大剂量吗啡戒断不同时程大鼠自然奖赏的动机改变研究：快感缺失vs. 动机敏感化

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	大剂量吗啡戒断不同时程大鼠自然奖赏的动机改变研究：快感缺失vs. 动机敏感化
其他题名	Multi-dimensional expressions of motivation for natural rewards after a binge-like morphine administration regimen：anhedonia vs. incentive sensitization
	李滢滢
	2014-05
摘要	不同成瘾药物对机体会产生不同的行为和神经效应，但几乎所有药物在停药后都会令机体出现戒断综合征（withdrawal syndrome），如快感缺失（anhedonia）、烦躁（dysphoria）、易激惹（irritability）等，这些负性状态均起源于重复用药导致的大脑奖赏系统（brain reward system）的长时程改变。大脑奖赏系统的失调是成瘾者在长期戒断后仍然容易诱发强迫性觅药用药行为（compulsive drug taking and seeking behavior）的神经基础，不仅影响机体对药物和药物相关线索的感知、评价和决策，还影响机体对其他自然奖赏，如食物、性和社会交往等的消耗（consumption）和趋近（approach）。尽管已有研究通过各种动物模型探讨了药物戒断对自然奖赏的动机影响，但大部分研究缺乏系统性。同时，多数研究仅使用某一特定类型奖赏或单一强化效力（reinforcing efficacy）的奖赏，或仅使用一两种行为程序，使得研究结果存在许多矛盾。因动机之复杂性，不仅受到机体本身，如情绪状态、过往经历、奖赏价值和可得性的评价系统、机体内稳态（homeostasis）和体内相关分子水平等的影响，还与外部环境，如奖赏属性、任务难度和强度和时间因素等有关，目前对成瘾药物戒断影响自然奖赏动机的过程和机制仍然不够明晰。要想系统地理清二者的相互作用，还需要考虑戒断时程。因为不同的戒断时程的神经适应性变化可能存在差异，并可能会诱发不同的动机状态。在本研究中，我们使用能够诱发严重戒断症状的大剂量吗啡模型，并将戒断分为两个时程：短程戒断（约为戒断后7-10天）和长程戒断（约为戒断后14-20天）来探讨药物戒断对多种自然奖赏物（多种浓度糖水、性和社会交往）消耗、趋近和强迫性样行为的影响。我们发现： 1. 在戒断前期，吗啡组对糖水、性和社交行为的消耗下降，表现出快感缺失样症状。但在需要付出更多努力的任务中，表现出对高奖赏的渴求。说明快感缺失可以与渴求并存。 2. 在戒断后期，吗啡组的快感缺失样症状逐渐减弱，在FR1、PR及其他在需要付出更多努力的任务中，表现出反应升高，提示存在对自然奖赏的交叉敏感化样表现。 3. 戒断后期的FR1（fixed ratio schedule）和PR程序（progressive ratio schedule）结果的相关分析提示，重复用药可能干扰了吗啡组的奖赏过程，即在奖赏评估、成本/收益的评估以及奖赏行为启动上影响吗啡组在PR程序下的行为表现。最后，上述行为表现可能与皮层-纹状体通路的多巴胺活动有关，尤其是内侧前额叶皮层（medial prefrontal cortex，mPFC）和伏隔核（nucleus accumbens，NAc）的多巴胺D2受体（D2R）、D3受体（D3R）的活动。又因BDNF（brain-derived neurotrophic factor，脑源性神经营养因子）亦是控制动机等相关行为的蛋白，且其与D3R存在相互作用，因此我们对mPFC和NAc中BDNF、D2R和D3R进行了免疫蛋白印迹试验，结果显示：戒断后期吗啡组mPFC中的BDNF、D3R表达显著上调，而NAc中BDNF和D3R显著下调，但进一步分析发现NAc中BDNF和D3R下调主要与药物前处理或戒断有关，mPFC的D3R可能才是调控戒断后PR反应增强主要原因。进一步干预mPFC的D3R活动可以有效降低吗啡组在PR中对15%糖水的反应，提示mPFC参与调控吗啡与糖水的交叉敏感化。
其他摘要	Though most drugs of abuse generate diverse behavioral and neurochemical effects, one feature common to many such drugs is the phenomenon of the withdrawal syndrome after the termination of drug administration, such as anhedonia, dysphoria and irritability etc. These negative emotional states result from the dysregulation of brain reward system, which is the neural basis of compulsive drug taking and seeking behavior that occur even after long-term withdrawal. The dysregulation of brain reward system not only influences perception, evaluation and decision-making of drugs of addictive and drug-related stimuli, but also plays an important role in consummatory andapproaching behaviors for natural rewards, such as food, sex and social interaction. Nevertheless, current research on the motivational alteration of natural rewards after drug withdrawal is lacking of systematicness. Meanwhile, there are full of discrapancies in different studies, which is most propably due to the adoption of diverged magnitudes of the rewards,different typesof behavioral tasks. The complexity of motivation is one of the contributors to the discrepancies among current research, and thus causes an unclarification on the psychological processes and the neural mechanisms of motivational behaviors for natural rewards following withdrawal. Motivation is affected by internal factors, such as emotional states, life experience, the evaluation of availability of the rewards, homeostasis and related molecular levels,et al. External factors, including reward properties, task difficulty and intensity, as well as time element, i.e., withdrawal durationare also playing indispensable parts in motivation.For thosereasons, in the present research, by using a binge-like morphine administration regimen that results in serious withdrawal symptoms, we aimed to explore the effects of drug withdrawalon motived behaviorsfor natural rewardsunder different circumstances. First, we dividedmorphine withdrawal into two phases: short-term phase (about 7-10 days after the last morphine injection) and long-term phase (about 2-3 weeks after the last injection).Then, we investigated consummatory, approaching and compulsive-like responses for food, sex and social rewards during different withdrawal phases. And we found: 1. After short-term withdrawal, morphine-pretreated rats exhibited declined consummatory responses for all kinds of natural rewards, indicating morphine withdrawal induced anhedonia-like behavior. However, in the tasks that required more efforts to obtain rewards, the same rats seemed to becraving for rewards of higher intensity. 2. During long-term withdrawal, the anhedonia-like behaviors showed in a short-term withdrawal were attenuated, no significant differences between morphine-pretreated and saline-pretreated rats under a FR 1 schedule or in a simple appetitive test, but responses for rewards are increased under a PR schedule and in risky-related tasks. 3. The correlation analysis of the results of a FR1 schedule and a PR schedule suggested that morphine withdrawal might interrupt the reward process, i.e., the evaluation of rewards, the evaluation of the effort requirement of the tasksand the initiation of responses, which induced a different behavior pattern under a PR schedule. In addition,those behavioral changes may be mediated by DA activities in the cortical-striatum pathway, especially through D2/3 receptor in medial prefrontal cortex (mPFC) and nucleus accumbens (NAc).And since BDNF (brain-derived neurotrophic factor) was also considered mediating motivated behaviors through its interaction with D3R. Thus, to confirm the above notion, we ran a western blotting assay, which showed thatBDNF and D3R expression increased in mPFC, while decreased in NAc after long-term withdrawal.Further analysis indicated that it is D3R in mPFC, not in NAc was involved in the enhanced motivation for sucrose under a PR schedule. Asingle injection of a D3R partial agonist, BP 897 into mPFC, effectively suppressed morphine withdrawal-induced high responses for a 15% sucrose solution under a PR schedule, suggesting mPFC may be involved in morphine cross sensitization to sucrose
学科领域	医学心理学
关键词	吗啡戒断快感缺失交叉敏感化自然奖赏多巴胺
学位类型	博士
语种	中文
学位专业	心理学
学位授予单位	中国科学院研究生院
学位授予地点	北京
文献类型	学位论文
条目标识符	http://ir.psych.ac.cn/handle/311026/19620
专题	健康与遗传心理学研究室
作者单位	中国科学院心理研究所
推荐引用方式 GB/T 7714	李滢滢. 大剂量吗啡戒断不同时程大鼠自然奖赏的动机改变研究：快感缺失vs. 动机敏感化[D]. 北京. 中国科学院研究生院,2014.

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