Nicotine compensates for the loss of cholinergic function to enhance long-term potentiation induction.

Long-term potentiation (LTP) in the hippocampal CA1 region is widely regarded to be the cellular substrate of learning and memory, and its induction critically depends on the activation of N-methyl-D-aspartate receptors (NMDARs). Nicotine reverses memory deficits caused by a lesion of the cholinergic system in animals. The mechanisms underlying this effect and the effect of nicotine on LTP after cholinergic degeneration are unknown. Here we show that cholinergic lesions impaired the induction of LTP, and nicotine reversed this effect and promoted the induction of LTP. The compensatory action of nicotine appears to be due to the enhancement of NMDAR responses mediated by nicotine-induced disinhibition of pyramidal cells. This may represent the cellular basis of nicotine-mediated cognitive enhancement observed in the presence of cholinergic deficits.