CART (cocaine and amphetamine regulated transcript) is a novel, brain-enriched mRNA which predicts a novel protein without homology to any known protein or peptide. In situ hybridization studies have identified many expression sites in the brain and periphery as well as clarify its expression in three known areas. CART mRNA has been localized to ganglion cells of the retina, lamina X of the spinal cord, mitral and tufted cells of the olfactory bulb, barrel field neurons of the somatosensory cortex, the anterior pituitary, and the medulla of the adrenal cortex. The two alternatively spliced CART variants present in the rat brain were found to have identical and overlapping distributions in the rat forebrain. This central nervous system expression pattern suggests a role for CART in processing of peripheral sensory information. Its localization within the pituitary completes its identification within the three levels of the hypothalamic-pituitary-adrenal axis and perhaps suggests a role in mediating stress responses. CART's distribution and predicted protein sequence is reminiscent of characteristics shared by many brain neuropeptides such as proopiomelanocortin; CART may encode a new peptide transmitter or signaling molecule.