Italia Maria, Scheggia Diego, DiLuca Monica, Gardoni Fabrizio
Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", University of Milan, Milan 20133, Italy.
Department of Pharmacological and Biomolecular Sciences "Rodolfo Paoletti", University of Milan, Milan 20133, Italy.
Pharmacol Res. 2025 Jul;217:107821. doi: 10.1016/j.phrs.2025.107821. Epub 2025 Jun 6.
Eating behaviors are governed by the complex interplay between homeostatic mechanisms, driven by metabolic needs, and hedonic pathways, supporting the rewarding aspects of food consumption. This review explores the role of AMPA-type glutamate receptors (AMPARs) in modulating both hedonic and homeostatic feeding, highlighting their contributions to reward sensitivity and metabolic regulation in specific neuronal circuitries and their putative role in eating disorders. In the nucleus accumbens, calcium-permeable AMPARs (Cp-AMPARs) mediate synaptic adaptations that enhance reward-seeking behavior under food restriction and after exposure to palatable diets. These molecular mechanisms resemble those observed in substance addiction, highlighting shared pathways between maladaptive eating and addictive behaviors. In hypothalamic circuits, AMPARs dynamically adjust synaptic composition in response to metabolic hormones, such as leptin and ghrelin, to maintain energy homeostasis, underscoring their role in fine-tuning hunger and satiety. Interestingly, peripheral metabolic signals and dietary states can modulate hippocampal synaptic plasticity through AMPAR-dependent mechanisms, thereby affecting meal-related memory formation and retrieval. Overall, these findings indicate the involvement of AMPAR in food-seeking behavior and, consequently, their potential role in eating disorders. However, despite the therapeutic potential of targeting AMPARs, available pharmacological strategies remain very limited. Preclinical data highlights new possible approaches, such as the development of AMPAR-allosteric and subunit-specific agents, yet challenges related to off-target effects in chronic treatments persist. By integrating insights into the neuroplastic mechanisms underlying feeding behaviors, this review lays the groundwork for advancing compounds targeting AMPARs for the therapy of metabolic and eating disorders.
进食行为受体内平衡机制与享乐途径之间复杂相互作用的支配，前者由代谢需求驱动，后者支持食物摄入的奖赏方面。本综述探讨了AMPA型谷氨酸受体（AMPARs）在调节享乐性和稳态性进食中的作用，强调了它们在特定神经回路中对奖赏敏感性和代谢调节的贡献，以及它们在饮食失调中的假定作用。在伏隔核中，钙通透性AMPARs（Cp-AMPARs）介导突触适应性变化，增强食物限制和接触美味饮食后的奖赏寻求行为。这些分子机制类似于在物质成瘾中观察到的机制，突出了适应不良饮食和成瘾行为之间的共同途径。在下丘脑回路中，AMPARs会根据瘦素和胃泌素等代谢激素动态调整突触组成，以维持能量稳态，强调了它们在微调饥饿和饱腹感方面的作用。有趣的是，外周代谢信号和饮食状态可通过AMPAR依赖机制调节海马突触可塑性，从而影响与进食相关的记忆形成和提取。总体而言，这些发现表明AMPAR参与了觅食行为，因此它们在饮食失调中具有潜在作用。然而，尽管靶向AMPARs具有治疗潜力，但现有的药理学策略仍然非常有限（。临床前数据突出了新的可能方法，如开发AMPAR变构剂和亚基特异性药物，但慢性治疗中与脱靶效应相关的挑战仍然存在。通过整合对进食行为潜在神经可塑性机制的见解，本综述为推进靶向AMPARs的化合物用于治疗代谢和饮食失调奠定了基础。
