期刊
GENES BRAIN AND BEHAVIOR
卷 12, 期 6, 页码 658-665出版社
WILEY
DOI: 10.1111/gbb.12057
关键词
Cocaine; dopamine-1 receptor; food intake; locomotor sensitization; melanocortin 4 receptor; obesity
资金
- NIDDK NIH HHS [DK081185-01, DK081182-01, PL1 DK081182, RL1 DK081185] Funding Source: Medline
- NIMH NIH HHS [K08 MH084058, MH084058-01A1] Funding Source: Medline
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-nullmice 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-32Thr-34 and GluR1Ser-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.
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