Inositol 1, 4, 5-trisphosphate (InsP3) and cAMP are the two second messengers that play an important role in neuronal signaling.Here, we investigated the interactions of InsP3-and cAMP-mediated signaling pathways activated by dopamine at presynaptic sites in the prelimbic cortex.The present paper studied the regulatory effect of phosphatidylinositol (PI)-linked D1-like receptor on the signaling of classical dopamine D1 receptors by examining the effect of PI-linked D1-like receptor agonists SKF83959 on the D1 receptor agonist-induced cAMP-dependent protein kinase (PKA) activation at presynaptie sites using the synaptosomes from the prelimbic cortex.The results showed that SKF83959 alone had no effects on the PKA activity, but could amplify the classical D1 receptor agonist-induced PKA activation.The conventional PKC (cPKC), especially the PKCα, and the extracellular Ca2+ influx, Phospho-DARPP-32 Thr75 also play key roles in the modulate effect of the SKF83959.These results suggest that PI-linked D1-like receptors may modulate the classical D1 receptor agonist-induced PKA activation by PI-linked D1-like receptors-cPKC (especially the PKCα)-Ca2+-Cdk5-Phospho-DAPRR-32 Thr 75 signaling pathway.This may provide a potential target for the drug discovery in Parkinsons disease.