Lüscher Christian, Janak Patricia H
Department of Basic Neurosciences, Faculty of Medicine, University of Geneva, CH-1211 Geneva, Switzerland; email:
Clinic of Neurology, Department of Clinical Neurosciences, Geneva University Hospital, CH-1211 Geneva, Switzerland.
Annu Rev Neurosci. 2021 Jul 8;44:173-195. doi: 10.1146/annurev-neuro-092920-123905. Epub 2021 Mar 5.
Addiction is a disease characterized by compulsive drug seeking and consumption observed in 20-30% of users. An addicted individual will favor drug reward over natural rewards, despite major negative consequences. Mechanistic research on rodents modeling core components of the disease has identified altered synaptic transmission as the functional substrate of pathological behavior. While the initial version of a circuit model for addiction focused on early drug adaptive behaviors observed in all individuals, it fell short of accounting for the stochastic nature of the transition to compulsion. The model builds on the initial pharmacological effect common to all addictive drugs-an increase in dopamine levels in the mesolimbic system. Here, we consolidate this early model by integrating circuits underlying compulsion and negative reinforcement. We discuss the genetic and epigenetic correlates of individual vulnerability. Many recent data converge on a gain-of-function explanation for circuit remodeling, revealing blueprints for novel addiction therapies.
成瘾是一种疾病，其特征是强迫性地寻求和使用药物，在20%至30%的使用者中可见。成瘾个体将偏爱药物奖赏而非自然奖赏，尽管会有重大负面后果。对模拟该疾病核心成分的啮齿动物进行的机制研究已确定突触传递改变是病理行为的功能基础。虽然成瘾的初始电路模型侧重于在所有个体中观察到的早期药物适应性行为，但它未能解释向强迫行为转变的随机性。该模型基于所有成瘾药物共有的初始药理作用——中脑边缘系统中多巴胺水平的升高。在此，我们通过整合强迫行为和负强化背后的电路来巩固这个早期模型。我们讨论了个体易感性的遗传和表观遗传相关性。许多最新数据都趋向于对电路重塑进行功能获得性解释，揭示了新型成瘾疗法的蓝图。
