Ostlund Sean B, LeBlanc Kimberly H, Kosheleff Alisa R, Wassum Kate M, Maidment Nigel T
1] Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles, Los Angeles, CA, USA [2] Brain Research Institute, University of California at Los Angeles, Los Angeles, CA, USA [3] Department of Anesthesiology and Perioperative Care, University of California at Irvine, Irvine, CA, USA.
NIDDK, National Institutes of Health, Bethesda, MD, USA.
Neuropsychopharmacology. 2014 Sep;39(10):2441-9. doi: 10.1038/npp.2014.96. Epub 2014 May 7.
Drug addiction is marked by pathological drug seeking and intense drug craving, particularly in response to drug-related stimuli. Repeated psychostimulant administration is known to induce long-term alterations in mesolimbic dopamine (DA) signaling that are hypothesized to mediate this heightened sensitivity to environmental stimuli. However, there is little direct evidence that drug-induced alteration in mesolimbic DA function underlies this hypersensitivity to motivational cues. In the current study, we tested this hypothesis using fast-scan cyclic voltammetry to monitor phasic DA signaling in the nucleus accumbens core of cocaine-pretreated (6 once-daily injections of 15 mg/kg, i.p.) and drug-naive rats during a test of cue-evoked incentive motivation for food-the Pavlovian-to-instrumental transfer task. We found that prior cocaine exposure augmented both reward seeking and DA release triggered by the presentation of a reward-paired cue. Furthermore, cue-evoked DA signaling positively correlated with cue-evoked food seeking and was found to be a statistical mediator of this behavioral effect of cocaine. Taken together, these findings provide support for the hypothesis that repeated cocaine exposure enhances cue-evoked incentive motivation through augmented phasic mesolimbic DA signaling. This work sheds new light on a fundamental neurobiological mechanism underlying motivated behavior and its role in the expression of compulsive reward seeking.
药物成瘾的特征是病理性的觅药行为和强烈的药物渴望，尤其是对与药物相关的刺激作出反应时。已知反复给予精神兴奋剂会引起中脑边缘多巴胺（DA）信号的长期改变，据推测这种改变介导了对环境刺激的这种高度敏感性。然而，几乎没有直接证据表明中脑边缘DA功能的药物诱导改变是这种对动机线索超敏反应的基础。在当前的研究中，我们使用快速扫描循环伏安法监测可卡因预处理（每天腹腔注射15mg/kg，共6次）的大鼠和未接触过药物的大鼠在食物线索诱发的动机性测试（巴甫洛夫到工具性转换任务）中伏隔核核心的阶段性DA信号，来验证这一假设。我们发现，先前接触可卡因增强了由呈现奖励配对线索所引发的奖赏寻求和DA释放。此外，线索诱发的DA信号与线索诱发的食物寻求呈正相关，并且被发现是可卡因这种行为效应的统计学中介因素。综上所述，这些发现支持了这样的假设，即反复接触可卡因通过增强阶段性中脑边缘DA信号来增强线索诱发的动机性。这项工作为动机行为背后的基本神经生物学机制及其在强迫性奖赏寻求表达中的作用提供了新的线索。
