. Whole cell patch clamp recordings were performed on enzymatically dissociated neurons of the diagonal band of Broca (DBB), a cholinergic basal forebrain nucleus. Bath application of hAmylin (1nM-5µM) resulted in a dose-dependent reduction in whole cell currents in a voltage range between -30 to +30 mV. Single cell RT-PCR analysis reveal that all DBB neurons responding to hAmylin or A were cholinergic. Using specific ion channel blockers, we identified hAmylin and A effects on whole cell currents to be mediated, in part, by calcium-dependent conductances. Human amylin also depressed the transient outward (I_A) and the delayed rectifier (I_K) potassium currents. The hAmylin effects on whole-cell currents could be occluded by A and vice versa. Human amylin and A responses could be blocked with AC187 (50nM-1µM), a specific antagonist for the amylin receptor. The present study indicates that hAmylin, like A, is capable of modulating ion channel function in cholinergic basal forebrain neurons. Furthermore, the two peptides may share a common mechanism of action. The ability of an amylin antagonist to block the responses evoked by hAmylin and A may provide a novel therapeutic approach for Alzheimer's disease.