|Thesis Advisor||隋南 ; 李勇辉|
|Place of Conferral||北京|
|Keyword||食欲素 丘脑室旁核 伏隔核壳部 药物成瘾 反应恢复|
复吸是药物成瘾的核心特征之一，也是治疗药物成瘾的难点所在。应激与成瘾药物再接触是诱发复吸行为的主要环境因素，其诱发复吸是一个复杂的生理心理过程，下丘脑是调节复吸行为的一个重要脑区，但具体作用机制不明确。食欲素(Orexin或hypocretin)是近年新发现的一种下丘脑神经肽，因其参与应激、觉醒、奖赏等多种生理过程而备受关注，并且与中脑边缘多巴胺系统存在广泛的神经联系，并且能调节多巴胺的释放，提示可能参与复吸行为的调节。近几年来研究逐渐发现食欲素参与应激和药物诱发的复吸行为的调节，是目前的研究热点。但具体的脑机制尚不清楚。本研究通过条件性位置偏爱行为(CPP)模型，采用行为药理学的方法来考察伏隔核(Nac)和丘脑室旁核(PVT)内的食欲素两种受体亚型在吗啡与应激诱发复吸过程中的作用。结果如下：(1) PVT注射3ug orexin A能直接诱发大鼠CPP的反应恢复(reinstatement)；而注射OXRl受体拮抗剂SB334867能显著抑制足部电击与吗啡诱发的CPP反应恢复；OXR2受体拮抗剂TCS能显著抑制足部电击诱发的CPP反应恢复，但不影响吗啡诱发的CPP的反应恢复；(2) PVT注射omxin A能显著减少大鼠在旷场中央停留的时间，增加大鼠的修饰和呆滞时间：(3) NAc壳部注射SB334867或者TCS都能显著抑制足部电击诱发和吗啡诱发的CPP反应恢复；但NAc壳部注射orexin A不能诱发大鼠在CPP中对吗啡的复吸，并显著抑制动物的活动性。以上结果表明激活PVT的食欲素受体能够诱发吗啡复吸行为，并且产生应激样行为反应，这一过程主要通过二型受体介导；伏隔核的食欲素受体同时参与吗啡与应激诱发的复吸行为。
|Other Abstract||Relapse is one of the core characteristics of drug addiction, and is also the difficulty for treatment of drug addiction. As a major cause of relapse, stress-induced relapse is an extremely complex physiological and psychological processes. Orexin (or hypocretin) is a recently discovered neurotransmitter system, it participate in stress, arousal, reward and other physiological processes, have attracted much attention. Recent studies have increasingly impruved that orexin involved in many physical processes, such as stress, arousal and reward,especially its role in the process of drug addiction is the focus of research. Studies show that, orexin plays an important role in the process of physiological and psychological stress, and activate the sympathetic nervous system, thus cause a variety of physiological stress response, such as increase gastric acid secretion, heart rate, blood flow and so on, these changes are important symbol of physiological stress responses. Central injection of orexin A can increase the stress related behaviors, such as face washing, grooming, digging, wet dog shakes and other responses, they are the important external behavioral responses to stress.The physiological and biochemical evidence shows that, orexin interact with the other neurotransmitter systems and participate the process metioned above, such as corticotropin-releasing factor, norepinephrine, dopamine, GABA, opioid peptide systems and etc. In 2005, it was first found that orexin are involved in the process of stress-induced relapse, which depends on its location,projection path, and interaction with the other stress-related neurotransmitter systems. This study aimed to investigate orexin neural projection pathway which from the lateral hypothalamus to the NAc shell and the paraventricular nucleus of thalamus, use the conditioned place preference model to study the role of orexin receptors within the NAc shell and PVT in stress and drug-induced reinstatement. The main results are: (1) Microinjection of orexin A into PVT induced reinstatement in morphine conditioned place preference (CPP);|
(2) Microinjection of SB334867 which is the antagonist of OXR1 receptor into PVT inhibited the footshock-induced reinstatement in morphine CPP.And microinjection of TCS which is the antagonist of OXR2 receptor into PVT significantly inhibited the footshock-induced reinstatement in morphine CPP;
(3) Microinjection of orexin A into PVT significantly reduced the time spent in the central area of open field.And microinjection of orexin A into NAc shell did not induce morphine dependent rats reinstatement in CPP. And microinjection of SB334867 into NAc shell can inhibit the footshock-induced reinstatement in morphine CPP,and microinjection of TCS into NAc shell inhibited the footshock-induced reinstatement in morphine CPP. These results suggest that:(1)the orexin receptors within PVT are involved in stress and morphine-induced CPP reinstatement, and activate the receptors induced stress-like behavior;(2) The orexin receptors within NAc shell are involved in morphine and stress-induced reinstatement too; (3) Activate the receptors strongly inhibited the locomotor activity.Therefore,both PVT and NAc shell orexin receptors are involved in stress and drug induced reinstatement, and may be play a important role in stress and relapse.
|魏楚光. 丘脑室旁核与伏隔核壳部食欲素受体在吗啡复吸相关行为中的作用[D]. 北京. 中国科学院研究生院,2010.|
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