Cyclic adenosine monophosphate (cAMP) levels in medial prefrontal cortex (mPFC) pyramidal neurons are altered in neuropsychiatric disorders. cAMP is a component of the transduction pathways involved in the control of ionic channels by metabotropic receptors. The purpose of this study was to determine whether cAMP modifies the activity of the G protein-dependent inward rectifier K(+) (GIRK)-like channel current in the mPFC pyramidal neurons of 3-week-old rats. Channel currents were recorded in a patch clamp cell-attached configuration. Membrane-permeable adenylyl cyclase activator forskolin (10 μM) and membrane-permeable protein kinase A (PKA) activator 8-Br-cAMP (100 μM) were found to significantly decrease the open probability (Po) of the GIRK-like channels. Conversely, selective protein kinase A inhibitors: H-89 (10 μM) and KT5720 (0.5 μM) increased the open probability of the GIRK-like channels. Also, the effect of forskolin was tested after preincubation of the neurons with the PKA inhibitor (KT5720). The application of forskolin, despite PKA inhibition, significantly decreased the Po of the GIRK-like channels. This finding suggested that GIRK-like channel current activity might also be inhibited by cAMP in a PKA-independent manner. A compound, 8CPT-2Me-cAMP (10 μM), which is a specific activator of the Epac protein, which in turn is another intracellular target of cAMP, was also found to inhibit GIRK-like channel activity. We conclude that the constitutive activity of neuronal GIRK-like channel currents is inhibited by cAMP. We suggest that PKA and Epac might be components of the transduction pathway between cAMP and the GIRK channels.