Alameen Alaa A, AlSharari Shakir D, Alshammari Musaad A, Damaj M I, Sari Y
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Department of Pharmacology & Toxicology, Virginia Commonwealth University, Richmond, VA, USA.
Saudi Pharm J. 2024 Aug;32(8):102138. doi: 10.1016/j.jsps.2024.102138. Epub 2024 Jul 4.
The recent global increase in obesity rates, coupled with excessive palatable food (PF) consumption, has become a serious societal concern. Literature indicates that rewarding PF, especially upon cessation, can lead to overeating, binge eating, and compulsive eating, potentially resulting in obesity. Challenges in dietary paradigms, alongside limitations in approved treatments for eating disorders and anti-obesity medications, underscore the need to explore novel targets. In this context, α7nAChR (alpha-7 nicotinic acetylcholine receptor) may serve as a promising therapeutic target in combating food dependence and obesity. The present study aims to assess the role of α7nAChR in palatable food-induced dependence-like behaviors.
The study involved male C57BL/6J mice exposed to three different feeding paradigms over 6 weeks to induce obesity and food addiction. On day 43, palatable food was replaced with standard chow, and the mice received treatments (vehicle, PNU-282987 [α7nAChR agonist], or methyllycaconitine citrate [MLA; α7nAChR antagonist]). Addiction-like behaviors, including craving for palatable food, motivation-effort interaction tests, and compulsive eating-like behavior, were measured during abstinence with and without treatment.
The present study shows that chronic intermittent and continuous exposure to palatable food induces craving, motivation, and effort interaction behaviors as well as compulsive eating-like behaviors in palatable food-abstinent mice. Administration of the α7nAChR agonist, PNU-282987, significantly attenuated the craving behavior only in mice continuously fed palatable food (reduced calorie intake from 63.19 % to 48.21 %; p = 0.0053). Also, PNU-282987 suppressed the effort behaviors in either intermittently or continuously fed mice (significant reduction in the Δ number of active events per minute; p-values = 0.038 and 0.0098, respectively). However, it attenuated the compulsive-like eating behavior exclusively in the continuously fed group (p = 0.0433). Active and total interaction efforts were reversed by the MLA. These findings indicate the involvement of α7nAChR in dependence-like behaviors toward palatable food in mice.
Our findings demonstrate that dependence-like behaviors toward palatable food can emerge after prolonged exposure. Mice fed on palatable food continuously exhibited more dependence-like behaviors toward palatable food, and activation of α7nAChR signaling attenuated the vulnerability to develop such behaviors.
近期全球肥胖率上升，加之过量食用美味食物（PF），已成为严重的社会问题。文献表明，对美味食物给予奖赏，尤其是在停止供应后，会导致暴饮暴食、强迫性进食，进而可能引发肥胖。饮食模式面临挑战，同时饮食失调和抗肥胖药物的获批治疗方法存在局限性，这凸显了探索新靶点的必要性。在此背景下，α7烟碱型乙酰胆碱受体（α7nAChR）可能是对抗食物依赖和肥胖的一个有前景的治疗靶点。本研究旨在评估α7nAChR在美味食物诱导的类似依赖行为中的作用。
本研究涉及雄性C57BL/6J小鼠，在6周内使其暴露于三种不同的喂养模式下以诱导肥胖和食物成瘾。在第43天，将美味食物替换为标准饲料，小鼠接受相应治疗（溶剂、PNU - 282987[α7nAChR激动剂]或柠檬酸甲基赖氨酸[MLA；α7nAChR拮抗剂]）。在戒断期间，无论是否接受治疗，均测量类似成瘾的行为，包括对美味食物的渴望、动机 - 努力相互作用测试以及强迫性进食样行为。
本研究表明，长期间歇性和持续性暴露于美味食物会在戒断的小鼠中诱导出对美味食物的渴望、动机和努力相互作用行为以及强迫性进食样行为。给予α7nAChR激动剂PNU - 282987，仅在持续喂食美味食物的小鼠中显著减轻了渴望行为（卡路里摄入量从63.19%降至48.21%；p = 0.0053）。此外，PNU - 282987抑制了间歇性或持续性喂食小鼠的努力行为（每分钟主动事件数量的Δ显著减少；p值分别为0.038和0.0098）。然而，它仅在持续喂食组中减轻了强迫性进食样行为（p = 0.0433）。MLA逆转了主动和总相互作用努力。这些发现表明α7nAChR参与了小鼠对美味食物的类似依赖行为。
我们的研究结果表明，长期暴露后会出现对美味食物的类似依赖行为。持续喂食美味食物的小鼠对美味食物表现出更多的类似依赖行为，并且α7nAChR信号的激活减弱了产生此类行为的易感性。
