We have previously shown that dopamine and NMDA (N-methyl-D-aspartat) converge on Extra cellular Regulated Kinase(ERK2) –Mitogen-Activated Protein Kinase(MAPK) signalling in the rat hippocampus slices and that ERK activation by dopamine is NMDA receptor dependent (Kaphzan et al., 2006). The complex interaction between dopamine and NMDA receptors is significant for different normal and abnormal learning processes. Here, we tested the hypothesis that dopamine interacts with NMDA receptors via tyrosine phosphorylation of the NR2 subunits A and B and that this interaction is upstream to MAPK cascade activation. We found that dopamine induces tyrosine phosphorylation of the NR2B Y1472 .Moreover, dopamine leads to induction in the phosphorylation of Src Y418 and the Src-protein tyrosine kinase inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) inhibits the dopamine effect on ERK2 and NR2B Y1472.In order to test causality between NR2B Y1472 phosphorylation and ERK2 activation by dopamine, we carried out similar pharmacological manipulations in hippocampal slices of wt and NR2B 1472 KI mice and detect clear induction in the WT (similar to rat hippocampal) ,but no changes from base-line was observed in the NR2B Y1472 KI mice. Since dopamine signaling is known to play key role in novelty learning in human and rodents, we tested the KI mice in 3 different behavioral paradigms of novelty (novel recognition, place and taste) and found clear attenuation in the KI compared with the WT mice in all 3 paradigms. These results demonstrate that dopamine signaling via tyrosine phosphorylation of NR2B subunit is playing pivotal role in novel learning and ERK activation. In addition, it is plausible that the specific sites of post-translation modifications of the NMDA receptor can serve as new targets for therapy of psychiatric diseases such as Schizophrenia.