Addiction-like Synaptic Impairments in Diet-Induced Obesity.
Addiction-like Synaptic Impairments in Diet-Induced Obesity.
复制标题
DOI：
10.1016/j.biopsych.2015.11.019
复制
发表时间：
2017-05-01
影响因子：
10.6
通讯作者：
Kalivas PW
中科院分区：
文献类型：
--
作者：
Brown RM;Kupchik YM;Spencer S;Garcia-Keller C;Spanswick DC;Lawrence AJ;Simonds SE;Schwartz DJ;Jordan KA;Jhou TC;Kalivas PW
越来越多的证据表明，某些形式的肥胖背后的病理性暴饮暴食本质上是强迫性的，因此包含成瘾性疾病的元素。然而，缺乏将肥胖与类似于成瘾中发生的突触可塑性联系起来的直接生理学证据。我们试图确定饮食诱导肥胖（DIO）的倾向是否与成瘾样行为有关，以及被认为是成瘾标志的丘脑核核心（NAcore）中的突触损伤。允许Sprague-Dawley大鼠自由获得可口的饮食8周，然后根据体重增加分为DIO倾向（OP）和抵抗（OR）亚组。然后，使用固定（FR 1、3和5）和渐进比例（PR）时间表，将获得可口食物的机会限制在每日操作性自我给药阶段。随后，制备NAcore脑切片，并测试AMPA和NMDA电流之间的比率（AMPA/NMDA）和表现出长期抑郁（LTD）的能力的变化。我们发现，DIO的发展倾向与NAcore中诱导LTD的能力不足有关，以及通过AMPA/NMDA电流测量的这些突触的增强作用增加。与这些损伤一致，我们在OP大鼠中观察到成瘾样行为，包括i）对可口食物的动机增强（ii）过量摄入和（iii）当食物不可用时增加食物寻求。我们的研究结果表明，DIO的倾向和与成瘾行为相关的突触变化之间存在重叠，支持强迫性暴饮暴食和药物成瘾的部分一致神经基础。
There is increasing evidence that the pathological overeating underlying some forms of obesity is compulsive in nature, and therefore contains elements of an addictive disorder. However, direct physiological evidence linking obesity to synaptic plasticity akin to that occurring in addiction is lacking. We sought to establish whether the propensity to diet-induced obesity (DIO) is associated with addictive-like behavior, as well as synaptic impairments in the nucleus accumbens core (NAcore) considered hallmarks of addiction. Sprague-Dawley rats were allowed free access to a palatable diet for 8 weeks then separated by weight gain into DIO prone (OP) and resistant (OR) subgroups. Access to palatable food was then restricted to daily operant self-administration sessions using fixed (FR1, 3 and 5) and progressive ratio (PR) schedules. Subsequently, NAcore brain slices were prepared and we tested for changes in the ratio between AMPA and NMDA currents (AMPA/NMDA) and the ability to exhibit long-term depression (LTD). We found that propensity to develop DIO is linked to deficits in the ability to induce LTD in the NAcore, as well as increased potentiation at these synapses as measured by AMPA/NMDA currents. Consistent with these impairments, we observed addictive-like behavior in OP rats, including i) heightened motivation for palatable food (ii) excessive intake and (iii) increased food-seeking when food was unavailable. Our results show overlap between the propensity for DIO and the synaptic changes associated with facets of addictive behavior, supporting partial coincident neurological underpinnings for compulsive overeating and drug addiction.