Blockade of melanocortin transmission inhibits cocaine reward.
Melanocortins and the melanocortin-4 receptor (MC4-R) are enriched in the nucleus accumbens, a brain region that has been implicated in the rewarding action of cocaine and other drugs of abuse. In the present study we use a number of rat behavioral models to show that infusion of a melanocortin peptide antagonist into the nucleus accumbens blocks the reinforcing, incentive motivational, and locomotor sensitizing effects of cocaine. We also show that locomotor responses to repeated cocaine exposure are completely blocked in MC4-R null mutant mice and reduced in Agouti mice that overexpress an endogenous inhibitor of melanocortins in the brain. The results also demonstrate that cocaine administration increases the expression of MC4-R in the nucleus accumbens and striatum, and that MC4-R is co-localized with prodynorphin in medium spiny neurons in the nucleus accumbens. Together, these findings indicate that the behavioral actions of cocaine are dependent on activation of MC4-R, and suggest that upregulation of this receptor by drug exposure may contribute to sensitization of these behavioral responses. Modulation of cocaine reward is a novel action of the melanocortin-MC4-R system and could be targeted for the development of new medications for cocaine addiction.
Hsu
Richard
R
Laboratory of Molecular Psychiatry, Center for Genes and Behaviour, Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06508, USA.
Taylor
Jane R
JR
Newton
Samuel S
SS
Alvaro
John D
JD
Haile
Colin
C
Han
G
G
Hruby
Victor J
VJ
Nestler
Eric J
EJ
Duman
Ronald S
RS
D054366:Agouti Signaling Protein; D000818:Animals; D001522:Behavior, Animal; D003042:Cocaine / Q000008:administration & dosage*; D003216:Conditioning, Operant / Q000187:drug effects; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004745:Enkephalins / Q000235:genetics / Q000378:metabolism; D017403:In Situ Hybridization / Q000379:methods; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency; D009074:Melanocyte-Stimulating Hormones / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects*; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011922:Rats, Mutant Strains; D044105:Receptor, Melanocortin, Type 4 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D012201:Reward; D012646:Self Administration; D013997:Time Factors; D000521:alpha-MSH / Q000037:antagonists & inhibitors
D054366:Agouti Signaling Protein; D018765:Dopamine Uptake Inhibitors; D004745:Enkephalins; D036341:Intercellular Signaling Peptides and Proteins; D011498:Protein Precursors; D012333:RNA, Messenger; D044105:Receptor, Melanocortin, Type 4; C103272:SHU 9119; D000521:alpha-MSH; D009074:Melanocyte-Stimulating Hormones; C033660:preproenkephalin; D003042:Cocaine