title: Morphine down-regulates melanocortin-4 receptor expression in brain regions that mediate opiate addiction.
abstract: Melanocortin peptides are reported to antagonize opiate dependence and tolerance, but the neural substrates underlying these actions are unknown. In this study, we characterize the rat melanocortin-4 receptor (MC4-R) and demonstrate that this receptor is regulated by opiate administration. The rat MC4-R is 95% identical to the human MC4-R, and the potency of melanocortin peptides to stimulate cAMP production is similar 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, nucleus accumbens, and periaque-ductal gray, all of which are regions implicated 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 striatum and periaqueductal gray. Expression of MC4-R mRNA was also decreased in the nucleus accumbens/ olfactory tubercle, but this effect was observed after 1 or 3 days of morphine treatment. In the striatum, the reduction of MC4-R mRNA was accompanied by a concomitant decrease in melanocortin receptor levels, shown by quantitative radioligand binding and autoradiography. In contrast, morphine administration did not influence levels of MC4-R mRNA in several other brain regions, including frontal cortex, olfactory bulb, hypothalamus, and ventral tegmentum/substantia nigra. In light of previous findings that melanocortins antagonize opiate self-administration, analgesic tolerance, and physical dependence, we hypothesize that decreased melanocortin function, via down-regulation of MC4-R expression, may contribute to the development of these opiate-induced behaviors.
authors.affiliation: Laboratory of Molecular Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06508, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Alvaro
authors.forename: J B
authors.initials: JB
authors.lastname: Tatro
authors.forename: J M
authors.initials: JM
authors.lastname: Quillan
authors.forename: M
authors.initials: M
authors.lastname: Fogliano
authors.forename: M
authors.initials: M
authors.lastname: Eisenhard
authors.forename: M R
authors.initials: MR
authors.lastname: Lerner
authors.forename: E J
authors.initials: EJ
authors.lastname: Nestler
authors.forename: R S
authors.initials: RS
authors.lastname: Duman
mesh_terms: D000818:Animals; D001345:Autoradiography; D001483:Base Sequence; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology*; D001931:Brain Mapping; D003001:Cloning, Molecular; D017124:Conserved Sequence; D000242:Cyclic AMP / Q000378:metabolism; D017931:DNA Primers; D015536:Down-Regulation / Q000187:drug effects*; D004361:Drug Tolerance; D015723:Gene Library; D006801:Humans; D007457:Iodine Radioisotopes; D007700:Kinetics; D051379:Mice; D008969:Molecular Sequence Data; D009020:Morphine / Q000494:pharmacology*; D009021:Morphine Dependence / Q000378:metabolism / Q000503:physiopathology; D009714:Nucleus Accumbens / Q000378:metabolism; D009833:Olfactory Pathways / Q000378:metabolism; D009293:Opioid-Related Disorders / Q000378:metabolism / Q000503:physiopathology*; D009928:Organ Specificity; D016133:Polymerase Chain Reaction; D051381:Rats; D044105:Receptor, Melanocortin, Type 4; D018000:Receptors, Peptide / Q000096:biosynthesis*; D017386:Sequence Homology, Amino Acid; D013997:Time Factors
chemical_list: D017931:DNA Primers; D007457:Iodine Radioisotopes; D044105:Receptor, Melanocortin, Type 4; D018000:Receptors, Peptide; D009020:Morphine; D000242:Cyclic AMP