Here, we show that chronic nicotine exposure induces changes in Src signaling for the modulation of N-methyl-D-aspartate receptor (NMDAR) function and LTP induction in CA1 pyramidal cells. Activation of muscarinic receptors normally potentiates NMDAR responses in pyramidal cells via a Gq/protein kinase C (PKC)/proline-rich tyrosine kinase 2/Src signaling cascade. However, muscarinic, PKC and Src stimulation had no effect on NMDAR responses after chronic nicotine treatment. The lack of effect was apparently due to enhanced tyrosine phosphorylation, and therefore further stimulation of the signaling cascade caused no effect on NMDAR responses. Interestingly, another Src-family kinase potentiated NMDAR responses after, but not before, chronic nicotine treatment. In control pyramidal cells, Src inhibitor peptides prevented tetanus-induced long-term potentiation (LTP). Conversely, in chronic nicotine-exposed cells, the inhibitor was ineffective in blocking tetanus-induced LTP. Furthermore, in control pyramidal cells, applying exogenous Src and administration of an endogenous Src-family kinase activator increased alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate receptor (AMPAR)-mediated responses. This increase was blocked by Src inhibitor peptides and occluded tetanus-induced LTP, as reported previously. In contrast, in chronic nicotine-treated pyramidal cells, applying exogenous Src had no effect on AMPAR-mediated responses and a tetanus-induced LTP. Interestingly, however, administration of an endogenous Src-family kinase activator enhanced AMPAR-mediated responses, which occluded tetanus-induced LTP. This enhancement was not prevented by co-application of Src inhibitor peptides. Thus, it appears that chronic nicotine exposure recruits another member of the Src-family for the regulation of NMDAR function and LTP induction. The nicotine-induced distinct signaling cascades may be involved in long-lasting memories of nicotine misuse.