健康与遗传心理学研究室知识库

目的:物质滥用对人类危害深远。物质(药物)使用障碍的核心诊断标准，是出现不计负性后果的强迫性觅药、用药。而且临床研究发现，接触致瘾物质是否成瘾，存在较大的个体差异。通过有效的行为模型，筛选强迫性表型，确认成瘾易感因素，对预防和治疗药物成瘾具有重要意义。由于阿片类药物本身的镇痛效应，不适用于前临床常用的不计后果(电击惩罚)的强迫性觅药用药行为范式，而缺乏良好的阿片药物诱导的强迫行为模型，成为阿片类药物成瘾研究的瓶颈。另外，应激因素可影响多种心理过程，对于维持和促进强迫行为具有重要意义。所以本研究致力于构建阿片药物(吗啡)诱导的大鼠强迫性奖赏寻求行为模型，筛选出强迫性表型个体，并且探讨急性应激对强迫行为的影响。

方法:本研究在高价值自然奖赏(性奖赏)和惩罚(足底电击)的冲突情境下，使大鼠建立“灯光信号一电击惩罚”连接，从而对环境安全与否进行辨别学习。通过考察动物在面对提示惩罚的信号以及受到惩罚时的奖赏寻求行为，建立稳定的强迫性奖赏寻求行为模型。以此为基础，在吗啡戒断大鼠内部筛选出稳定的强迫表型。最后，引入急性应激，考察其对不同药物前处理或不同表型大鼠的奖赏寻求行为影响。

结果:1)吗啡和盐水前处理动物能够建立“灯光信号一电击惩罚”连接，面对惩罚信号提示以及惩罚时，盐水处理组动物会犹豫更长时间趋近奖赏或回避惩罚，而吗啡组会犹豫较短时间获得奖赏。2)只有少数吗啡戒断动物表现出明显的抗惩罚性，有效筛选出稳定的奖赏寻求行为强迫表型(试次完成率，zone 2,3停留时间等)。3)急性应激增加动物的强迫性奖赏寻求行为，应激当天不同表型个体之间仍然表现出稳定差异，应激后盐水组奖赏寻求行为恢复且有上升，而吗啡组有下降趋势。4)吗啡暴露不影响个体的性动机、痛觉感受阂限、电击敏感性以及恐惧记忆的获得和表达能力，且在不同表型之间没有显著差异。

结论:本研究成功建立可靠有效的阿片药物(吗啡)诱导的强迫性奖赏寻求行为模型，且能够筛选出稳定的强迫表型，为研究阿片类药物依赖的神经机制、易感因素提供了新范式。另外，急性应激会明显促进了强迫性奖赏寻求行为。

Objectives: Substance abuse is far-reaching to humans. The core diagnostic criteria for drug addiction are compulsive drugs seeking that do not count negative consequences. Moreover, clinical studies have found that there are large individual differences that exposure to addictive substances develops addiction. Through effective behavioral models, screening compulsive phenotypes and identifying factors of addiction are important for prevention and treatment of drug addiction. Because of the analgesic effect of opioids, it is not suitable for the pre-clinical compulsive drug seeking paradigm (foot-shock). The lack of good opioid-induced compulsive behavioral models has become a bottleneck in opioid addiction research. In addition, stress factors can affect a variety of psychological processes, and are important for maintaining and promoting compulsive behavior. Therefore, this study is aimed at constructing a compulsive reward seeking behavior model induced by opioids (morphine) in rats, screening compulsive phenotype individuals, and exploring the effects of acute stress on compulsive behavior.

Methods: In the conflict situation of high-value natural reward (sexual reward) and punishment (foot-shock), the study established a "light signal-foot shock" connection to distinguish the environmental safety. A stable compulsive reward seeking behavior model is established by examining the animal's reward seeking behavior in the face of prompting the punishment signal and being punished. Based on this, a stable compulsive phenotype was screened in morphine withdrawal rats. Finally, we investigated the effects of acute stress on reward seeking behaviors in different drug pretreatments or in different phenotypes of rats.

Results: 1) Morphine and saline pretreatment animals can establish a "light signal-foot shock" connection. In the face of punished signal and punishment, the saline-treated group will hesitate to approach the reward or avoid punishment in a longer time, while the morphine group will get rewards in a shorter time. 2) Only a small number of morphine withdrawal animals showed significant anti-punitiveness and can effectively screen out compulsive phenotypes (percentage of completed trials, time spent in zone 2, 3 etc.). 3) Acute stress increased the compulsive reward seeking behavior of animals. On the day of stress, different phenotypic individuals still showed stable differences. After the stress, the reward seeking behavior of the saline group animals recovered and increased, while the morphine group showed a downward trend. 4) Morphine exposure does not affect individual sexual motivation pain perception threshold, shock sensitivity, and ability to acquire and express fear memory, and there is no significant difference between different phenotypes.

Conclusion: This study successfully established a reliable and effective opioid (morphine)一induced compulsive reward seeking behavior model, and was able to screen out a stable forced phenotype, providing a new paradigm for studying the neurological mechanisms and susceptibility factors of opioid dependence. In addition acute stress can significantly promote compulsive reward seeking behavior.ence between different phenotypes.