Department of Psychology, University of North Carolina at Chapel Hill, NC 27599, USA.
Alcohol Clin Exp Res. 2011 Jun;35(6):1058-66. doi: 10.1111/j.1530-0277.2011.01438.x. Epub 2011 Feb 17.
The melanocortin (MC) system is composed of peptides that are cleaved from the polypeptide precursor proopiomelanocortin (POMC). Recent evidence shows that chronic exposure to ethanol significantly blunts central MC peptide immunoreactivity and MC receptor (MCR) agonists protect against high ethanol intake characteristic of C57BL/6J mice. Here, we assessed the role of the MC-4 receptor (MC4R) in voluntary ethanol intake and in modulating the effects of the nonselective MCR agonist melanotan-II (MTII) on ethanol consumption.
To assess the role of the MC4R, MC4R knockout (Mc4r(-/-) ) and littermate wild-type (Mc4r(+/+) ) mice on a C57BL/6J background were used. Voluntary ethanol (3, 5, 8, 10, 15, and 20%, v/v) and water intake were assessed using standard two-bottle procedures. In separate experiments, Mc4r(-/-) and Mc4r(+/+) mice were given intracerebroventricular (i.c.v.) infusion of MTII (0, 0.5, or 1.0 μg/1 μl) or intraperitoneal (i.p.) injection of MTII (0 or 5 mg/kg/5 ml). The effects of MTII (0 or 0.5 μg/1 μl, i.c.v.) on 10% sucrose and 0.15% saccharin intake were assessed in C57BL/6J mice.
Mc4r(-/-) mice showed normal consumption of ethanol over all concentrations tested. I.c.v. infusion of MTII significantly reduced ethanol drinking in Mc4r(+/+) mice, but failed to influence ethanol intake in Mc4r(-/-) mice. When administered in an i.p. injection, MTII significantly reduced ethanol drinking in both Mc4r(-/-) and Mc4r(+/+) mice. MTII attenuated consumption of caloric (ethanol, sucrose, and food) and noncaloric (saccharin) reinforcers.
When given centrally, the MCR agonist MTII reduced ethanol drinking by signaling through the MC4R. On the other hand, MTII-induced reduction of ethanol drinking did not require the MC4R when administered peripherally. Together, the present observations show that the MC4R is necessary for the central actions of MCR agonists on ethanol drinking and that MTII blunts the consumption natural reinforcers, regardless of caloric content, in addition to ethanol.
黑色素皮质素（MC）系统由多肽组成，这些多肽是从多肽前体 proopiomelanocortin（POMC）中切割而来。最近的证据表明，慢性暴露于乙醇会显著削弱中枢 MC 肽免疫反应，而 MC 受体（MCR）激动剂可防止 C57BL/6J 小鼠摄入高浓度乙醇。在这里，我们评估了 MC-4 受体（MC4R）在自愿性乙醇摄入中的作用，以及在调节非选择性 MCR 激动剂黑素促黑激素 II（MTII）对乙醇消耗的影响中的作用。
为了评估 MC4R 的作用，使用了 MC4R 敲除（Mc4r(-/-)）和同窝野生型（Mc4r(+/+)）小鼠作为 C57BL/6J 背景。使用标准双瓶程序评估自愿性乙醇（3、5、8、10、15 和 20%，v/v）和水的摄入。在单独的实验中，将 Mc4r(-/-)和 Mc4r(+/+)小鼠给予脑室内（i.c.v.）注射 MTII（0、0.5 或 1.0 μg/1 μl）或腹腔内（i.p.）注射 MTII（0 或 5 mg/kg/5 ml）。在 C57BL/6J 小鼠中，评估了 MTII（0 或 0.5 μg/1 μl，i.c.v.）对 10%蔗糖和 0.15%糖精摄入的影响。
Mc4r(-/-) 小鼠在所有测试浓度下均表现出正常的乙醇消耗。i.c.v. 注射 MTII 显著减少 Mc4r(+/+) 小鼠的乙醇摄入量，但未能影响 Mc4r(-/-) 小鼠的乙醇摄入量。当以腹腔内注射给药时，MTII 显著减少了 Mc4r(-/-) 和 Mc4r(+/+) 小鼠的乙醇摄入量。MTII 减弱了对热能（乙醇、蔗糖和食物）和非热能（糖精）强化剂的消耗。
当给予中枢时，MCR 激动剂 MTII 通过 MC4R 信号传递减少乙醇摄入。另一方面，当给予外周时，MTII 诱导的乙醇摄入量减少并不需要 MC4R。综上所述，目前的观察结果表明，MC4R 是 MCR 激动剂对乙醇摄入的中枢作用所必需的，并且 MTII 减弱了对自然强化剂的消耗，而不管其热量含量如何，除了乙醇之外。
