The efficacy of the D1/5 agonist SKF38393 (100nM-60microM) to increase long-term potentiation (LTP) in the CA1 region was investigated in the rat hippocampal slice preparation. The receptor specificity of this enhancing effect was confirmed using the D1/5 antagonist SKF83566 (2microM). Although the ability of D1/5 receptors to increase both the persistence and the early magnitude of LTP has previously been linked to activation of the cAMP/PKA pathway, the subsequent molecular events leading to the enhancement of LTP have not been characterized. In experiments using SKF38393 (20microM), a requirement for the activation of both protein kinase A (PKA) and Src family tyrosine kinase pathways was demonstrated, as pretreatment with either H89 (10microM) or PP2 (10microM) kinase inhibitors prevented the D1/5-mediated enhancement of LTP. In addition, NMDA receptors containing the NR2B subunit were identified as a potential downstream target for this signaling pathway, as pretreatment with the selective antagonist Ro 25-6981 (1microM) also prevented the D1/5-mediated enhancement of LTP. The results identify a crucial role for NR2B-containing NMDA receptors in the modulation of LTP by D1/5-receptors in the CA1, suggesting that endogenously released dopamine may act through this mechanism as a modulator of hippocampal-dependent learning and memory tasks.