ArticleThe Journal of clinical investigation2018
Motivational valence is determined by striatal melanocortin 4 receptors.
Article in The Journal of clinical investigation, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 31 citations in OpenAlex.
- The tectal melanocortin system modulates energy-dependent visual avoidance behavior in zebrafish.iScience · 2026Article
- Melanocortin 4 receptor-expressing neurons in the lateral stripe of the striatum regulate affect and motor control.iScience · 2025Article
- Differential potentiation of odor aversion and yawning by melanocortin 4 receptor signaling in distinct regions of the ventral striatum.Frontiers in neuroscience · 2025Article
- Chronic Nicotine Consumption and Withdrawal Regulate Melanocortin Receptor, CRF, and CRF Receptor mRNA Levels in the Rat Brain.Brain sciences · 2024Article
- Targeting the central melanocortin system for the treatment of metabolic disorders.Nature reviews. Endocrinology · 2023Review
- Proopiomelanocortin projections to the nucleus accumbens modulate acquisition and maintenance of operant palatable pellet administration in mice.Physiology & behavior · 2023Article
- The Melanocortin System: A Promising Target for the Development of New Antidepressant Drugs.International journal of molecular sciences · 2023Review
- A novel small molecule, AS1, reverses the negative hedonic valence of noxious stimuli.BMC biology · 2023Article
- Melanocortin-4 receptor signaling in the central amygdala mediates chronic inflammatory pain effects on nociception.Neuropharmacology · 2022Article
- Inter-individual variability amplified through breeding reveals control of reward-related action strategies by Melanocortin-4 Receptor in the dorsomedial striatum.Communications biology · 2022Article
- Individual arcuate nucleus proopiomelanocortin neurons project to select target sites.American journal of physiology. Regulatory, integrative and comparative physiology · 2021Article
- Cellular activity in insular cortex across seconds to hours: Sensations and predictions of bodily states.Neuron · 2021Review
- Translational PET applications for brain circuit mapping with transgenic neuromodulation tools.Pharmacology, biochemistry, and behavior · 2021Review
- The melanocortin-3 receptor is a pharmacological target for the regulation of anorexia.Science translational medicine · 2021Article
- POMC neuronal heterogeneity in energy balance and beyond: an integrated view.Nature metabolism · 2021Review
- The Role of Melanocortin Plasticity in Pain-Related Outcomes After Alcohol Exposure.Frontiers in psychiatry · 2021Review
- Structural and biochemical imaging reveals systemic LPS-induced changes in the rat brain.Journal of neuroimmunology · 2020Article
- Defining circuit-specific roles for G protein-coupled receptors in aversive learning.Current opinion in behavioral sciences · 2019Article
- Melanocortin 4 receptors switch reward to aversion.The Journal of clinical investigation · 2018Article
- Nucleus Accumbens Modulation in Reward and Aversion.Cold Spring Harbor symposia on quantitative biology · 2018Article
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Authors and funding
12 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
It is critical for survival to assign positive or negative valence to salient stimuli in a correct manner. Accordingly, harmful stimuli and internal states characterized by perturbed homeostasis are accompanied by discomfort, unease, and aversion. Aversive signaling causes extensive suffering during chronic diseases, including inflammatory conditions, cancer, and depression. Here, we investigated the role of melanocortin 4 receptors (MC4Rs) in aversive processing using genetically modified mice and a behavioral test in which mice avoid an environment that they have learned to associate with aversive stimuli. In normal mice, robust aversions were induced by systemic inflammation, nausea, pain, and κ opioid receptor-induced dysphoria. In sharp contrast, mice lacking MC4Rs displayed preference or indifference toward the aversive stimuli. The unusual flip from aversion to reward in mice lacking MC4Rs was dopamine dependent and associated with a change from decreased to increased activity of the dopamine system. The responses to aversive stimuli were normalized when MC4Rs were reexpressed on dopamine D1 receptor-expressing cells or in the striatum of mice otherwise lacking MC4Rs. Furthermore, activation of arcuate nucleus proopiomelanocortin neurons projecting to the ventral striatum increased the activity of striatal neurons in an MC4R-dependent manner and elicited aversion. Our findings demonstrate that melanocortin signaling through striatal MC4Rs is critical for assigning negative motivational valence to harmful stimuli.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.