腹侧被盖区D2受体敲低增强大鼠延迟折扣任务中的选择冲动性。

Ventral tegmental area D2 receptor knockdown enhances choice impulsivity in a delay-discounting task in rats.

作者信息

Bernosky-Smith Kimberly A, Qiu Yan-Yan, Feja Malte, Lee Yun Beom, Loughlin Brian, Li Jun-Xu, Bass Caroline E

机构信息

D'Youville College, Department of Biology and Mathematics, 320 Porter Avenue, Buffalo, NY 14201, USA.

Department of Pharmacology and Toxicology, Jacobs School of Medicine, University at Buffalo, SUNY, 102 Farber Hall, 3435 Main St., Buffalo, NY 14214, USA.

出版信息

Behav Brain Res. 2018 Apr 2;341:129-134. doi: 10.1016/j.bbr.2017.12.029. Epub 2017 Dec 26.

Abstract

Impulsivity associated with abnormal dopamine (DA) function has been observed in several disorders, including addiction. Choice impulsivity is the preference for small, immediate rewards over larger rewards after a delay, caused by excessive discounting of future rewards. Addicts have abnormally high discount rates and prefer the smaller rewards sooner. While impulsivity has been inversely correlated with DA D2 receptor (D2R) availability in the midbrain and striatum, it is difficult to mechanistically link the two, due to the diverse neuroanatomical localization of D2Rs, which are found throughout the brain, in many types of neurons and neuronal subcompartments. To determine if ventral tegmental area (VTA) D2R hypofunction is linked to impulsivity, we knocked down D2 receptors from the VTA, using an adeno-associated viral (AAV) vector that delivers short hairpin RNAs (shRNA) targeted against the D2R. The D2R knockdown is restricted to neurons whose cell bodies reside in the VTA, leaving postsynaptic D2Rs intact in the striatum, prefrontal cortex, and other mesocorticolimbic structures. Rats were trained in a delay-discounting task to assess impulsive choice until a stable discounting curve was obtained, and then received bilateral VTA infusions of the D2R shRNA or a scrambled control virus. Over the next six weeks, the discounting curve of the VTA D2R knockdown rats shifted to the left, indicating a preference for the smaller, immediate reward, whereas the curve for control rats remained stable and unchanged. Together these results demonstrate that a decrease in VTA D2Rs enhances choice impulsivity.

摘要

在包括成瘾在内的多种疾病中,均观察到与多巴胺(DA)功能异常相关的冲动性。选择冲动性是指在延迟后,偏好小的即时奖励而非更大的奖励,这是由于对未来奖励过度贴现所致。成瘾者的贴现率异常高,且更喜欢更快获得较小的奖励。虽然冲动性与中脑和纹状体中DA D2受体(D2R)的可用性呈负相关,但由于D2R在整个大脑的多种神经元和神经元亚区室中均有发现,其神经解剖定位多样,因此很难从机制上把二者联系起来。为了确定腹侧被盖区(VTA)的D2R功能减退是否与冲动性有关,我们使用一种腺相关病毒(AAV)载体敲低了VTA中的D2受体,该载体可传递靶向D2R的短发夹RNA(shRNA)。D2R的敲低仅限于细胞体位于VTA的神经元,使纹状体、前额叶皮质和其他中脑边缘结构中的突触后D2R保持完整。对大鼠进行延迟折扣任务训练以评估冲动选择,直到获得稳定的折扣曲线,然后给它们双侧VTA注射D2R shRNA或 scrambled对照病毒。在接下来的六周里,VTA D2R敲低大鼠的折扣曲线向左移动,表明其偏好较小的即时奖励,而对照大鼠的曲线则保持稳定且未改变。这些结果共同表明,VTA中D2R的减少会增强选择冲动性。

文献AI研究员

20分钟写一篇综述,助力文献阅读效率提升50倍

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索