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伏隔核和背外侧纹状体调控吗啡成瘾形成及觅药行为的多巴胺能机制
其他题名Dopaminergic mechanisms of the nucleus accumbens and dorsolateral caudate-putman in morphine-addiction formation and morphine seeking
高军
学位类型博士
导师隋南
2012-05
学位授予单位中国科学院研究生院
学位授予地点北京
学位专业心理学
关键词伏隔核 背外侧纹状体 多巴胺 为 吗啡 成瘾 觅药行为
摘要研究认为药物成瘾是从目标导向的用药到习惯性的觅药行为转换的过程,而NAc和dlCPu的DA系统分别是调控目标导向和习惯行为的关键。虽然可卡因研究提示两个脑区的DA系统分别参与成瘾形成和觅药,但对其在阿片类成瘾不同阶段中的机制认识不足。故本研究采用自身给药和戒断-复吸模型对NAc和dlCPu参与调控吗啡成瘾形成和线索诱发觅药行为的多巴胺机制进行系统比较。 1)建立吗啡自身给药和戒断-复吸模型模型,考察吗啡的剂量效应及训练时间、食物强化的对该模型建立的影响。结果发现:采用FR1强化程序可建立稳定的大鼠自身给药模型;单次吗啡注射由0.1 -1.0 mg/kg变化时,给药次数逐渐下降但给药总量逐渐增加;单日训练时程延长不能缩短获得稳定自身给药行为的训练天数;食物强化训练可以缩短获得稳定自身给药行为的训练天数;通过建立戒断-复吸模型,发现吗啡渴求存在孵育(incubation)现象; 2)为了比较NAc shell和dlCPu的多巴胺能支配在吗啡成瘾形成和觅药行为中的作用,在自身给药训练或觅药行为检测前进行6-OHDA定位损毁DA能纤维末梢, 结果发现:损毁NAshell(非dlCPu)损害吗啡自身给药行为的获得,而二者损毁均降低吗啡觅药行为; 3)为了比较研究NAc shell和dlCPu多巴胺调控吗啡觅药行为的D1和D2样受体机制,在觅药行为检测前分别向两个核团定位注射SCH23390或Eticlopride(分别为D1和D2样受体拮抗剂),结果发现:阻断NAc shell的D1(非D2)样受体、阻断dlCPu的D1或D2样受体均降低吗啡觅药行为; 4)为了比较戒断不同时程后的觅药行为对NAc core、shell和dlCPu内多巴胺能活动的影响,在戒断1和21天后进行觅药行为伴随的微透析检测,结果表明:戒断21天后的吗啡觅药行为引起dlCPu而非NAc core和shell内DOPAC含量增加,而戒断1天后的觅药行为不改变三脑区的DOPAC及HVA含量。 这些结果说明NAc的多巴胺能支配参与调控吗啡成瘾形成,而多巴胺在NAc(通过D1样受体)和dlCPu(通过D1和D2样受体)都参与调控长期戒断后线索诱发的吗啡觅药行为,有助于深入的理解奖赏和习惯系统在成瘾形成和复吸中的不同机制。
其他摘要Drug addiction is hypothesized as a transition from NAc-DA dependent goal-directed drug-taking to dlCPu-DA dependent habitual drug-seeking. Evidence from cocaine addiction studies suggests DA in NAc and dlCPu regulates addiction formation and cocaine seeking respectively, however, less is known about their roles in opiate-addiction formation and opiate seeking. Accordingly, current study explored roles of NAc and dlCPu in morphine-addiction formation and cue-induced morphine seeking and the underlying dopaminergic mechanisms. 1) We constructed the morphine self-administration model, and explored morphine dose effect, and effects of training time, food reinforcement training on self-administration behaviors. Results showed: we successfully constructed the morphine self-administration model using a FR1 reinforcing procedure; morphine infusions reduced while morphine intake doses increased as long as the injection dosage increased from 0.1 to 1.0 mg/kg; daily long access training did not but food reinforcement training did reduce the number of sessions to get the stable self-administration behavior; the incubation effect of morphine craving was shown in the constructed abstinence-relapse model. 2) To explore the roles of dopaminergic innervation in NAc shell and dlCPu in morphine-addiction formation or morphine seeking, rats were microinjected with 6-OHDA, and results showed that the acquisition of morphine self-administration was inhibited by lesions in NAc shell (not dlCPu), while morphine seeking was attenuated by lesions of either region. 3) To explore the D1- and D2-like receptor mechanisms in NAc shell and dlCPu, D1 antagonist SCH23390, or D2 antagonist eticlopride was locally injected prior to the seeking test, and results showed that morphine seeking was attenuated by D1 (not D2)-like receptor blockade in NAshell, or by blockade of either D1- or D2-like receptors in dlCPu. 4) To explore effects of morphine seeking on dopaminergic activity in NAc core, shell and dlCPu, microdialysis samples were got prior to or during morphine seeking test after abstinence for 1 day or 21 days, and results showed that morphine seeking evoked a significant elevation of DOPAC in dlCPu (not NAc core or shell) after abstinence for 21 days, while DOPAC or HVA in all three regions was not changed during morphine seeking after abstinence for 1 day. These data indicate a critical role of dopaminergic innervation in NAc in acquisition of morphine self-administration, and a critical role of dopaminergic transmission in the NAc (via D1-like receptors) and dlCPu (via D1- and D2-like receptors) in cue-induced morphine seeking after prolonged abstinence. These findings were important for elucidating different mechanisms of rewarding system and habitual system in formation and relapse. Key Words:nucleus accumbens (NAc); dorsolateral caudate-putman (dlCPu); dopamine; morphine; addiction; seeking 
学科领域医学心理学
语种中文
文献类型学位论文
条目标识符http://ir.psych.ac.cn/handle/311026/20264
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
高军. 伏隔核和背外侧纹状体调控吗啡成瘾形成及觅药行为的多巴胺能机制[D]. 北京. 中国科学院研究生院,2012.
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