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The heart peptide hormone atrial natriuretic peptide (ANP) regulates blood pressure by stimulating guanylyl cyclase-A to produce cyclic guanosine monophosphate (cGMP). ANP and guanylyl cyclase-A are also expressed in many brain areas, but their physiological functions and downstream signaling pathways remain enigmatic. Here we investigated the physiological functions of ANP signaling in the neural pathway from the medial habenula (MHb) to the interpeduncular nucleus (IPN). Biochemical assays indicate that ANP increases cGMP accumulation in the IPN of mouse brain slices. Using optogenetic stimulation and electrophysiological recordings, we show that both ANP and brain natriuretic peptide profoundly block glutamate release from MHb neurons. Pharmacological applications reveal that this blockade is mediated by phosphodiesterase 2A (PDE2A) but not by cGMP-stimulated protein kinase-G or …