VTA-NAc内orexin A在吗啡和性奖赏相关行为中作用的研究

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	VTA-NAc内orexin A在吗啡和性奖赏相关行为中作用的研究
其他题名	The roles of orexin A in the VTA-NAc pathway on drug- and sex-associated behaviors
	白云静
	2008-06-13
摘要	尽管药物奖赏和自然奖赏有共同的神经基础，但二者间亦存在巨大的差异。揭示二者间存在的共同和不同的神经机制将推动药物成瘾研究。在诸种自然奖赏中，性奖赏由于和药物奖赏具有更多的相似性而被经常拿来与毒品相提并论，因此，将性奖赏与药物奖赏进行比较研究既有理论意义又有现实意义。中脑边缘多巴胺系统（VTA-NAc通路）在正常体内介导着奖赏、情绪和动机，是自然强化物以及各种成瘾药物作用的共同通路。成瘾药物反复作用下中枢神经系统包括中脑边缘多巴胺系统发生的适应性变化又是药物渴求长期存在的重要神经基础。食欲素（orexin）作为下丘脑分泌的一种神经肽，在各种奖赏和动机行为中发挥调控作用。而orexin与中脑边缘多巴胺系统之间的纤维联系是其参与奖赏相关行为调节的重要神经基础。因而，为进一步揭示orexin在药物奖赏中的作用，本研究除了初步探讨orexin A是否参与性奖赏外，主要考察了orexin A在中脑边缘多巴胺系统的重要核团（VTA和NAc）内如何调节药物强化（CPP形成）和觅药行为（CPP表达），并与性奖赏进行了比较。主要的实验结果有: （1）侧脑室注射OXR1拮抗剂SB334867可抑制吗啡条件性位置偏爱（CPP）的表达；（2）侧脑室注射SB334867不影响雄鼠非条件性动机的表达，但侧脑室注射orexin A显著抑制高性动机大鼠的非条件性动机，不影响低性动机大鼠的非条件性动机；（3） VTA内注射SB334867显著抑制吗啡CPP形成，而NAcSh内注射SB334867或orexin A都不影响吗啡CPP形成。NAcSh内注射orexin A可增加吗啡处理大鼠的自发活动性；（4） VTA内注射SB334867不影响雄鼠的交配行为，也不影响交配CPP形成；（5） Orexin A神经元激活与交配CPP表达相关，VTA内注射SB334867抑制交配CPP表达。以上结果表明，（1）内源性orexin A不参与雄鼠非条件性动机，而参与觅药动机；（2）Orexin A主要通过VTA而不是NAcSh参与药物强化过程；（3）Orexin A 通过VTA促进觅药行为表达，而在NAcSh内的作用仍不明确；（4）VTA内的orexin A不参与性奖赏的强化过程，与其在药物强化中的作用出现分离。orexin A对觅药行为和性奖赏寻求行为的调控存在行为上的相似性，因为VTA内的orexin A参与性奖赏寻求行为的表达。可能有不同的orexin A神经元亚群参与药物和性奖赏寻求行为。从本研究的结果来看，orexin A是药物成瘾行为调节的重要分子，orexin A在药物奖赏和性奖赏相关行为中的作用存在分离。
其他摘要	There are a lot of differences in the neural mechanisms underlying between drug reward and natural reward despite the common neual basis. Undoubtedly, revealing the common and the different mechanisms underlying drug reward and natural reward will promote the development of research on drug addiction. Among diversified natural rewards, sex is often compared to drug because sexual reward has more similarities to drug. The mesolimbic dopamine system (VTA-NAc pathway) is a common pathway activated by natural reinforcers and addictive drugs, mediating reward, emotion and motivation under physiological conditions. The neuroadaptations taking place in the central nervous system including the mesolimbic dopamine system after repeatedly drug taking leads to persistent drug craving, Orexin, a neuropeptide produced in the lateral hypothalamus, plays an important role in reward-associated, motivated behaviors. Orexin neurons have extensive projections to the mesolimbic dopamine system. In order to further investigate the roles of orexin A in drug reward, this study examined the regulatory roles of orexin A in the VTA and NAcSh on drug reinforcement (acqusition of morphine CPP) and drug-seeking behavior (expression of morphine CPP). Moreover, the roles of orexin A on drug reward were compared with sexual reward. The main results are as follows: 1. The expression of morphine CPP was inhibited by intracerebroventricularly (i.c.v.) administered OX1R antagonist SB334867; 2. The male unconditioned sexual motivation was not affected by i.c.v. administered SB334867. However, i.c.v. given orexin A inhibited unconditioned sexual motivation in sexually high-motivated rats but did not affect sexual motivation in low-motivated rats; 3. The acquisition and expression of morphine CPP was inhibited by SB334867 microinjected into the VTA. SB334867 or orexin A injected into the NAcSh did not influence the acquisition of morphine CPP, but orexin A increased the locomotor activity in rats treated with morphine (3mg/kg); 4. SB334867 microinjected into the VTA did not affect male copulatory behavior, neither affect the acqusition of copulatory CPP; 5. The expression of copulatory CPP was associated with increased Fos protein expression in hypothalamic orexin A neurons, and SB334867 microinjected into the VTA inhibited expression of copulatory CPP. These results suggest that, (1) endogenous orexin A is not involved in male unconditioned sexual motivation, but involved in drug craving; (2) orexin A in the VTA instead of in the NAc is involved in drug reinforcement; (3) orexin A in the VTA is critical for drug-seeking behavior, but it is still unclear for the role of orexin A in the NAcSh; (4) in contrast to drug reinforcement, orexin A in the VTA is not involved in reinforcing effect of sexual reward. Orexin A plays a role both in drug-seeking behavior and in sexual reward-seeking behavior, but the different orexin A neuron populations may be responsible for the roles of orexin A in two types of reward. In a word, the differential roles of orexin A in drug and sexual reward are found in the present study, which provides some evidence for further research on the mechanisms of drug addiction.
关键词	吗啡性奖赏条件性位置偏爱中脑腹侧背盖食欲素
学位类型	博士
语种	中文
学位授予单位	中国科学院心理研究所
学位授予地点	心理研究所
文献类型	学位论文
条目标识符	http://ir.psych.ac.cn/handle/311026/4546
专题	中国科学院心理研究所回溯数据库(1956-2010)
推荐引用方式 GB/T 7714	白云静. VTA-NAc内orexin A在吗啡和性奖赏相关行为中作用的研究[D]. 心理研究所. 中国科学院心理研究所,2008.

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