The expression of MC4Rs in D1R neurons regulates food intake and locomotor sensitization to cocaine

Authors

  • H. Cui,

    Corresponding author
    1. Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA
    • Department of Psychiatry
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    • Present address: University of Iowa Carver College of Medicine, Iowa City, IA, USA

  • M. Lutter

    1. Department of Psychiatry
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    • Present address: University of Iowa Carver College of Medicine, Iowa City, IA, USA


Corresponding author: H. Cui, PhD, 200 Hawkins Dr. B020 ML, Iowa City, IA 52242, USA. E-mail: Huxing-Cui@uiowa.edu

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-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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