title: The expression of MC4Rs in D1R neurons regulates food intake and locomotor sensitization to cocaine.
abstract: While it is known that mice lacking melanocortin 4 receptor (MC4R) expression develop hyperphagia resulting in early-onset obesity, the specific neural circuits that mediate this process remain unclear. Here, we report that selective restoration of MC4R expression within dopamine-1 receptor-expressing neurons [MC4R/dopamine 1 receptor (D1R) mice] partially blunts the severe obesity seen in MC4R-null mice by decreasing meal size, but not meal frequency, in the dark cycle. We also report that both acute cocaine-induced anorexia and the development of locomotor sensitization to repeated administration of cocaine are blunted in MC4R-null mice and normalized in MC4R/D1R mice. Neuronal retrograde tracing identifies the lateral hypothalamic area as the primary target of MC4R-expressing neurons in the nucleus accumbens. Biochemical studies in the ventral striatum show that phosphorylation of DARPP-32(Thr) (-34) and GluR1(Ser) (-845) is diminished in MC4R-null mice after chronic cocaine administration but rescued in MC4R/D1R mice. These findings highlight a physiological role of MC4R-mediated signaling within D1R neurons in the long-term regulation of energy balance and behavioral responses to cocaine.
authors.affiliation: Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX, USA. Huxing-Cui@uiowa.edu
authors.forename: H
authors.initials: H
authors.lastname: Cui
authors.forename: M
authors.initials: M
authors.lastname: Lutter
mesh_terms: D000818:Animals; D000855:Anorexia / Q000139:chemically induced / Q000235:genetics; D001479:Basal Ganglia / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology* / Q000633:toxicity; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000235:genetics / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism*; D004435:Eating; D008124:Locomotion; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009714:Nucleus Accumbens / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation; D044105:Receptor, Melanocortin, Type 4 / Q000235:genetics* / Q000378:metabolism; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D003042:Cocaine; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; D044105:Receptor, Melanocortin, Type 4; D018091:Receptors, AMPA; D017447:Receptors, Dopamine D1; C574273:MC4R protein, mouse; C497929:Ppp1r1b protein, mouse
keywords: Cocaine; dopamine-1 receptor; food intake; locomotor sensitization; melanocortin 4 receptor; obesity