Department of Pharmacology, Addiction Science and Toxicology, College of Medicine, University of Tennessee Health Science Center (UTHSC), 71 S. Manassas St., Suite 217, Memphis, TN, 38103, USA.
Sci Rep. 2022 Feb 2;12(1):1804. doi: 10.1038/s41598-022-05256-1.
Despite the catastrophic consequences of alcohol abuse, alcohol use disorders (AUD) and comorbidities continue to strain the healthcare system, largely due to the effects of alcohol-seeking behavior. An improved understanding of the molecular basis of alcohol seeking will lead to enriched treatments for these disorders. Compulsive alcohol seeking is characterized by an imbalance between the superior drive to consume alcohol and the disruption or erosion in control of alcohol use. To model the development of compulsive engagement in alcohol seeking, we simultaneously exploited two distinct and conflicting Caenorhabditis elegans behavioral programs, ethanol preference and avoidance of aversive stimulus. We demonstrate that the C. elegans model recapitulated the pivotal features of compulsive alcohol seeking in mammals, specifically repeated attempts, endurance, and finally aversion-resistant alcohol seeking. We found that neuropeptide signaling via SEB-3, a CRF receptor-like GPCR, facilitates the development of ethanol preference and compels animals to seek ethanol compulsively. Furthermore, our functional genomic approach and behavioral elucidation suggest that the SEB-3 regulates another neuropeptidergic signaling, the neurokinin receptor orthologue TKR-1, to facilitate compulsive ethanol-seeking behavior.
尽管酗酒会带来灾难性的后果，但酒精使用障碍（AUD）和共病仍在给医疗系统带来压力，这主要是由于觅酒行为的影响。对酒精觅药行为分子基础的深入了解将为这些疾病带来更丰富的治疗方法。强迫性觅酒的特点是饮酒的强烈欲望与控制饮酒的破坏或削弱之间的失衡。为了模拟强迫性饮酒觅药的发展，我们同时利用了秀丽隐杆线虫两种截然不同且相互冲突的行为程序，即乙醇偏好和回避厌恶刺激。我们证明，秀丽隐杆线虫模型再现了哺乳动物强迫性饮酒觅药的关键特征，特别是反复尝试、持久和最终的抗厌酒觅药。我们发现，通过 SEB-3（一种 CRF 受体样 GPCR）进行的神经肽信号传导促进了乙醇偏好的发展，并迫使动物强迫性地寻找乙醇。此外，我们的功能基因组方法和行为阐明表明，SEB-3 调节另一种神经肽信号传导，即神经激肽受体同源物 TKR-1，以促进强迫性乙醇觅药行为。
