MORPHINE DOWN-REGULATES MELANOCORTIN-4 RECEPTOR EXPRESSION IN BRAIN-REGIONS THAT MEDIATE OPIATE ADDICTION

Melanocortin peptides are reported to antagonize opiate dependence and tolerance, but the neural substrates underlying these actions are unk nown. In this study, we characterize the rat melanocortin-4 receptor ( MC4-R) and demonstrate that this receptor is regulated by opiate admin istration. The rat MC4-R is 95% identical to the human MC4-R, and the potency of melanocortin peptides to stimulate cAMP production is simil ar in these two species homologs (alpha-melanocyte-stimulating hormone = adrenocorticotropic hormone > gamma-melanocyte-stimulating hormone) . Expression of MC4-R mRNA was found to be enriched in the striatum, n ucleus accumbens, and periaqueductal gray, all of which are regions im plicated in the behavioral effects of opiates. In contrast, MC1-, MC3- , and MC5-R are expressed at very low or undetectable levels in these brain regions. Chronic administration of morphine (5 days) resulted in a time-dependent down-regulation of MC4-R mRNA expression in the stri atum and periaqueductal gray. Expression of MC4-R mRNA was also decrea sed in the nucleus accumbens/olfactory tubercle, but this effect was o bserved after 1 or 3 days of morphine treatment. In the striatum, the reduction of MC4-R mRNA was accompanied by a concomitant decrease in m elanocortin receptor levels, shown by quantitative radioligand binding and autoradiography. In contrast, morphine administration did not inf luence levels of MC4-R mRNA in several other brain regions, including frontal cortex, olfactory bulb, hypothalamus, and ventral tegmentum/su bstantia nigra. In light of previous findings that melanocortins antag onize opiate self-administration, analgesic tolerance, and physical de pendence, we hypothesize that decreased melanocortin function, via dow nregulation of MC4-R expression, may contribute to the development of these opiate-induced behaviors.