Department of Psychiatry, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, NC, United States; Department of Pharmacology, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, NC, United States; Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, NC, United States.
Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, NC, United States; Neuroscience Curriculum, University of North Carolina at Chapel Hill, School of Medicine, Chapel Hill, NC, United States.
Int Rev Neurobiol. 2024;178:59-96. doi: 10.1016/bs.irn.2024.07.004. Epub 2024 Jul 20.
Many lines of research have suggested that the neuroactive pregnane steroids, including pregnenolone, progesterone, and allopregnanolone ([3α,5α]-3-hydroxypregnan-20-one, 3α,5α-THP), have therapeutic potential for treatment of alcohol use disorders (AUDs). In this chapter, we systematically address the preclinical and clinical evidence that supports this approach for AUD treatment, describe the underlying neurobiology of AUDs that are targeted by these treatments, and delineate how pregnane steroids may address various components of the disease. This review updates the theoretical framework for understanding how endogenous steroids that modulate the effects of alcohol, stress, excitatory/inhibitory and dopamine transmission, and the innate immune system appear to play a key role in the prevention and mitigation of AUDs. We further discuss newly discovered limitations of pregnane steroid therapies as well as the challenges that are inherent to development of endogenous compounds for therapeutics. We argue that overcoming these challenges presents the opportunity to help millions who suffer from AUDs across the world.
许多研究表明，神经活性孕甾烷类固醇，包括孕烯醇酮、孕酮和别孕烯醇酮（[3α,5α]-3-羟基孕烷-20-酮，3α,5α-THP），具有治疗酒精使用障碍（AUDs）的潜力。在这一章中，我们系统地介绍了支持这种 AUD 治疗方法的临床前和临床证据，描述了这些治疗方法针对的 AUD 的潜在神经生物学，并阐述了孕甾烷类固醇如何解决该疾病的各种成分。本综述更新了理解内源性类固醇如何调节酒精、应激、兴奋/抑制和多巴胺传递以及先天免疫系统的作用的理论框架，这些内源性类固醇似乎在预防和缓解 AUDs 方面发挥着关键作用。我们进一步讨论了孕甾烷类固醇疗法的新发现的局限性，以及为治疗开发内源性化合物所固有的挑战。我们认为，克服这些挑战为帮助全世界数百万 AUD 患者提供了机会。
