The natriuretic peptide clearance receptor (NPR-C) binds atrial natriuretic peptide, brain natriuretic peptide and C-type natriuretic peptide with high affinity. This receptor lacks an intracellular guanylate cyclase domain, and is believed to exert biological actions by sequestration of released natriuretic peptides and/or inhibition of adenylate cyclase. The present report summarizes the first detailed mapping of NPR-C mRNA in rat brain. In situ hybridization analysis revealed high levels of NPR-C mRNA expression in frontal and retrosplenial granular cortices, medial preoptic nucleus, ventral cochlear nucleus and choroid plexus. NPR-C mRNA expression was also observed in deep layers of neocortex and limbic cortex, posterior cortical amygdala, ventral subiculum, amygdalohippocampal area, and dentate gyrus. Positive hybridization signal was observed in both anterior and intermediate lobes of the pituitary gland. Regulatory studies indicated that expression of NPR-C mRNA was increased in the medial preoptic nucleus of adrenalectomized rats, suggesting negative glucocorticoid regulation. No changes in NPR-C mRNA expression were observed in frontal cortex or choroid plexus. These results suggest a role for the NPR-C in modulation of natriuretic peptide availability and/or adenylate cyclase activity in a subset of central natriuretic peptide circuits concerned with cortical, olfactory and neuroendocrine functions. Response of the NPR-C gene to changes in circulating hormones suggests the capacity for glucocorticoid modulation of natriuretic peptide action at the receptor level.