阿片药物依赖的神经机制---内侧前额叶与药物的心理依赖

Mental dependence, characterized by craving and impulsive seeking behavior, is the matter of intensive study in the field of drug addiction. The mesolimbic dopamine system has been suggested to play an important role in rewarding of drugs and relapse. Although chronic drug use can induce neuroadaptations of the mesolimbic system and changes of drug reinforcement, these mechanisms cannot fully account for the craving and the compulsive drug-using behavior of addicts. Acknowledging the reinforcement effects of drugs, most previous studies have studied the impact of environmental cues and conditioned learning on addiction behavior, often using established classical or operant conditioning model. These studies, however, paid little attention to the role of cognitive control and emotion in addiction. These mental factors that are believed to have an important influence on conditioned learning. The medial prefrontal cortex (mPFC) has close anatomic and functional connections with the mesolimbic dopamine system. A number of the cognitive neurological studies demonstrate that mPFC is involved in motivation, emotional regulation, monitoring of responses and other executive functions. Thus we speculated that the function of abnormality in mPFC following chronic drug use would cause related to the abnormal behavior in addicts including impulse and emotional changes. In the present study of a series of experiments, we used functional magnetic resonance imaging to examine the hemodynamic response of the mPFC and related circuits to various cognitive and emotional stimuli in heroin addicts and to explore the underlying dopamine neuromechnism by microinjection of tool drugs into the mPFC in laboratory animals. In the first experiment, we found that heroin patients, relative to the normal controls, took a much shorter time and committed more errors in completing the more demanding of cognitive regulation in the reverse condition of the task, while the neural activity in anterior cingulate cortex (ACC) was attenuated. In the second experiment, the scores of the heroin patients in self-rating depression scale (SDS) and Self-rating anxiety scale (SAS) were significantly higher than the normal controls and they rated the negative pictures more aversive than the normal controls. Being congruent with the behavioral results, hemodynamic response to negative pictures showed significant difference between the two groups in bilateral ventral mPFC (VMPFC), amygdala, and right thalamus. The VMPFC of patients showed increased activation than normal controls, whereas activation in the amygdala of patients was weaker than that in normal subjects. Our third experiment showed that microinjection of D1 receptor agonist SKF38393 into the mPFC of rats decreased hyperactivity, which was induced by morphine injection, in contrast, D1 receptor antagonist SCH23390 increased the hyperactivity, These findings suggest: (1) The behavior and neural activity in ACC of addicts changed in chronic drug users. Their impulsive behavior might result from the abnormal neural activity in the mPFC especially the ACC. (2) Heroine patients were more depress and anxiety than normal controls. The dysfunction of the mPFC---amygdala circuit of heroine addicts might be related to the abnormal emotion response. (3) Dopamine in the mPFC has an inhibitory effect on morphine induced behavior. The hyperactivity induced by chronic morphine was reduced by dopamine increase with D1 receptor agonist, confirm the first experiment that the neuroadaption of mPFC system induced by chronic morphine administration appears to be the substrate the impulse behavior of drug users.

心理依赖是成瘾机制研究的核心问题，表现为心理渴求和冲动的觅药行为。边缘中脑多巴胺系统在药物条件性奖赏和复吸过程中起着重要作用。然而药物引起的中脑边缘多巴胺系统的神经适应性改变和强化作用的变化并不能解释成瘾者的渴求和强迫性的用药行为。已有的研究大多从药物的强化作用出发建立经典条件或操作性条件反射的学习模型来研究条件线索和条件学习对成瘾行为影响的机制；对影响经典条件和操作性条件反射的认知、情绪等机体内在心理因素与成瘾行为之间的关系的研究相对不够深入。内侧前额叶(medial prefrontal cortex, mPFC)与边缘中脑多巴胺系统有着紧密的解剖和功能联系。认知神经科学研究显示，内侧前额额叶通过与边缘中脑的神经联系参与动机、运动控制和情绪反应等心理过程的调控和加工。因此推测药物引起的内侧前额叶及有关回路的功能异常是影响药物依赖者冲动行为和情绪改变的基础。 本研究的一系列实验主要用人类功能核磁共振成像考察成瘾者内侧前额叶及有关回路在冲动控制和情绪调节任务时的血流动力学反应，并进一步用mPFC局部脑区微量注射在动物模型上探讨其可能的多巴胺机制。实验一结果发现，海洛因病人在认知控制要求更高的reverse条件时其反应时和错误率均高于正常对照，其mPFC的前部扣带皮层部位对冲突任务的激活弱于正常人；实验二数据显示，海洛因病人抑郁和焦虑自评水平均显著高于正常人，并且对负性内容图片的评分显著高于健康对照，相应地海洛因病人血流动力学反应也明显不同于正常组：腹内侧前额叶特异性地对负性内容图片的神经激活反应强于正常被试，而其杏仁核对负性内容图片的激活相对于正常人来说明显减弱；实验三动物研究显示，大鼠mPFC DA参与调节吗啡诱导的大鼠精神运动行为敏化的表达，mPFC微量注射D1受体激动剂可以显著降低精神运动行为敏化的表达，D1受体拮抗剂则增加动物的活动水平。 上述结果提示：（1）成瘾者出现冲动行为和ACC的神经活动异常。前部扣带皮层对冲突任务的认知控制减弱可能是导致海洛因病人冲动行为的基础；（2）海洛因病人的抑郁和焦虑水平高于正常人，病人的mPFC---杏仁核情绪回路功能改变与其异常情绪行为有关；（3）动物研究表明，慢性吗啡使用引起动物的活动水平持续增强，吗啡引起的高活动性与mPFC DA对活动的抑制作用下降有关。这些结果进一步提示海洛因病人mPFC DA及其适应性改变可能是其冲动行为的神经机础。