Neuroimaging Research Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224.
Department of Psychology and Behavioral Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, P.R. China.
Proc Natl Acad Sci U S A. 2022 Dec 13;119(50):e2208867119. doi: 10.1073/pnas.2208867119. Epub 2022 Dec 5.
As a critical node connecting the forebrain with the midbrain, the lateral habenula (LHb) processes negative feedback in response to aversive events and plays an essential role in value-based decision-making. Compulsive drug use, a hallmark of substance use disorder, is attributed to maladaptive decision-making regarding aversive drug-use-related events and has been associated with dysregulation of various frontal-midbrain circuits. To understand the contributions of frontal-habenula-midbrain circuits in the development of drug dependence, we employed a rat model of methamphetamine self-administration (SA) in the presence of concomitant footshock, which has been proposed to model compulsive drug-taking in humans. In this longitudinal study, functional MRI data were collected at pretraining baseline, after 20 d of long-access SA phase, and after 5 d of concomitant footshock coupled with SA (punishment phase). Individual differences in response to punishment were quantified by a "compulsivity index (CI)," defined as drug infusions at the end of punishment phase, normalized by those at the end of SA phase. Functional connectivity of LHb with the frontal cortices and substantia nigra (SN) after the punishment phase was positively correlated with the CI in rats that maintained drug SA despite receiving increasing-intensity footshock. In contrast, functional connectivity of the same circuits was negatively correlated with CI in rats that significantly reduced SA. These findings suggest that individual differences in compulsive drug-taking are reflected by alterations within frontal-LHb-SN circuits after experiencing the negative consequences from SA, suggesting these circuits may serve as unique biomarkers and potential therapeutic targets for individualized treatment of addiction.
作为连接前脑和中脑的关键节点，外侧缰核（LHb）对厌恶事件产生负反馈，在基于价值的决策中发挥着重要作用。强迫性药物使用是物质使用障碍的一个标志，归因于对厌恶药物相关事件的适应不良决策，并与各种额-中脑回路的失调有关。为了了解额-缰核-中脑回路在药物依赖发展中的贡献，我们采用了在同时给予足部电击的情况下进行 methamphetamine 自我给药（SA）的大鼠模型，该模型被提议模拟人类的强迫性药物使用。在这项纵向研究中，在预训练基线、20 天的长时 SA 阶段后和 5 天的同时足部电击与 SA 结合（惩罚阶段）后收集功能磁共振成像数据。通过“强迫性指数（CI）”来量化对惩罚的反应的个体差异，该指数定义为惩罚阶段结束时的药物输注量，除以 SA 阶段结束时的药物输注量。惩罚阶段后 LHb 与额皮质和黑质（SN）的功能连接与在接受递增强度足部电击的情况下仍保持药物 SA 的大鼠的 CI 呈正相关。相比之下，在显著减少 SA 的大鼠中，相同回路的功能连接与 CI 呈负相关。这些发现表明，在经历了 SA 的负面后果后，额-缰核-SN 回路内的变化反映了强迫性药物使用的个体差异，这表明这些回路可能作为独特的生物标志物和潜在的治疗靶点，用于成瘾的个体化治疗。
