Chambers Robert Andrew, Sentir Alena M
Department of Psychiatry, Indiana University School of Medicine, Indianapolis, Indiana, USA,
Laboratory for Translational Neuroscience of Dual Diagnosis & Development, IU Neuroscience Research Center, Indianapolis, Indiana, USA,
Dev Neurosci. 2019;41(5-6):263-273. doi: 10.1159/000506227. Epub 2020 Mar 11.
A wide range of mental illnesses show high rates of addiction comorbidities regardless of their genetic, neurodevelopmental, and/or adverse-environmental etiologies. Understanding how the spectrum of mental illnesses produce addiction vulnerability will be key to discovering more effective preventions and integrated treatments for adults with addiction and dual diagnosis comorbidities. A population of 131 rats containing a spectrum of etiological mental illness models and degrees of severity was experimentally generated by crossing neonatal ventral hippocampal lesions (NVHL; n = 68) or controls (SHAM-operated; n = 63) with adolescent rearing in environmentally/socially enriched (ENR; n = 66) or impoverished (IMP; n = 65) conditions. This population was divided into 2 experiments: first, examining NVHL and IMP effects on novelty and mild stress-induced locomotion across 3 adolescent ages; second, looking at initial cocaine reactivity and long-term cocaine behavioral sensitization in adulthood. NVHL and IMP-environmental conditions independently produced remarkably similar and robustly significant abnormalities of hyperreactivity to novelty, mild stress, and long-term cocaine sensitization. The combined NVHL-IMP groups showed the most severe phenotypes across the board, so that the mental illness and addiction vulnerability phenotypes increased together in severity in a consistent stepwise progression from the healthiest rats to those with the greatest loading of etiological models. These findings add weight to our understanding of mental illness and addiction vulnerability as brain disorders that are biologically and developmentally unified in ways that transcend etiological causes, and yet co-intensify with increased loading of etiological conditions. Combining neurodevelopmental and adverse-environmental models of mental illness may provide an approach to identifying and therapeutically targeting cortical-striatal-limbic network mechanisms that generate addiction and dual diagnosis diseases.
广泛的精神疾病都显示出高成瘾共病率，无论其遗传、神经发育和/或不良环境病因如何。了解精神疾病谱如何产生成瘾易感性，将是为有成瘾和双重诊断共病的成年人发现更有效预防措施和综合治疗方法的关键。通过将新生大鼠腹侧海马损伤（NVHL；n = 68）或对照组（假手术；n = 63）与在环境/社会丰富（ENR；n = 66）或贫困（IMP；n = 65）条件下饲养的青少年进行杂交，实验产生了一个包含一系列病因性精神疾病模型和严重程度的131只大鼠群体。该群体被分为2个实验：第一，研究NVHL和IMP对3个青少年年龄段新奇性和轻度应激诱导运动的影响；第二，观察成年期最初的可卡因反应性和长期可卡因行为敏化。NVHL和IMP环境条件独立产生了对新奇性、轻度应激和长期可卡因敏化的过度反应的非常相似且极为显著的异常。联合的NVHL-IMP组在各方面表现出最严重的表型，因此从最健康的大鼠到病因模型负荷最大的大鼠，精神疾病和成瘾易感性表型的严重程度以一致的逐步进展共同增加。这些发现进一步加深了我们对精神疾病和成瘾易感性的理解，即它们是在生物学和发育上以超越病因的方式统一的脑部疾病，但会随着病因条件负荷的增加而共同加剧。结合精神疾病的神经发育和不良环境模型，可能为识别和治疗靶向产生成瘾和双重诊断疾病的皮质-纹状体-边缘网络机制提供一种方法。
