LOCALIZATION OF THE MELANOCORTIN-4 RECEPTOR (MC4-R) IN NEUROENDOCRINEAND AUTONOMIC CONTROL-CIRCUITS IN THE BRAIN

POMC, the precursor of ACTH, MSH, and beta-endorphin peptides, is expr essed in the pituitary and in two sites in the brain, in the arcuate n ucleus of the hypothalamus and the commissural nucleus of the solitary tract of the brain stem. Little is known regarding the functions of m elanocortin (ACTH and MSH) peptides in the brain. We report here the d etailed neuroanatomical distribution of the MC4-R mRNA in the adult ra t brain. The melanocortin 3 receptor (MC3-R), characterized previously , was found to be expressed in arcuate nucleus neurons and in a subset of their presumptive terminal fields but in few regions of the brains tem. The highly conserved MC4-R is much more widely expressed than MC3 -R and is pharmacologically distinct. MC4-R mRNA was found in multiple sites in virtually every brain region, including the cortex, thalamus , hypothalamus, brainstem, and spinal cord. Unlike the MC3-R, MC4-R mR NA is found in both parvicellular and magnocellular neurons of the par aventricular nucleus of the hypothalamus, suggesting a role in the cen tral control of pituitary function. MC4-R is also unique in its expres sion in numerous cortical and brainstem nuclei. Together, MC3-R and/or MC-4R mRNA are found in every nucleus reported to bind MSH in the adu lt rat brain and define neuronal circuitry known to be involved in the control of diverse neuroendocrine and autonomic functions. The high d egree of conservation, distinct pharmacology, and unique neuronal dist ribution of the MC4 receptor suggest specific and complex roles for th e melanocortin peptides in neuroendocrine and autonomic control.