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In the prefrontal cortex, dopamine D1-like and M1 muscarinic receptors are both involved in the regulation of attentional, cognitive and emotional processes but so far no information has been provided on their functional interaction. In the present study we show that in mouse medial prefrontal cortex, concomitant activation of M1 muscarinic receptors potentiated D1-like receptor-induced cyclic AMP formation through a mechanism involving activation of Gq/11 and the release of G protein βγ subunits. Immunohistochemical studies indicated that the adenylyl cyclase isoforms AC2 and AC4 are expressed in mouse prefrontal cortex and that they colocalize with D1-like receptors with a greater association for AC4. In primary cultures of frontal cortex neurons, D1-like receptor-induced Ser133 phosphorylation of the transcription factor cyclic AMP-responsive element binding protein (CREB) was potentiated by concurrent stimulation of M1 receptors. Suppression of AC4 expression with small interfering RNA transfection reduced D1 stimulation of cyclic AMP formation and CREB phosphorylation and abolished the M1 potentiation, whereas knockdown of AC2 had no significant effects. These data indicate that in mouse prefrontal cortex Gq/11-coupled M1 receptor and Gs-coupled D1-like receptor inputs converge on AC4 with a consequent enhancement of cyclic AMP formation and signaling to the nucleus.