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Updated: Sep 20, 2026
Restraint to Induce Stress in Mice and Rats
Published on: December 6, 2024
Involvement of the melanocortin MC4 receptor in stress-related behavior in rodents
Shigeyuki Chaki1, Shin-ichi Ogawa, Yoshihisa Toda
1Psychiatric Diseases and Pain Research, Medicinal Pharmacology Laboratory, Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., 1-403 Yoshino-cho, Kita-ku, Saitama, Saitama 331-9530, Japan. s.chaki@po.rd.taisho.co.jp
Abstract:
The melanocortin subtype 4 (MC4) receptor has been postulated to be involved in stress and stress-related behavior. We made use of melanocortin MC4 receptor agonists and antagonist to investigate the relationship between the melanocortin MC4 receptor and stress related disorders. The nonspecific melanocortin receptor agonist alpha-melanocyte stimulating hormone (alpha-MSH) and the melanocortin MC4 receptor agonist, Ac-[Nle4,Asp5,D-Phe7,Lys10]alpha-MSH-(4-10)-NH2 (MT II) dose-dependently and significantly reduced the number of licking periods in the rat Vogel conflict test, suggesting that stimulation of the melanocortin MC4 receptor causes anxiogenic-like activity in rats. We synthesized a peptidemimetic melanocortin MC4 receptor selective antagonist, Ac-D-2Nal-Arg-2Nal-NH2 (MCL0020), which has high affinity for the melanocortin MC4 receptor with IC50 values of 11.63 +/- 1.48 nM, in contrast, the affinities for melanocortin MC1 and MC3 receptors were negligible. In addition, MCL0020 significantly attenuated the cAMP formation induced by alpha-MSH in COS-1 cells expressing the melanocortin MC4 receptor without affecting basal cAMP contents. Thus, we considered MCL0020 to be a selective melanocrotin MC4 receptor antagonist among melanocortin receptors. Restraint stress significantly reduced food intake in rats, and i.c.v. administration of MCL0020 dose-dependently and significantly attenuated restraint stress-induced anorexia without affecting food intake. Swim stress induced reduction in the time spent in the light area in the mouse light/dark exploration test, and MCL0020 significantly prevented it. Taken together our findings suggest that the melanocortin MC4 receptor might be related to stress-induced changes in behavior, and blockade of the melanocortin MC4 receptor may prevent stress-induced disorders such as anxiety.
Insights
The melanocortin MC4 receptor plays a role in stress responses. Blocking this receptor with MCL0020 can prevent stress-induced anorexia and anxiety-like behaviors in animal models.
Area of Science:
- Neuroscience
- Pharmacology
- Behavioral Science
Background:
- The melanocortin subtype 4 (MC4) receptor is implicated in regulating stress and related behaviors.
- Understanding the MC4 receptor's role is crucial for developing treatments for stress-related disorders.
Purpose of the Study:
- To investigate the relationship between the MC4 receptor and stress-related disorders using agonists and a novel antagonist.
- To characterize the selectivity and efficacy of the MC4 receptor antagonist MCL0020.
Main Methods:
- Utilized melanocortin MC4 receptor agonists (alpha-MSH, MT II) in the rat Vogel conflict test.
- Synthesized and characterized a selective MC4 receptor antagonist (MCL0020) for affinity and functional assays.
- Administered MCL0020 in rat restraint stress and mouse light/dark exploration tests to assess effects on stress-induced behaviors.
Main Results:
- MC4 receptor agonists induced anxiogenic-like activity in rats.
- MCL0020 demonstrated high affinity and selectivity for the MC4 receptor, inhibiting alpha-MSH-induced cAMP.
- MCL0020 dose-dependently attenuated restraint stress-induced anorexia and prevented swim stress-induced anxiety-like behavior.
Conclusions:
- The melanocortin MC4 receptor is involved in stress-induced behavioral changes.
- Blockade of the MC4 receptor with MCL0020 shows potential in preventing stress-related disorders like anxiety and anorexia.
