CCK-8及其受体拮抗剂对吗啡戒断大鼠不同脑区CREB和pCREB的影响
|
摘要
目的:当前,毒品滥用日趋严重,严重地危害着社会进步和经济发展。阿片类(如吗啡、海洛因)是我国吸毒人员使用最多的成瘾物质,其特征是强迫性使用药物,但其成瘾机制尚不完全明确。吗啡成瘾涉及到神经系统多种神经递质、调质及神经肽的改变。胆囊收缩素(cholecystokinin,CCK)是一种存在于体内多个系统的神经肽,在中枢神经系统内有着广泛分布,参与机体多种功能的调控。其中八肽胆囊收缩素(CCK-8)是目前已知的作用最强的内源性抗阿片肽。有研究表明吗啡依赖时在多个脑区发现了CCK-8的上调,CCK-8通过其受体参与了吗啡成瘾过程。
研究表明长期应用阿片类药物可导致多个脑区神经元的一系列适应性和可塑性变化,如尾壳核(caudate putamen,CPu)、伏隔核(nucleus accumbens,NAc)、杏仁核(amygdaloid nucleus,Amy)、腹侧被盖区(ventral tegmental area,VTA)、黒质(substantia nigra,SN)、导水管周围灰质(periaoueductal gray matter,PAG)、蓝斑(locus caeruleus, LC)等。吗啡的长期使用使特定脑区和核团的某些蛋白和基因表达的改变,如阿片受体、G蛋白、第二信使合成酶、蛋白激酶及转录因子等。转录因子cAMP反应元件结合蛋白(cAMP response element binding protein, CREB)在吗啡成瘾过程中至关重要。
本研究在以剂量递增法建立吗啡依赖及戒断模型的基础上,采用腹腔和侧脑室局部注射的方式,观察CCK-8及其受体拮抗剂对吗啡戒断症状及多个脑区内CREB和pCREB的变化,以探讨CCK-8参与吗啡依赖和戒断的受体后机制。
方法:研究采用成年雄性Wistar大鼠(由河北医科大学实验动物中心提供),体重200-220g,以吗啡剂量递增法(10、20、30、40、50mg·kg-1)皮下注射吗啡5天,每日2次(8:00, 20:00),第6天给予吗啡后两小时腹腔注射纳洛酮5mg·kg-1急性催促戒断,建立吗啡依赖及戒断模型。应用免疫组织化学方法观察与吗啡成瘾相关的多个脑区内CREB和pCREB的变化。
研究采用腹腔注射及侧脑室注射两种给药途径,在每日给予吗啡前30min注射CCK-8(50μg·kg-1, i.p.; 0.1μg/rat,i.c.v)、CCK1受体拮抗剂L-364,718(1mg·kg-1, i.p.; 1μg/rat,i.c.v)、CCK2受体拮抗剂LY-288,513 (1mg·kg-1, i.p.;1μg/rat,i.c.v)进行干预,末次注射吗啡后2小时给予纳洛酮(5mg·kg-1)催促戒断,按照戒断症状评分表评价CCK-8及其受体拮抗剂对吗啡依赖大鼠戒断症状的影响,用免疫组化检测各脑区在依赖和戒断后CREB和pCREB的变化。
结果:1 CCK-8及其受体拮抗剂对吗啡依赖形成及戒断症状的影响在成功建立吗啡依赖及催促戒断模型基础上,腹腔和侧脑室给予CCK-8及L-364,718、LY-288,415,均不同程度的抑制了吗啡依赖的形成,戒断症状明显减轻。
2 CCK-8及其受体拮抗剂对吗啡戒断大鼠尾壳核、伏隔核、杏仁核、黒质、腹侧被盖区、导水管周围灰质和蓝斑CREB和pCREB的影响
应用免疫组织化学方法观察了CCK-8及CCK受体拮抗剂对各组大鼠尾壳核、伏隔核、杏仁核、黒质、腹侧被盖区、导水管周围灰质和蓝斑内CREB和pCREB的影响。结果发现:在伏核内CREB和pCREB的趋势一致,即依赖组明显升高(P<0.01),戒断后进一步升高,与依赖组相比有显著差异(P<0.01),腹腔及侧脑室注射CCK-8、L-364,718、LY-288,513均使伏核内CREB和pCREB下降,与戒断组相比有显著差异(P<0.01);在隔核内,CREB和pCREB在依赖组明显升高(P<0.01),CREB在戒断后,进一步升高,与依赖组相比有显著差异(P<0.01),而pCREB在戒断组与依赖组相比无显著差异(P>0.05),腹腔注射L-364,718、LY-288,513,侧脑室注射CCK-8、L-364,718、LY-288,513均使隔核内CREB和pCREB下降,与戒断组相比有显著性差异(P<0.01),但是腹腔注射CCK-8对CREB和pCREB无明显影响,与戒断组相比无显著差异(P>0.05);在尾壳核CREB和pCREB的趋势一致,即依赖后明显升高(P<0.01),戒断后进一步升高,与依赖组相比具有显著差异(P<0.01),腹腔及侧脑室注射CCK-8、L-364,718、LY-288,513均使尾壳核内CREB和pCREB水平下降,与戒断组相比具有显著差异(P<0.01);在杏仁核内,CREB在依赖组相对于盐水组无明显差异(P>0.05),pCREB在依赖组明显升高,与盐水组相比具有显著差异(P<0.01),戒断后CREB和pCREB均明显升高,与依赖组相比具有显著差异(P<0.01),仅腹腔及侧脑室注射LY-288,513使CREB下降,与戒断组相比具有显著差异(P<0.01),其余干预对CREB无影响,与戒断组相比无显著差异(P>0.05),腹腔注射L-364,718、LY-288,513和侧脑室注射CCK-8、L-364,718、LY-288,513均使pCREB下降,与戒断组相比具有显著差异(P<0.01),但是腹腔注射CCK-8对pCREB无影响,与戒断组相比无显著差异(P>0.05);在腹侧被盖区内,CREB在各组之间无明显差异(P>0.05),pCREB在依赖组明显升高(P<0.01),戒断组相对于依赖组无明显变化(P>0.05),腹腔及侧脑室注射CCK-8、L-364,718、LY-288,513对pCREB无明显影响,与戒断组相比无明显差异(P>0.05);在黒质内,CREB在各组之间无明显差异(P>0.05),pCREB在依赖组明显升高(P<0.01),戒断组相对于依赖组无明显差异(P>0.05),仅侧脑室注射CCK-8使黒质内pCREB的下降,与戒断组相比有显著差异(P<0.01),其余干预均对pCREB无明显影响,与戒断组相比无显著差异(P>0.05);在中脑导水管周围灰质内,CREB在各组之间无明显差异(P>0.05),pCREB在依赖后明显升高(P<0.01),戒断后pCREB明显下降,与依赖组相比具有显著差异(P<0.01),腹腔及侧脑室注射CCK-8、L-364,718、LY-288,513均使中脑导水管周围灰质内pCREB水平升高,与戒断组相比具有显著差异(P<0.01);在蓝斑内,CREB在各组之间无显著差异(P>0.05),pCREB在依赖后明显升高,与盐水组相比具有显著差异(P<0.01),戒断后进一步升高,与依赖组相比具有显著差异(P<0.01),腹腔及侧脑室注射L-364,718、LY-288,513均使蓝斑内pCREB的水平下降,与戒断组相比具有显著差异(P<0.01),但是腹腔及侧脑室注射CCK-8对pCREB水平无明显影响,与戒断组相比无显著差异(P>0.05)。
结论:本研究证实尾壳核、伏隔核、杏仁核、黒质、腹侧被盖区、导水管周围灰质和蓝斑参与了吗啡依赖和戒断过程,CCK-8及其受体拮抗剂均可减轻吗啡依赖大鼠的戒断症状,并通过不同方式调节上述脑区CREB发挥作用。
Objective: For the moment, drug abuse become more and more severe which restrict social and economic development. Opioid(such as morphine and heroin) is the most commonly abused drug in our country, characterized by compulsive drug use, but the mechanism is not indentified yet. Morphine addiction involve many kinds of neurotransmitters, neuro-modulators and neuropeptide. Cholecystokinin (CCK) is a neuropeptide found in varieties systems, which has a borad distribution in the central system and takes part in regulation of mang physiological functions. Study reported that CCK-8 is the most potent endogenous anti-opioid peptides and there is a CCK-8 up-regulation in muti-brain region with morphine dependence, therefore CCK-8 participates in the morphine dependence by combining with its receptors.
Long-term application of opium results in neural adaptive and plasticity change in many diffirent brain regions, such as caudate putamen, nucleus accumbens, amygdaloid nucleus, ventral tegmental area, substantia nigra, periaou- eductal gray matter, locus caeruleus and so on. Morphine addiction involves temporary protein and long-term gene expression changes in these regions, such as opioid receptor, G-protein, second messenger synthetase, protein kinase, transcription factor. CREB, as a nuclear factor, plays a important role in this process.
In our study, morphine dependent and withdrawal models were established by subcutaneous injection of morphine in gradually increased dose. CCK-8 and its recepter antagoists were injected by i.p and i.c.v to observe their effect on morphine withdrawal. Then, immunohistochemical method was used to measure the change of CREB and pCREB in the brain region concerned to explore the cellular signal transduction mechanism of CCK on morphine dependent and withdrawal.
Method: Adult male Wistar rats were used(200-220g) which were provided by Experimental Animal Center of Hebei Province.The morphine dependent model was established by subcutaneous injectiong of morphine. The daily dose gradually increased as following: 10, 20, 30, 40, 50mg·kg-1 twice a day, at 8:00 and 20:00, for 5 days. On the 6th day, 50mg·kg-1 morphine was given at 8:00, withdrawal syndrome was precipitated by intraperitoneal injection of naloxone 5 mg·kg-1 two hours later.
Two ways, i.p and i.c.v, were used in our research to observe the effect of CCK on morphine withdrawal syndrome, CCK-8(50μg·kg-1, i.p.; 0.1μg/rat, i.c.v), L-364,718(1mg·kg-1, i.p.; 1μg/rat, i.c.v), LY-288,513(1mg·kg-1, i.p.; 1μg/rat,i.c.v) were given 30min before morphine injection every day. At the last day, naloxone was used two hours after morphine given. Then, the morphine withdrawal syndrome was observed and estimated by Gellert-Holtzman scale. The change of CREB and pCREB were measured by immunohistochemical method in the related brain regions
Result:
1 CCK-8 and its antagosists on morphine dependent and morphine withdrawal syndrome. Morphine dependent and withdrawal models were successfully established. After chronic treatment with CCK-8 and its receptor antagosists by i.p or i.v.c, development of morphine dependence was inhibited and morphine withdrawal syndrome was alleviated.
2 Effect of CCk-8 and its receptor antagosists on CREB and pCREB in caudate putamen, nucleus accumbens, amygdaloid nucleus, ventral tegmental area, substantia nigra, periaoueductal gray matterand locus caeruleus of morphine withdrawal rats.
The change of CREB and pCREB were measured in caudate putamen, nucleus accumbens,amygdaloid nucleus, ventral tegmental area, substantia nigra,periaoueductal gray matter,and locus caeruleus to observe the effect of CCK-8 and its receptor antagosists on morphine dependent and withdrawal by immunohistochemical method.
The results showed that in the AcbSH there was a similar tendency of CREB and pCREB. Chornic morphine treatment increased CREB and pCREB expression(P<0.01) and they further increased after naloxone precipitation(P<0.01). CCK-8(i.p.;i.c.v), L-364,718(i.p.; i.c.v), LY-288,513(i.p.; i.c.v)could decrease their expression(P<0.01). In the LSI, chornic morphine treatment incressed CREB and pCREB (P<0.01). Naloxone treatment increased CREB (P<0.01) but had no effect on pCREB (P>0.05). CCK-8 (i.c.v), L-364,718(i.p.; i.c.v), LY-288,513(i.p.;i.c.v)treatment decreased the CREB and pCREB expression(P<0.01), but CCK-8 (i.p.) had no effect (P>0.05). In the CPu , there was a similar tendency of CREB and pCREB. Chornic morphine treatment increased CREB and pCREB expression(P<0.01) and they further increased after naloxone precipitation(P<0.01). CCK-8(i.p.;i.c.v), L-364,718 (i.p.; i.c.v), LY-288,513(i.p.; i.c.v)could decrease their expression(P<0.01). In amygdaloid nucleus, chornic morphine treatment increased pCREB(P<0.01)but had no effect on CREB. Naloxone treatment increased CREB and pCREB(P<0.01). LY-288,513(i.p.; i.c.v)decreased CREB expression(P<0.01), but CCK-8 (i.p.; i.c.v),L-364,718(i.p.; i.c.v)had no effect on CREB(P>0.05). CCK-8 (i.c.v),L-364,718(i.p.;i.c.v),LY-288,513(i.p. ;i.c.v)decreased pCREB(P<0.01), but CCK-8 (i.p.)had no effect on pCREB(P>0.05).In the VTA, there was no distinct difference of CREB among each group.Chornic morphine treatment increased pCREB(P<0.01). Naloxone treatment had no effect on pCREB (P>0.05). CCK-8 (i.p; i.c.v), L-364,718(i.p.;i.c.v), LY-288,513(i.p.;i.c.v) had no effect on pCREB (P>0.05).In the substantia nigra, there was no obvious difference of CREB among each group. Chornic morphine treatment increased pCREB (P<0.01).Naloxone treatment has no effect on pCREB(P>0.05).CCK-8 (i.c.v)decreased pCREB (P<0.01), but CCK-8 (i.p.),L-364,718(i.p.;i.c.v), LY-288,513(i.p.;i.c.v)had no effect on pCREB (P>0.05). In PAG, there was no distinct difference of CREB among each group. Chornic morphine treatment increased pCREB (P<0.01). Naloxone treatment decreased pCREB (P < 0.01), CCK-8 (i.p.;i.c.v ) , L-364,718(i.p.;i.c.v), LY-288,513(i.p.;i.c.v)increased pCREB(P<0.01).In LC, there was no obvious difference of CREB among each group. Chornic morphine treatment increased pCREB ( P < 0.01 ) .Naloxone treatment increased pCREB (P<0.01), L-364,718(i.p.;i.c.v), LY-288,513(i.p.;i.c.v)decreased pCREB (P<0.01), but CCK-8 (i.p. ;i.c.v)had no effect on pCREB.
Conclusion:Our findings suggested that caudate putamen, nucleus accumbens, amygdaloid nucleus, ventral tegmental area, substantia nigra, periaoueductal gray matter and locus caeruleus were involved in the morphine dependent and withdrawal process. CCK-8、L-364,718、LY-288,513 could alleviate morphine withdrawal syndrome through regulating CREB and/or pCREB expression in different brain regions.
研究表明长期应用阿片类药物可导致多个脑区神经元的一系列适应性和可塑性变化,如尾壳核(caudate putamen,CPu)、伏隔核(nucleus accumbens,NAc)、杏仁核(amygdaloid nucleus,Amy)、腹侧被盖区(ventral tegmental area,VTA)、黒质(substantia nigra,SN)、导水管周围灰质(periaoueductal gray matter,PAG)、蓝斑(locus caeruleus, LC)等。吗啡的长期使用使特定脑区和核团的某些蛋白和基因表达的改变,如阿片受体、G蛋白、第二信使合成酶、蛋白激酶及转录因子等。转录因子cAMP反应元件结合蛋白(cAMP response element binding protein, CREB)在吗啡成瘾过程中至关重要。
本研究在以剂量递增法建立吗啡依赖及戒断模型的基础上,采用腹腔和侧脑室局部注射的方式,观察CCK-8及其受体拮抗剂对吗啡戒断症状及多个脑区内CREB和pCREB的变化,以探讨CCK-8参与吗啡依赖和戒断的受体后机制。
方法:研究采用成年雄性Wistar大鼠(由河北医科大学实验动物中心提供),体重200-220g,以吗啡剂量递增法(10、20、30、40、50mg·kg-1)皮下注射吗啡5天,每日2次(8:00, 20:00),第6天给予吗啡后两小时腹腔注射纳洛酮5mg·kg-1急性催促戒断,建立吗啡依赖及戒断模型。应用免疫组织化学方法观察与吗啡成瘾相关的多个脑区内CREB和pCREB的变化。
研究采用腹腔注射及侧脑室注射两种给药途径,在每日给予吗啡前30min注射CCK-8(50μg·kg-1, i.p.; 0.1μg/rat,i.c.v)、CCK1受体拮抗剂L-364,718(1mg·kg-1, i.p.; 1μg/rat,i.c.v)、CCK2受体拮抗剂LY-288,513 (1mg·kg-1, i.p.;1μg/rat,i.c.v)进行干预,末次注射吗啡后2小时给予纳洛酮(5mg·kg-1)催促戒断,按照戒断症状评分表评价CCK-8及其受体拮抗剂对吗啡依赖大鼠戒断症状的影响,用免疫组化检测各脑区在依赖和戒断后CREB和pCREB的变化。
结果:1 CCK-8及其受体拮抗剂对吗啡依赖形成及戒断症状的影响在成功建立吗啡依赖及催促戒断模型基础上,腹腔和侧脑室给予CCK-8及L-364,718、LY-288,415,均不同程度的抑制了吗啡依赖的形成,戒断症状明显减轻。
2 CCK-8及其受体拮抗剂对吗啡戒断大鼠尾壳核、伏隔核、杏仁核、黒质、腹侧被盖区、导水管周围灰质和蓝斑CREB和pCREB的影响
应用免疫组织化学方法观察了CCK-8及CCK受体拮抗剂对各组大鼠尾壳核、伏隔核、杏仁核、黒质、腹侧被盖区、导水管周围灰质和蓝斑内CREB和pCREB的影响。结果发现:在伏核内CREB和pCREB的趋势一致,即依赖组明显升高(P<0.01),戒断后进一步升高,与依赖组相比有显著差异(P<0.01),腹腔及侧脑室注射CCK-8、L-364,718、LY-288,513均使伏核内CREB和pCREB下降,与戒断组相比有显著差异(P<0.01);在隔核内,CREB和pCREB在依赖组明显升高(P<0.01),CREB在戒断后,进一步升高,与依赖组相比有显著差异(P<0.01),而pCREB在戒断组与依赖组相比无显著差异(P>0.05),腹腔注射L-364,718、LY-288,513,侧脑室注射CCK-8、L-364,718、LY-288,513均使隔核内CREB和pCREB下降,与戒断组相比有显著性差异(P<0.01),但是腹腔注射CCK-8对CREB和pCREB无明显影响,与戒断组相比无显著差异(P>0.05);在尾壳核CREB和pCREB的趋势一致,即依赖后明显升高(P<0.01),戒断后进一步升高,与依赖组相比具有显著差异(P<0.01),腹腔及侧脑室注射CCK-8、L-364,718、LY-288,513均使尾壳核内CREB和pCREB水平下降,与戒断组相比具有显著差异(P<0.01);在杏仁核内,CREB在依赖组相对于盐水组无明显差异(P>0.05),pCREB在依赖组明显升高,与盐水组相比具有显著差异(P<0.01),戒断后CREB和pCREB均明显升高,与依赖组相比具有显著差异(P<0.01),仅腹腔及侧脑室注射LY-288,513使CREB下降,与戒断组相比具有显著差异(P<0.01),其余干预对CREB无影响,与戒断组相比无显著差异(P>0.05),腹腔注射L-364,718、LY-288,513和侧脑室注射CCK-8、L-364,718、LY-288,513均使pCREB下降,与戒断组相比具有显著差异(P<0.01),但是腹腔注射CCK-8对pCREB无影响,与戒断组相比无显著差异(P>0.05);在腹侧被盖区内,CREB在各组之间无明显差异(P>0.05),pCREB在依赖组明显升高(P<0.01),戒断组相对于依赖组无明显变化(P>0.05),腹腔及侧脑室注射CCK-8、L-364,718、LY-288,513对pCREB无明显影响,与戒断组相比无明显差异(P>0.05);在黒质内,CREB在各组之间无明显差异(P>0.05),pCREB在依赖组明显升高(P<0.01),戒断组相对于依赖组无明显差异(P>0.05),仅侧脑室注射CCK-8使黒质内pCREB的下降,与戒断组相比有显著差异(P<0.01),其余干预均对pCREB无明显影响,与戒断组相比无显著差异(P>0.05);在中脑导水管周围灰质内,CREB在各组之间无明显差异(P>0.05),pCREB在依赖后明显升高(P<0.01),戒断后pCREB明显下降,与依赖组相比具有显著差异(P<0.01),腹腔及侧脑室注射CCK-8、L-364,718、LY-288,513均使中脑导水管周围灰质内pCREB水平升高,与戒断组相比具有显著差异(P<0.01);在蓝斑内,CREB在各组之间无显著差异(P>0.05),pCREB在依赖后明显升高,与盐水组相比具有显著差异(P<0.01),戒断后进一步升高,与依赖组相比具有显著差异(P<0.01),腹腔及侧脑室注射L-364,718、LY-288,513均使蓝斑内pCREB的水平下降,与戒断组相比具有显著差异(P<0.01),但是腹腔及侧脑室注射CCK-8对pCREB水平无明显影响,与戒断组相比无显著差异(P>0.05)。
结论:本研究证实尾壳核、伏隔核、杏仁核、黒质、腹侧被盖区、导水管周围灰质和蓝斑参与了吗啡依赖和戒断过程,CCK-8及其受体拮抗剂均可减轻吗啡依赖大鼠的戒断症状,并通过不同方式调节上述脑区CREB发挥作用。
Objective: For the moment, drug abuse become more and more severe which restrict social and economic development. Opioid(such as morphine and heroin) is the most commonly abused drug in our country, characterized by compulsive drug use, but the mechanism is not indentified yet. Morphine addiction involve many kinds of neurotransmitters, neuro-modulators and neuropeptide. Cholecystokinin (CCK) is a neuropeptide found in varieties systems, which has a borad distribution in the central system and takes part in regulation of mang physiological functions. Study reported that CCK-8 is the most potent endogenous anti-opioid peptides and there is a CCK-8 up-regulation in muti-brain region with morphine dependence, therefore CCK-8 participates in the morphine dependence by combining with its receptors.
Long-term application of opium results in neural adaptive and plasticity change in many diffirent brain regions, such as caudate putamen, nucleus accumbens, amygdaloid nucleus, ventral tegmental area, substantia nigra, periaou- eductal gray matter, locus caeruleus and so on. Morphine addiction involves temporary protein and long-term gene expression changes in these regions, such as opioid receptor, G-protein, second messenger synthetase, protein kinase, transcription factor. CREB, as a nuclear factor, plays a important role in this process.
In our study, morphine dependent and withdrawal models were established by subcutaneous injection of morphine in gradually increased dose. CCK-8 and its recepter antagoists were injected by i.p and i.c.v to observe their effect on morphine withdrawal. Then, immunohistochemical method was used to measure the change of CREB and pCREB in the brain region concerned to explore the cellular signal transduction mechanism of CCK on morphine dependent and withdrawal.
Method: Adult male Wistar rats were used(200-220g) which were provided by Experimental Animal Center of Hebei Province.The morphine dependent model was established by subcutaneous injectiong of morphine. The daily dose gradually increased as following: 10, 20, 30, 40, 50mg·kg-1 twice a day, at 8:00 and 20:00, for 5 days. On the 6th day, 50mg·kg-1 morphine was given at 8:00, withdrawal syndrome was precipitated by intraperitoneal injection of naloxone 5 mg·kg-1 two hours later.
Two ways, i.p and i.c.v, were used in our research to observe the effect of CCK on morphine withdrawal syndrome, CCK-8(50μg·kg-1, i.p.; 0.1μg/rat, i.c.v), L-364,718(1mg·kg-1, i.p.; 1μg/rat, i.c.v), LY-288,513(1mg·kg-1, i.p.; 1μg/rat,i.c.v) were given 30min before morphine injection every day. At the last day, naloxone was used two hours after morphine given. Then, the morphine withdrawal syndrome was observed and estimated by Gellert-Holtzman scale. The change of CREB and pCREB were measured by immunohistochemical method in the related brain regions
Result:
1 CCK-8 and its antagosists on morphine dependent and morphine withdrawal syndrome. Morphine dependent and withdrawal models were successfully established. After chronic treatment with CCK-8 and its receptor antagosists by i.p or i.v.c, development of morphine dependence was inhibited and morphine withdrawal syndrome was alleviated.
2 Effect of CCk-8 and its receptor antagosists on CREB and pCREB in caudate putamen, nucleus accumbens, amygdaloid nucleus, ventral tegmental area, substantia nigra, periaoueductal gray matterand locus caeruleus of morphine withdrawal rats.
The change of CREB and pCREB were measured in caudate putamen, nucleus accumbens,amygdaloid nucleus, ventral tegmental area, substantia nigra,periaoueductal gray matter,and locus caeruleus to observe the effect of CCK-8 and its receptor antagosists on morphine dependent and withdrawal by immunohistochemical method.
The results showed that in the AcbSH there was a similar tendency of CREB and pCREB. Chornic morphine treatment increased CREB and pCREB expression(P<0.01) and they further increased after naloxone precipitation(P<0.01). CCK-8(i.p.;i.c.v), L-364,718(i.p.; i.c.v), LY-288,513(i.p.; i.c.v)could decrease their expression(P<0.01). In the LSI, chornic morphine treatment incressed CREB and pCREB (P<0.01). Naloxone treatment increased CREB (P<0.01) but had no effect on pCREB (P>0.05). CCK-8 (i.c.v), L-364,718(i.p.; i.c.v), LY-288,513(i.p.;i.c.v)treatment decreased the CREB and pCREB expression(P<0.01), but CCK-8 (i.p.) had no effect (P>0.05). In the CPu , there was a similar tendency of CREB and pCREB. Chornic morphine treatment increased CREB and pCREB expression(P<0.01) and they further increased after naloxone precipitation(P<0.01). CCK-8(i.p.;i.c.v), L-364,718 (i.p.; i.c.v), LY-288,513(i.p.; i.c.v)could decrease their expression(P<0.01). In amygdaloid nucleus, chornic morphine treatment increased pCREB(P<0.01)but had no effect on CREB. Naloxone treatment increased CREB and pCREB(P<0.01). LY-288,513(i.p.; i.c.v)decreased CREB expression(P<0.01), but CCK-8 (i.p.; i.c.v),L-364,718(i.p.; i.c.v)had no effect on CREB(P>0.05). CCK-8 (i.c.v),L-364,718(i.p.;i.c.v),LY-288,513(i.p. ;i.c.v)decreased pCREB(P<0.01), but CCK-8 (i.p.)had no effect on pCREB(P>0.05).In the VTA, there was no distinct difference of CREB among each group.Chornic morphine treatment increased pCREB(P<0.01). Naloxone treatment had no effect on pCREB (P>0.05). CCK-8 (i.p; i.c.v), L-364,718(i.p.;i.c.v), LY-288,513(i.p.;i.c.v) had no effect on pCREB (P>0.05).In the substantia nigra, there was no obvious difference of CREB among each group. Chornic morphine treatment increased pCREB (P<0.01).Naloxone treatment has no effect on pCREB(P>0.05).CCK-8 (i.c.v)decreased pCREB (P<0.01), but CCK-8 (i.p.),L-364,718(i.p.;i.c.v), LY-288,513(i.p.;i.c.v)had no effect on pCREB (P>0.05). In PAG, there was no distinct difference of CREB among each group. Chornic morphine treatment increased pCREB (P<0.01). Naloxone treatment decreased pCREB (P < 0.01), CCK-8 (i.p.;i.c.v ) , L-364,718(i.p.;i.c.v), LY-288,513(i.p.;i.c.v)increased pCREB(P<0.01).In LC, there was no obvious difference of CREB among each group. Chornic morphine treatment increased pCREB ( P < 0.01 ) .Naloxone treatment increased pCREB (P<0.01), L-364,718(i.p.;i.c.v), LY-288,513(i.p.;i.c.v)decreased pCREB (P<0.01), but CCK-8 (i.p. ;i.c.v)had no effect on pCREB.
Conclusion:Our findings suggested that caudate putamen, nucleus accumbens, amygdaloid nucleus, ventral tegmental area, substantia nigra, periaoueductal gray matter and locus caeruleus were involved in the morphine dependent and withdrawal process. CCK-8、L-364,718、LY-288,513 could alleviate morphine withdrawal syndrome through regulating CREB and/or pCREB expression in different brain regions.
引文
1 Koob GF. Drugs of abuse: anatomy, pharmacology and function of reward pathways. TIPS 2000, 9(1): 5-8
2 George F, Koob GF. Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology, 2001, 24(2): 97 -129
3 Garzon J, de Antonio I, Sanchez Blazquez P. In vivo modulation of G proteins and opioid receptor function by antisense oligodeoxynucleotides. Methods Enzymol, 2006, 314(1): 3
4 Leite-Morris KA, Fukudome EY, Kaplan GB. Opiate-induced motor stimulations regulated by gamma-aminobutyric acid type B receptors found in the ventral tegmental area in mice. Neurosci lett , 2002, 317(3): 119 -122
5 Miller AD, Forster GL , Yeomans JS , et al . Midbrain muscarinic receptors modulate morphine induced accumbal and striatal dopamine efflux in the rat. Neuroscience , 2005 ,136 (2):531-538.
6 De Rover M , Lodder JC , Schoffelmeer AN , et al . Intermittentmorphine treatment induces a long lasting increase in cholinergicmodulation of GABAergic synapses in nucleus accumbens of adultrats. Synapse , 2005 , 55 (1):17-25.
7 Qun LIU, Gan CAI. Content of somatostatin and cholecystokinin-8 in hypothalamus and colons in a rat. model of spleen-deficiency syndrome. Journal of Chinese Integrative Medicine. 2007, 5 (5): 555-558
8 Pellegrino LJ. Pellegrino M, Lundeberg T.Exogenous cholecystokinin-8 reduces vagal efferent nerve activity in rats through CCK(A) recepters. Pharmacol, 2000, 129:1649-1654
9 Agnes R S,Lee Y S,Davis P, et al.Structure activity relationships of bifunctional peptides based on overlapping pharmacophores at opioid and cholecystokinin receptors. J Med Chem , 2006, 49(10):2868-2875
10赵丽,丛斌,吴嫒嫒,等.吗啡对原代培养大鼠海马神经元CCK受体mRNA表达的影响.中国药理学通报, 2006, 22(4):479-483.
11 Blandine P, Franc B, Axelle S, et al. Deletion of CCK2 recep tor in mice results in an up regulation of the endogenous opioid system. Neurosci, 2002, 22 (5): 2005 -2011.
12 Hansen TVO. Cholecystokinin gene transcription: promoter elements transcription factors and signaling pathways. Peptides, 2001,22(3):1201 -1211.
13 Zhao L, Cong B,Wu Y Y, et al. Effect of expression of cholecystokinin receptor mRNA in primary culturing hippocampus neurons ofnewborn rat induced by morphine .China Pharmacol Bull, 2006,22 (4):479-483.
14 Mitchell J M,Bergren L J, Chen K S, et al. Cholecystokininis necessary for the expression of morphine conditioned place preference. Pharmacol Biochem Behav, 2006, 85 (4):787 - 95.
15 Oob GF, Le Moal M. Drug addiction, dysregulation of reward, and allostasis. Neuro-psychopharmacology, 2001, 24(2): 97-129
16 ValverdeO, MantamadiotisT, TorrecillaM, et al. Modula-Tionofanxiety like behavior and morphine dependece in CREB deficientmice. Ne- uro-psychopharmacology, 2005; 29 (6): 1122-1133
17王育红,甄利波,刘义军.电针对海洛因引燃诱导大鼠觅药行为及相关脑区FosB表达的影响.中南大学学报(医学版).2003 ,12 (2): 299-304
18 Yoburn BC, Purohit V, et al.Opioid agonist and antagonist treatment differentially regulates immune-oreactiveμ-opioid receptors and dynamin-2 in vivo. European Journal of Pharmacology, 2005, 498 (1-3): 87-96
19 Agnes RS, Lee YS, Davis P, et al. Structure-activity relationships of bifunctional peptides based on overlapping pharmacophores at opioid and cholecystokinin receptors. Journal of Medical Chemistry, 2006, 49(10): 2868-2875
20 Florence Noble,Stephen A.Wank, Jacqueline N, et al. Opioid and CCK systems in anxiety and reward.In: Cholecystokinin and anxiety: From neuron to behavior. Pharmacological Reviews, 1999, 51(4):745-781
21谷建平,丛斌,朱桂云,等.褪黑素对吗啡戒断大鼠脑内cAMP和cGMP含量的影响.中国药物依赖性杂志, 2005,14 (1):24-26
22 Zhang Y, Su J, XuM Y. Role of droperidol in modulation of dopamine on central painful sense in morphinistic rat. Chin Pharmacol Bull, 2007, 23 (5):594-597
23谭北平,李勇辉,隋南.药物依赖过程中多巴胺受体的作用及其研究进展.中国药物依赖性杂志,2003 ,12 (2): 81-85
24 Kelley AE, Berridge KC. The neuroscience of natural rewards: relevance to addictive drugs. Neurosci, 2002, 22(9):3306-3311
25 Berke JD, Hyman SE. Addiction, dopamine, and the molecular mechanisms of memory. Neuron, 2000, 25(3):515 -532
26 Cole C.J, Josselyn S.A. Transcription Regulation of Memory: CREB, CaMKIV, Fos/Jun, CBP, and SRF. Learning and Memory: A Comprehensive Reference. 2008,4(4): 547-566
27 Hawes JJ, Narasimhaiah R, Picciotto MR. Galanin attenuates cyclic AMP regulatory element-binding protein (CREB) phosphorylation induced by chronic morphine and naloxone challenge in Cath.a cells and primary striatal cultures. Neurochem, 2006, 96(4):1160-1168
28洪仕君,李俊麟,李利华等.吗啡依赖鼠成瘾相关脑区腺苷酸环化酶的变化.中国法医学杂志. 2006,22(4):254-257
29 Carlezon Jr WA, Duman RS, Nestler EJ. The many faces of CREB. Trends Neurosci, 2005, 28(8):436-445
30 Mouravlev A, Dunning J, Young D, et al. Somatic genetransfer of cAMP response element-binding proteinattenuates memory impairment in aging rats. Proc NatlAcad Sci USA, 2006, 103(12):4705-4710
31 Josselyn SA, Kida S, Silva AJ. Inducible repression of CREB function disrupts amygdala-dependent memory.Neurobiol Learn Mem, 2004, 82(2): 159-163
32 McClung CA, Nestler EJ. Neuroplasticity mediated byaltered gene expression. Neuropsychopharmacology, 2008,33(1):3-17
33杨春晓,杨宝峰,张辉等. CCK-8对吗啡成瘾大鼠戒断症状及尾核内c-jun蛋白表达的影响.中国药理学通报, 2008, 24 (9):1166-1170
34 Noble F, Wank A, Crawley J.N, et al. International Union of Pharmacology XXI Structure, distribution, and functions of cholecystokinin receptors. Pharmacol Rev. 1999,51(4):745-778
35 Mitchell J.M,Bergren L.J, Chen K.S, et al. Cholecystokinin is necessary for the expression of morphine conditioned placepreference.Pharmacology Biochemistry and Behavior. 2006,85(4): 787-795
1 Cami J, Farre M. Drug addiction. N Engl J Med, 2003,349(10):9759-986
2朱海燕,沈模卫,张锋等.药物成瘾过程的心理-神经理论模型.心理科学, 2004, 27 (3) : 449-452
3许艳,徐满英.阿片成瘾戒断机制及治疗的研究现状.哈尔滨医科大学学报. 2005, 39(2):198-201
4许望超.脑奖赏系统研究进展.广州医药, 2008,39 (2):1-2
5 Koob GF. Drug of abuse: anatomy, pharmacology and function of reward pathways. TIPS, 1992, 13:177-184
6陈晗晖,郝伟,赵敏.物质成瘾中重要神经核团的作用. Chinese Journal of Drug Abuse Prevention and Treatment, 2006 , 12(6):338-340
7 Margolis EB, Lock H, Hjelmstad GO, et al.The ventraltegmental area revisited: is there an electrophysiologicalmarker for dopaminergic neurons? Physiology, 2006, 577 (11):907-924
8 Vezina P, McGehee DS, Green WN. Exposure to nicotine and sensitization of nicotine-induced behaviors. Prog Neuropsychopharmacol Biol Psychiatry, 2007, 31 (8):1625-1638
9魏强,魏倩,许丹丹等.多巴胺受体与药物成瘾的研究进展.中国药物滥用防治杂志,2008 , 14 (6):329-332
10 Leite-Morris KA, Fukudome EY, Kaplan GB. Opiate-induced motor stimulations regulated by gamma-aminobutyric acid type B receptors found in the ventral tegmental area in mice. Neuroscilett , 2002 ,317 (3) : 119-122
11 Andrea LO, Hebb, Jean-Franc? et al.Cholecystokinin and endogenous opioid peptides: Interactive influence on pain, cognition and emotion. Progress in Neuro-Psychopharmacology and Biological, Psychiatry, 2005; 29(8): 1225-1238
12 Georges F ,Aston Jones G. Potent regulation of midbrain dopamine neurons by the bed nucleus of the stria terminalis. Neuroscience ,2001, 21 (160):1-6
13 Qin Z, Nyberg F. Injection of substance P(sp) N-terminal fragment SP intothe ventral tegmental area modulates the levels of nucleus accumbens dopamine and dihydroxypheny lacetic acid in male rats during morphine withdrawal. Neuroscilett, 2002, 320(3):117-120
14顾钧,杨国栋.中脑多巴胺神经系统与成瘾的研究进展.中国药物滥用防治杂志, 2004,10 (2):101-103
15 Rodd ZA, Gryszowka VE, Toalston JE, et al.The reinforcing actions of a serotonin-3 receptor agonist within the ventral tegmental area: evidence for subregional and genetic differences and involvement of dopamine neurons.Pharmacol Exp Ther, 2007, 321 (3):1003-1012
16 Liu HF, ZhouWH, Zhu HQ,et al. Microinjection of M5 muscarinic receptor antisense oligonucleotide into VTA inhibits FosB expression in the NAc and the hippocampus of heroin sensitized rats. Neurosci Bull, 2007, 23 (1): 1-8
17刘惠芬,朱华强,陈为升等.腹侧被盖区注射M5受体反义寡脱氧核苷酸对大鼠海洛因敏化的抑制作用.中国药理学与毒理学杂, 2009,Feb;23 (1):11-16
18周文华,张富强,杨国栋.复吸的神经网络、神经元适应和复吸模型.中国药物依赖性杂志, 2001, 10(1):6-8
19司京玉,陈志宏,陈瑛等.吗啡依赖大鼠腹侧被盖区多巴胺神经元的形态学改变.中国药物依赖性杂志, 2003 ,12 (3) :180-183
20 Li Jun Heng, Guo Dong Gao. The function of nucleus accumbens in drug addiction.Neuroscience Bulletin, 2005 ,21(2):165-169
21邵云,魏孝琴,薛一雪.毁损伏隔核对吗啡给药大鼠条件性位置偏爱与脑功能的影响.中国医科大学学报. 2006 ,35(2):155-157
22 Albertson DN, Pruetz B, Schmidt CJ, et al.Al1Gene expression profile of the nucleus accumbens of human cocaine abusers: evidence for dysregulation of myelin. Neurochem, 2005, 88 (5): 1211-1219
23李楠,王学廉,高国栋等.毁损双侧伏隔核对大鼠吗啡条件性位置偏爱复燃的影响.中国神经精神疾病杂志, 2007, 33(6): 361-362
24崔鹏,王桂松,徐纪文等.吗啡成瘾对大鼠伏隔核神经元自发放电的影响.立体定向和功能性神经外科杂志, 2009 , 22 (2): 121-129
25 Huda A, Meng F, Devine DF,et al. Molecular and neuroanatomical properties of endogenous opiate system: implications for treatment of opiate addiction. Seminars in Neuroscience ,1997,(3-4):70-83
26 Weiss F.Neurobiology of craving, conditioned reward and relapse. Current Opinion in Pharmacology, 2005, 5 (1):9-19
27 Hyman SE, Malenka RC, Nestler EJ. Neural mechanisms of addiction: the role of reward-related learningand memory. Annu Rev Neurosci, 2005, 29:565-598
28 Zarrindast MR, Farahmandfar M, Rostam IP, et al. Theinfluence of central adm inistration of dopaminergic andcholinergic agents on morphin induced amnesia in mo rph ine sensitized mice. Psychopharmacol, 2006, 20 (1):59-66
29 Zarrindast MR, Khalilzadeh A, Rezayat SM. Influence of intrace- rebroventricular administration of h istam inergic drugs on morphine state-dependent memory in the stepdown passive avoidance test. Psychopharmacology, 2005,74 (2):106-112
30 Williams,JT, Christie,MJ, Manzoni,0, Cellular nadsynpatie adpat- ations,mediatingo-PioiddPeendence.Physiol.Rev. 2001, 81(1), 299-343
31赵永娜,方正梅,邵晓霞等.大鼠相关脑区p-CREB和c-Fos在吗啡点燃条件性位置偏爱条件下的变化.中国临床药理学与治疗学, 2009,14 (1):10-13
32邝满元,邓鹏程,徐松.吗啡成瘾戒断对大鼠海马CA1区P-CREB表达的影响.解剖学研究, 2009,31 (1), 110-113
33 Nader K, Majidishad P, Amorapanth P, et al. Damage to the lateral and central, but not other, amygdaloid nuclei prevents the acquisition of auditory fear conditioning. Learn Mem, 2001, 8(3):156-163.
34李毅,郝伟.杏仁核复合体与药物依赖.中国药物依赖性杂志. 2005,14 (2):81-84
35 Panagis G, Hildebrand BE, Svensson TH, et al. Selective c-fos induction and decreased dopamine release in the central nucleus of amygdala in rats displaying a mecamylamine-precipitated nicotine withdrawal syndrome.Synapse, 2000, (35):15-25
36 Ciccocioppo R, Sanna PP,Weiss F. Cocaine-predictive stimulus induces drug-seeking behavior and neural activeation in limbic brain regions after multiple months of abstinence : reversal by D1 antagonists. Proc Natl Acad Sci USA, 2001, 98(4):1976-1981
37 Murphy CA, Russig H,Pezze MA, et al. Amphetamine withdrawal modu- lates FosB expression in mesolimbic dopaminergic target nuclei:effects of different schedules of administration. Neuropharmacology, 2005, 44 (7): 926-939
38 Franken, IH. Drug-craving and addiction: integrating-psychologicall and neuro-psychopharmacological approaches. Prog-Neuropsychopharmacol Biol-Psychiatry, 2003, 27(4):563-579
39 Vanderschuren LJ, Di Ciano P, Everitt BJ. Involvement of the dorsal striatum in cue-controlled cocaine seeking. Neuroscic,2005,25(38):8665- 8670
40鲍云非,郑希耕,隋南.纹状体在药物成瘾有关的联想性学习中的作用.生理科学进展,2006, 37(2):165-168
41 Deisseorht K, Heist EK, Tsine RW. Tnarsloeation of ealmodullntoh- tenucleus supports CREB PhosPhoyrlation in hippocampal neurons, Nature, 1998,392 (6672):198-202
42 Meyer PJ, Fossum EN, Ingram SL, et al. Analgesic tolerance to microinjection of the micro-opioid agonist DAMGO into the ventrolateral periaqueductal gray. Neuropharmacology, 2007, 52 (8):1580-1585
43 Pavlovic ZW, Cooper ML, Bodnar RJ. Opioid antagonists in the periaqueductal gray inhibit morphine and beta–endorphin analgesia elicited from the amygdala of rats . Brain Res, 1996, 741 (1-2):13-26
2 George F, Koob GF. Drug addiction, dysregulation of reward, and allostasis. Neuropsychopharmacology, 2001, 24(2): 97 -129
3 Garzon J, de Antonio I, Sanchez Blazquez P. In vivo modulation of G proteins and opioid receptor function by antisense oligodeoxynucleotides. Methods Enzymol, 2006, 314(1): 3
4 Leite-Morris KA, Fukudome EY, Kaplan GB. Opiate-induced motor stimulations regulated by gamma-aminobutyric acid type B receptors found in the ventral tegmental area in mice. Neurosci lett , 2002, 317(3): 119 -122
5 Miller AD, Forster GL , Yeomans JS , et al . Midbrain muscarinic receptors modulate morphine induced accumbal and striatal dopamine efflux in the rat. Neuroscience , 2005 ,136 (2):531-538.
6 De Rover M , Lodder JC , Schoffelmeer AN , et al . Intermittentmorphine treatment induces a long lasting increase in cholinergicmodulation of GABAergic synapses in nucleus accumbens of adultrats. Synapse , 2005 , 55 (1):17-25.
7 Qun LIU, Gan CAI. Content of somatostatin and cholecystokinin-8 in hypothalamus and colons in a rat. model of spleen-deficiency syndrome. Journal of Chinese Integrative Medicine. 2007, 5 (5): 555-558
8 Pellegrino LJ. Pellegrino M, Lundeberg T.Exogenous cholecystokinin-8 reduces vagal efferent nerve activity in rats through CCK(A) recepters. Pharmacol, 2000, 129:1649-1654
9 Agnes R S,Lee Y S,Davis P, et al.Structure activity relationships of bifunctional peptides based on overlapping pharmacophores at opioid and cholecystokinin receptors. J Med Chem , 2006, 49(10):2868-2875
10赵丽,丛斌,吴嫒嫒,等.吗啡对原代培养大鼠海马神经元CCK受体mRNA表达的影响.中国药理学通报, 2006, 22(4):479-483.
11 Blandine P, Franc B, Axelle S, et al. Deletion of CCK2 recep tor in mice results in an up regulation of the endogenous opioid system. Neurosci, 2002, 22 (5): 2005 -2011.
12 Hansen TVO. Cholecystokinin gene transcription: promoter elements transcription factors and signaling pathways. Peptides, 2001,22(3):1201 -1211.
13 Zhao L, Cong B,Wu Y Y, et al. Effect of expression of cholecystokinin receptor mRNA in primary culturing hippocampus neurons ofnewborn rat induced by morphine .China Pharmacol Bull, 2006,22 (4):479-483.
14 Mitchell J M,Bergren L J, Chen K S, et al. Cholecystokininis necessary for the expression of morphine conditioned place preference. Pharmacol Biochem Behav, 2006, 85 (4):787 - 95.
15 Oob GF, Le Moal M. Drug addiction, dysregulation of reward, and allostasis. Neuro-psychopharmacology, 2001, 24(2): 97-129
16 ValverdeO, MantamadiotisT, TorrecillaM, et al. Modula-Tionofanxiety like behavior and morphine dependece in CREB deficientmice. Ne- uro-psychopharmacology, 2005; 29 (6): 1122-1133
17王育红,甄利波,刘义军.电针对海洛因引燃诱导大鼠觅药行为及相关脑区FosB表达的影响.中南大学学报(医学版).2003 ,12 (2): 299-304
18 Yoburn BC, Purohit V, et al.Opioid agonist and antagonist treatment differentially regulates immune-oreactiveμ-opioid receptors and dynamin-2 in vivo. European Journal of Pharmacology, 2005, 498 (1-3): 87-96
19 Agnes RS, Lee YS, Davis P, et al. Structure-activity relationships of bifunctional peptides based on overlapping pharmacophores at opioid and cholecystokinin receptors. Journal of Medical Chemistry, 2006, 49(10): 2868-2875
20 Florence Noble,Stephen A.Wank, Jacqueline N, et al. Opioid and CCK systems in anxiety and reward.In: Cholecystokinin and anxiety: From neuron to behavior. Pharmacological Reviews, 1999, 51(4):745-781
21谷建平,丛斌,朱桂云,等.褪黑素对吗啡戒断大鼠脑内cAMP和cGMP含量的影响.中国药物依赖性杂志, 2005,14 (1):24-26
22 Zhang Y, Su J, XuM Y. Role of droperidol in modulation of dopamine on central painful sense in morphinistic rat. Chin Pharmacol Bull, 2007, 23 (5):594-597
23谭北平,李勇辉,隋南.药物依赖过程中多巴胺受体的作用及其研究进展.中国药物依赖性杂志,2003 ,12 (2): 81-85
24 Kelley AE, Berridge KC. The neuroscience of natural rewards: relevance to addictive drugs. Neurosci, 2002, 22(9):3306-3311
25 Berke JD, Hyman SE. Addiction, dopamine, and the molecular mechanisms of memory. Neuron, 2000, 25(3):515 -532
26 Cole C.J, Josselyn S.A. Transcription Regulation of Memory: CREB, CaMKIV, Fos/Jun, CBP, and SRF. Learning and Memory: A Comprehensive Reference. 2008,4(4): 547-566
27 Hawes JJ, Narasimhaiah R, Picciotto MR. Galanin attenuates cyclic AMP regulatory element-binding protein (CREB) phosphorylation induced by chronic morphine and naloxone challenge in Cath.a cells and primary striatal cultures. Neurochem, 2006, 96(4):1160-1168
28洪仕君,李俊麟,李利华等.吗啡依赖鼠成瘾相关脑区腺苷酸环化酶的变化.中国法医学杂志. 2006,22(4):254-257
29 Carlezon Jr WA, Duman RS, Nestler EJ. The many faces of CREB. Trends Neurosci, 2005, 28(8):436-445
30 Mouravlev A, Dunning J, Young D, et al. Somatic genetransfer of cAMP response element-binding proteinattenuates memory impairment in aging rats. Proc NatlAcad Sci USA, 2006, 103(12):4705-4710
31 Josselyn SA, Kida S, Silva AJ. Inducible repression of CREB function disrupts amygdala-dependent memory.Neurobiol Learn Mem, 2004, 82(2): 159-163
32 McClung CA, Nestler EJ. Neuroplasticity mediated byaltered gene expression. Neuropsychopharmacology, 2008,33(1):3-17
33杨春晓,杨宝峰,张辉等. CCK-8对吗啡成瘾大鼠戒断症状及尾核内c-jun蛋白表达的影响.中国药理学通报, 2008, 24 (9):1166-1170
34 Noble F, Wank A, Crawley J.N, et al. International Union of Pharmacology XXI Structure, distribution, and functions of cholecystokinin receptors. Pharmacol Rev. 1999,51(4):745-778
35 Mitchell J.M,Bergren L.J, Chen K.S, et al. Cholecystokinin is necessary for the expression of morphine conditioned placepreference.Pharmacology Biochemistry and Behavior. 2006,85(4): 787-795
1 Cami J, Farre M. Drug addiction. N Engl J Med, 2003,349(10):9759-986
2朱海燕,沈模卫,张锋等.药物成瘾过程的心理-神经理论模型.心理科学, 2004, 27 (3) : 449-452
3许艳,徐满英.阿片成瘾戒断机制及治疗的研究现状.哈尔滨医科大学学报. 2005, 39(2):198-201
4许望超.脑奖赏系统研究进展.广州医药, 2008,39 (2):1-2
5 Koob GF. Drug of abuse: anatomy, pharmacology and function of reward pathways. TIPS, 1992, 13:177-184
6陈晗晖,郝伟,赵敏.物质成瘾中重要神经核团的作用. Chinese Journal of Drug Abuse Prevention and Treatment, 2006 , 12(6):338-340
7 Margolis EB, Lock H, Hjelmstad GO, et al.The ventraltegmental area revisited: is there an electrophysiologicalmarker for dopaminergic neurons? Physiology, 2006, 577 (11):907-924
8 Vezina P, McGehee DS, Green WN. Exposure to nicotine and sensitization of nicotine-induced behaviors. Prog Neuropsychopharmacol Biol Psychiatry, 2007, 31 (8):1625-1638
9魏强,魏倩,许丹丹等.多巴胺受体与药物成瘾的研究进展.中国药物滥用防治杂志,2008 , 14 (6):329-332
10 Leite-Morris KA, Fukudome EY, Kaplan GB. Opiate-induced motor stimulations regulated by gamma-aminobutyric acid type B receptors found in the ventral tegmental area in mice. Neuroscilett , 2002 ,317 (3) : 119-122
11 Andrea LO, Hebb, Jean-Franc? et al.Cholecystokinin and endogenous opioid peptides: Interactive influence on pain, cognition and emotion. Progress in Neuro-Psychopharmacology and Biological, Psychiatry, 2005; 29(8): 1225-1238
12 Georges F ,Aston Jones G. Potent regulation of midbrain dopamine neurons by the bed nucleus of the stria terminalis. Neuroscience ,2001, 21 (160):1-6
13 Qin Z, Nyberg F. Injection of substance P(sp) N-terminal fragment SP intothe ventral tegmental area modulates the levels of nucleus accumbens dopamine and dihydroxypheny lacetic acid in male rats during morphine withdrawal. Neuroscilett, 2002, 320(3):117-120
14顾钧,杨国栋.中脑多巴胺神经系统与成瘾的研究进展.中国药物滥用防治杂志, 2004,10 (2):101-103
15 Rodd ZA, Gryszowka VE, Toalston JE, et al.The reinforcing actions of a serotonin-3 receptor agonist within the ventral tegmental area: evidence for subregional and genetic differences and involvement of dopamine neurons.Pharmacol Exp Ther, 2007, 321 (3):1003-1012
16 Liu HF, ZhouWH, Zhu HQ,et al. Microinjection of M5 muscarinic receptor antisense oligonucleotide into VTA inhibits FosB expression in the NAc and the hippocampus of heroin sensitized rats. Neurosci Bull, 2007, 23 (1): 1-8
17刘惠芬,朱华强,陈为升等.腹侧被盖区注射M5受体反义寡脱氧核苷酸对大鼠海洛因敏化的抑制作用.中国药理学与毒理学杂, 2009,Feb;23 (1):11-16
18周文华,张富强,杨国栋.复吸的神经网络、神经元适应和复吸模型.中国药物依赖性杂志, 2001, 10(1):6-8
19司京玉,陈志宏,陈瑛等.吗啡依赖大鼠腹侧被盖区多巴胺神经元的形态学改变.中国药物依赖性杂志, 2003 ,12 (3) :180-183
20 Li Jun Heng, Guo Dong Gao. The function of nucleus accumbens in drug addiction.Neuroscience Bulletin, 2005 ,21(2):165-169
21邵云,魏孝琴,薛一雪.毁损伏隔核对吗啡给药大鼠条件性位置偏爱与脑功能的影响.中国医科大学学报. 2006 ,35(2):155-157
22 Albertson DN, Pruetz B, Schmidt CJ, et al.Al1Gene expression profile of the nucleus accumbens of human cocaine abusers: evidence for dysregulation of myelin. Neurochem, 2005, 88 (5): 1211-1219
23李楠,王学廉,高国栋等.毁损双侧伏隔核对大鼠吗啡条件性位置偏爱复燃的影响.中国神经精神疾病杂志, 2007, 33(6): 361-362
24崔鹏,王桂松,徐纪文等.吗啡成瘾对大鼠伏隔核神经元自发放电的影响.立体定向和功能性神经外科杂志, 2009 , 22 (2): 121-129
25 Huda A, Meng F, Devine DF,et al. Molecular and neuroanatomical properties of endogenous opiate system: implications for treatment of opiate addiction. Seminars in Neuroscience ,1997,(3-4):70-83
26 Weiss F.Neurobiology of craving, conditioned reward and relapse. Current Opinion in Pharmacology, 2005, 5 (1):9-19
27 Hyman SE, Malenka RC, Nestler EJ. Neural mechanisms of addiction: the role of reward-related learningand memory. Annu Rev Neurosci, 2005, 29:565-598
28 Zarrindast MR, Farahmandfar M, Rostam IP, et al. Theinfluence of central adm inistration of dopaminergic andcholinergic agents on morphin induced amnesia in mo rph ine sensitized mice. Psychopharmacol, 2006, 20 (1):59-66
29 Zarrindast MR, Khalilzadeh A, Rezayat SM. Influence of intrace- rebroventricular administration of h istam inergic drugs on morphine state-dependent memory in the stepdown passive avoidance test. Psychopharmacology, 2005,74 (2):106-112
30 Williams,JT, Christie,MJ, Manzoni,0, Cellular nadsynpatie adpat- ations,mediatingo-PioiddPeendence.Physiol.Rev. 2001, 81(1), 299-343
31赵永娜,方正梅,邵晓霞等.大鼠相关脑区p-CREB和c-Fos在吗啡点燃条件性位置偏爱条件下的变化.中国临床药理学与治疗学, 2009,14 (1):10-13
32邝满元,邓鹏程,徐松.吗啡成瘾戒断对大鼠海马CA1区P-CREB表达的影响.解剖学研究, 2009,31 (1), 110-113
33 Nader K, Majidishad P, Amorapanth P, et al. Damage to the lateral and central, but not other, amygdaloid nuclei prevents the acquisition of auditory fear conditioning. Learn Mem, 2001, 8(3):156-163.
34李毅,郝伟.杏仁核复合体与药物依赖.中国药物依赖性杂志. 2005,14 (2):81-84
35 Panagis G, Hildebrand BE, Svensson TH, et al. Selective c-fos induction and decreased dopamine release in the central nucleus of amygdala in rats displaying a mecamylamine-precipitated nicotine withdrawal syndrome.Synapse, 2000, (35):15-25
36 Ciccocioppo R, Sanna PP,Weiss F. Cocaine-predictive stimulus induces drug-seeking behavior and neural activeation in limbic brain regions after multiple months of abstinence : reversal by D1 antagonists. Proc Natl Acad Sci USA, 2001, 98(4):1976-1981
37 Murphy CA, Russig H,Pezze MA, et al. Amphetamine withdrawal modu- lates FosB expression in mesolimbic dopaminergic target nuclei:effects of different schedules of administration. Neuropharmacology, 2005, 44 (7): 926-939
38 Franken, IH. Drug-craving and addiction: integrating-psychologicall and neuro-psychopharmacological approaches. Prog-Neuropsychopharmacol Biol-Psychiatry, 2003, 27(4):563-579
39 Vanderschuren LJ, Di Ciano P, Everitt BJ. Involvement of the dorsal striatum in cue-controlled cocaine seeking. Neuroscic,2005,25(38):8665- 8670
40鲍云非,郑希耕,隋南.纹状体在药物成瘾有关的联想性学习中的作用.生理科学进展,2006, 37(2):165-168
41 Deisseorht K, Heist EK, Tsine RW. Tnarsloeation of ealmodullntoh- tenucleus supports CREB PhosPhoyrlation in hippocampal neurons, Nature, 1998,392 (6672):198-202
42 Meyer PJ, Fossum EN, Ingram SL, et al. Analgesic tolerance to microinjection of the micro-opioid agonist DAMGO into the ventrolateral periaqueductal gray. Neuropharmacology, 2007, 52 (8):1580-1585
43 Pavlovic ZW, Cooper ML, Bodnar RJ. Opioid antagonists in the periaqueductal gray inhibit morphine and beta–endorphin analgesia elicited from the amygdala of rats . Brain Res, 1996, 741 (1-2):13-26