美国加州大学Scott M. Sternson团队的一项最新研究探明了可卡因化学遗传学通过合成生理学削弱了寻找毒品的能力。相关论文于2025年8月27日发表于国际顶尖学术期刊《自然》杂志上。

受生理控制系统的启发，该研究团队开发了一种高度选择性的合成生理学方法，通过在这个身体-大脑信号回路中安装一个依赖可卡因的对立信号过程来干扰成瘾的正反馈循环。课题组研究人员以蛋白质工程为主题，创造可卡因门控离子通道，对可卡因有选择性，而不是其他药物和内源性分子。在大鼠外侧缰带（一个通常被可卡因抑制的大脑区域）中，兴奋性可卡因门控通道的表达抑制了可卡因的自我给药，而不影响食物动机。这种人工可卡因激活的化学发生过程减少了可卡因诱导的伏隔核细胞外多巴胺的上升。

他们的研究结果表明，可卡因化学遗传学是一种选择性的方法，通过控制可卡因存在时多巴胺的释放来对抗药物强化。在未来，化学发生受体可以用于其他成瘾药物或激素和代谢物，这将有助于通过合成生理学方法探索其神经回路机制。由于这些化学发生离子通道是针对可卡因而非自然奖励的，它们也可能为可卡因成瘾的基因治疗提供一条途径。

据悉，化学反馈在生理学中是普遍存在的，但在不干扰基础功能的情况下进行研究是具有挑战性的。一个例子是成瘾性药物，它通过作用于大脑增加多巴胺信号，引发寻求药物和摄入药物的正反馈循环。然而，通过改变基础多巴胺来干扰这一过程也会对学习、运动、注意力和清醒产生不利影响。

附：英文原文

Title: Cocaine chemogenetics blunts drug-seeking by synthetic physiology

Author: Gomez, Juan L., Magnus, Christopher J., Bonaventura, Jordi, Solis, Oscar, Curry, Fallon P., Levinstein, Marjorie R., Budinich, Reece C., Carlton, Meghan L., Ventriglia, Emilya N., Lam, Sherry, Wang, Le, Schoenborn, Ingrid, Dunne, William, Michaelides, Michael, Sternson, Scott M.

Issue&Volume: 2025-08-27

Abstract: Chemical feedback is ubiquitous in physiology but is challenging to study without perturbing basal functions. One example is addictive drugs, which elicit a positive-feedback cycle of drug-seeking and ingestion by acting on the brain to increase dopamine signalling1,2,3. However, interfering with this process by altering basal dopamine also adversely affects learning, movement, attention and wakefulness4. Here, inspired by physiological control systems, we developed a highly selective synthetic physiology approach to interfere with the positive-feedback cycle of addiction by installing a cocaine-dependent opposing signalling process into this body–brain signalling loop. We used protein engineering to create cocaine-gated ion channels that are selective for cocaine over other drugs and endogenous molecules. Expression of an excitatory cocaine-gated channel in the rat lateral habenula, a brain region that is normally inhibited by cocaine, suppressed cocaine self-administration without affecting food motivation. This artificial cocaine-activated chemogenetic process reduced the cocaine-induced extracellular dopamine rise in the nucleus accumbens. Our results show that cocaine chemogenetics is a selective approach for countering drug reinforcement by clamping dopamine release in the presence of cocaine. In the future, chemogenetic receptors could be developed for additional addictive drugs or hormones and metabolites, which would facilitate efforts to probe their neural circuit mechanisms using a synthetic physiology approach. As these chemogenetic ion channels are specific for cocaine over natural rewards, they may also offer a route towards gene therapies for cocaine addiction.

DOI: 10.1038/s41586-025-09427-8

Source: https://www.nature.com/articles/s41586-025-09427-8