中脑腹侧背盖区κ-阿片受体系统对吗啡依赖的调控作用
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摘要
阿片依赖是严重的医学和社会问题。神经生物学和药理学的研究均表明,阿片类物质依赖与中脑皮层边缘系统直接相关。吗啡等阿片类物质进入体内后,可以与GABA能神经元上的μ-阿片受体结合,使位于腹侧背盖区(ventral tegmentalarea,VTA)的多巴胺(dopamine,DA)能神经元因去抑制而激活,从而引起DA能神经元的投射靶区伏隔核(nucleus accumbens,NAc)、内侧前额叶皮层(medialprefrontal cortex,mPFC)中DA释放增加。这是阿片类物质产生欣快效应进而诱导成瘾的起始事件。除了引起欣快效应外,阿片类物质还激活一系列转录因子如CREB,Fos家族的表达。Fos家族蛋白,尤其是ΔFosB被认为与依赖性药物引起的敏化效应相关,是启动和维持药物依赖状态的分子开关。
κ-阿片受体及其内源性的配体强啡肽(Dynorphin,Dyn)在中枢神经系统有广泛的分布。κ-阿片受体与μ-阿片受体介导的生物效应通常相互对抗:μ-激动剂激活DA能神经元,使DA释放增加,而κ-激动剂则抑制DA能神经传递;μ-激动剂用药后产生欣快,具有奖赏、强化效应,而κ-激动剂则介导烦躁、厌恶的情绪,没有奖赏、强化效应。这些结果提示,κ-阿片受体与μ-阿片受体就像古代哲学中的“阴”和“阳”一样,共同参与情绪、动机相关的精神神经活动的调节,维持机体阿片系统功能的内稳态。
大量的研究表明,κ-阿片受体系统可以调控吗啡的药物依赖。选择性的κ-受体激动剂U-50488系统给药可以逆转吗啡诱导的条件性位置偏爱,阻断吗啡诱导的行为敏化,抑制吗啡自身给药行为,而且U-50488的这些作用可为选择性的κ-受体拮抗剂nor-BNI所阻断。而另一方面,在κ-阿片受体基因敲除的动物,依赖性药物引起的DA释放显著增加。κ-受体系统对DA能神经传递的调节可能是κ-激动剂对抗吗啡依赖的作用机制。
中脑皮层边缘系统是与药物依赖密切相关的脑内结构。在该系统中,DA能神经元占据相对主导的地位,也是该系统参与药物依赖的主要功能性物质基础。其中,VTA是DA能神经元胞体密集的核团,由它发出的神经纤维可以投射到NAc和mPFC,分别形成DA能神经元的中脑边缘通路和中脑皮层通路。近年来的一些研究对于VTA是否存在κ-阿片受体、VTA中的κ-受体系统是否参与了吗啡依赖、κ-激动剂能否直接抑制该区内的DA能神经元以及其抑制作用的机制等问题尚存争议。本研究即拟从多个方面对上述问题进行探讨。
我们首先应用实时定量PCR技术以及蛋白免疫印迹实验方法,考察了吗啡急慢性给药对中脑皮层边缘系统的三个重要脑区VTA、NAc、mPFC中κ-阿片受体mRNA和蛋白水平的影响。实验结果表明,吗啡急性给药可使上述三个脑区中的κ-阿片受体mRNA水平显著升高,但蛋白水平没有显著性改变。而吗啡慢性给药后,NAc和VTA中κ-阿片受体mRNA水平回复正常,而mPFC中mRNA含量维持高水平;慢性给药还使mPFC和VTA中的κ-受体蛋白显著下降,但对NAc中的蛋白水平没有显著影响。这些结果提示中脑皮层边缘系统内的κ-阿片受体可能参与了药物依赖的过程。而VTA、NAc、mPFC中κ-阿片受体表达改变的区域差异性说明κ-受体在这些脑区的合成和降解受到不同方式的调节,提示这些脑区在调控药物依赖中可能处于不同的地位。
前人和我们的实验结果均表明VTA中的κ-受体可能参与了吗啡依赖的过程,同时VTA微注射κ-激动剂在正常动物可引起显著的行为改变,于是我们推测VTA微注射κ-激动剂U-50488有可能影响吗啡诱导的精神依赖。我们在两个动物行为模型上对此进行考察。在大鼠条件性位置偏爱实验中,VTA微注射U-50488,至少在所用剂量下并不产生显著的条件性位置厌恶(或偏爱),但却可以显著抑制吗啡所致的条件性位置偏爱;在大鼠行为敏化实验中,VTA微注射U-50488在并不影响动物自发活动的剂量下可显著抑制吗啡所致的行为敏化。这些结果表明,VTA微注射U-50488可以抑制吗啡诱导的精神依赖。
在进一步的实验中,我们对VTA微注射κ-激动剂影响吗啡依赖的机制进行了初步探讨。采用脑组织匀浆的实验方法,我们检测了mPFC和NAc中单胺类神经递质及其代谢产物浓度的改变。实验结果表明,吗啡急性给药使mPFC和NAc中DA转化率升高,表明这两个脑区中DA能神经传递加强。而VTA微注射U-50488可显著抑制吗啡引起的DA转化率的升高。在吗啡慢性给药情况下,各处理组间虽无显著性差异,但也表现出类似趋势。在清醒动物脑微透析实验中,VTA微注射U-50488还可显著抑制吗啡引起的NAc细胞外液中DA和5-HT代谢产物的升高。免疫组化实验的结果表明,形成行为敏化的大鼠,NAc(包括核部和壳部)和mPFC中的FosB阳性细胞显著增加,而VTA微注射U-50488显著抑制吗啡引起的变化。以上结果提示,VTA微注射U-50488影响吗啡依赖的机制可能包括抑制DA能神经传递,抑制转录因子FosB的表达。VTA微注射U-50488对投射靶区NAc和mPFC均可产生显著影响,提示VTA中κ-阿片受体的作用可能并无VTA-NAc或VTA-mPFC投射通路的选择性。
通过以上研究我们发现,吗啡急慢性给药可引起中脑皮层边缘系统中κ-阿片受体表达的改变,提示该系统中的κ-阿片受体可能参与了对吗啡依赖的调节。在中脑皮层边缘系统的核心区域VTA给予κ-激动剂可以抑制吗啡诱导的精神依赖,其作用可能与其对单胺类神经递质以及FosB基因表达的调节有关。而且VTA给予κ-激动剂可同时影响靶区NAc和mPFC,提示VTA中κ-阿片受体的作用并无投射通路的选择性。本研究对全面理解κ-受体对中脑DA能神经传递的调控作用以及κ-受体系统与药物依赖的关系有一定意义。
Opioid dependence remains a serious medical and social issue.Neurobiological and pharmacological studies have revealed that there is a direct correlation between the mesocorticolimbic system and opioid dependence.Opioids,such as morphine, disinhibit the dopaminergic neurons by activating theμ-opioid receptor on the GABAergic interneurons in ventral tegmental area(VTA).The subsequent DA efflux in the dopaminergic projecting targets(such as nucleus accumbens,medial prefrontal cortex) is believed to be initial events that trigger reward and dependence.In addition, exposure to opioids results in activation of some transcription factors,such as CREB and Fos family.ΔFosB,a truncated splice variant of full-length FosB,is considered to be a molecular switch of addiction.
Kappa-opioid receptor,as well as its endogenous ligand dynorphin,hss a wide distribution in central nervous system.Activation of theκ-receptor antagonizes variousμ-receptor-mediated actions in the brain.κ-agonists inhibit the DA neurons and DA release,whileμ-agonists activate the dopaminergic neurotransmission.μ-agonists produce euphoria and function as positive reinforcers.In contrast,κ-agonists produce dysphoria and function as negative reinforcers.Taking together,μ-andκ-receptor act as an opposing pair in opioid signaling in the brain.
Evidence is increasing to indicate that activation ofκ-opioid receptor suppress the morphine dependence.U-50488,a selectiveκ-agonist,abolishes the reinforcing effects of morphine in both self-administration and conditioned place preference paradigms.Without any effect by its self,selective-antagonist nor-BNI blocks the inhibitory effects of U-50488 on the morphine dependence.On the other hand,DA release stimulated by addictive drugs is exacerbated inκ-receptor knockout mice.The dual modulations of the midbrain dopaminergic system byμ- andκ-receptors may underlie the mechanism through whichκ-agonist inhibits the morphine dependence.
It has long been recognized that drug dependence processing relies heavily on mesocorticolimbic DA systems,comprising DA neurons in VTA and their projections to NAc,mPFC and other forebrain regions.Recently,major efforts have attempted to specify what functionκ-receptor contribute in VTA.Doesκ-receptor exist in VTA? Doesκ-receptor in VTA exert an inhibitory effect of DA neurotransmission? Does intra-VTA administration ofκ-agonist inhibit morphine dependence and what is the mechanism? We are now trying to explore these issues.
Using the real-time quantitative PCR and western blot tequniques,we measure theκ-receptor mRNA and protein levels in mPFC,NAc and VTA.Acute exposure to morphine increases the mRNA levels in all three regions,but have no significant effects on protein levels.After chronic exposure to morphine,whereasκ-receptor mRNA returns to basal level in NAc and VTA,the relatively modest induction in mPFC persists.Moreover,κ-receptor protein levels decrease in mPFC and VTA,but remain unchanged in NAc.These results suggest the involvement of mesocorticolimbicκ-receptors in the development of morphine dependence.
Given the findings metioned above,we speculate that intra-VTA administration ofκ-agonist might influence the morphine dependence.Thus,the effects of U-50488 following VTA microinjetion on the morphine dependence were evaluated in behavior models of conditioned place preference and locomotor sensitization.Intra-VTA administraion of U-50488,at the doses we tested,did not produce significant effects on place conditioning and locomotor activity in naive rats.However,the morphine-induced place preference and locomotor sensitization were attenuated in U-50488-treated rats,suggesting a VTAκ-receptor-mediated mechanism in the modulation of morphine depedence.
In further studies,we explored the neurochemical and neurobiological mechanisms through whichκ-agonist inhibit the morphine dependence.We found that acute exposure to morphine elevated the DA turnover in NAc and mPFC extracts. These elevations were significantly suppressed in extracts obtained from the rats treated with U-50488.A similar tendency was observed in animals received chronic drug administration,although there were no significant changes in DA turnover.In microdialysis study,U-50488,following microinjection into VTA,also attenuated the morphine-induced elevation of DA metabolite(HVA) and 5-HT metabolite(5-HIAA). In addition,the number of FosB-positive neurons significantly increased in mPFC and NAc during the development of locomotor sensitization.U-50488,following microinjection into VTA,reduced the number of FosB-positive neurons significantly, indicating that the inhibitory effects of intra-VTA U-50488 on morphine dependence might be related to its modulatory effects on expression of the transcription factor FosB.
In conclusion,κ-opioid receptor in VTA was found to be involved in the morphine dependence.Activation of theκ-opioid receptor in VTA exhibits inhibitory effects on morphine-induce place preference and locomotor sensitization.The mechanism is related to its modulation on DA release and FosB expression.
κ-阿片受体及其内源性的配体强啡肽(Dynorphin,Dyn)在中枢神经系统有广泛的分布。κ-阿片受体与μ-阿片受体介导的生物效应通常相互对抗:μ-激动剂激活DA能神经元,使DA释放增加,而κ-激动剂则抑制DA能神经传递;μ-激动剂用药后产生欣快,具有奖赏、强化效应,而κ-激动剂则介导烦躁、厌恶的情绪,没有奖赏、强化效应。这些结果提示,κ-阿片受体与μ-阿片受体就像古代哲学中的“阴”和“阳”一样,共同参与情绪、动机相关的精神神经活动的调节,维持机体阿片系统功能的内稳态。
大量的研究表明,κ-阿片受体系统可以调控吗啡的药物依赖。选择性的κ-受体激动剂U-50488系统给药可以逆转吗啡诱导的条件性位置偏爱,阻断吗啡诱导的行为敏化,抑制吗啡自身给药行为,而且U-50488的这些作用可为选择性的κ-受体拮抗剂nor-BNI所阻断。而另一方面,在κ-阿片受体基因敲除的动物,依赖性药物引起的DA释放显著增加。κ-受体系统对DA能神经传递的调节可能是κ-激动剂对抗吗啡依赖的作用机制。
中脑皮层边缘系统是与药物依赖密切相关的脑内结构。在该系统中,DA能神经元占据相对主导的地位,也是该系统参与药物依赖的主要功能性物质基础。其中,VTA是DA能神经元胞体密集的核团,由它发出的神经纤维可以投射到NAc和mPFC,分别形成DA能神经元的中脑边缘通路和中脑皮层通路。近年来的一些研究对于VTA是否存在κ-阿片受体、VTA中的κ-受体系统是否参与了吗啡依赖、κ-激动剂能否直接抑制该区内的DA能神经元以及其抑制作用的机制等问题尚存争议。本研究即拟从多个方面对上述问题进行探讨。
我们首先应用实时定量PCR技术以及蛋白免疫印迹实验方法,考察了吗啡急慢性给药对中脑皮层边缘系统的三个重要脑区VTA、NAc、mPFC中κ-阿片受体mRNA和蛋白水平的影响。实验结果表明,吗啡急性给药可使上述三个脑区中的κ-阿片受体mRNA水平显著升高,但蛋白水平没有显著性改变。而吗啡慢性给药后,NAc和VTA中κ-阿片受体mRNA水平回复正常,而mPFC中mRNA含量维持高水平;慢性给药还使mPFC和VTA中的κ-受体蛋白显著下降,但对NAc中的蛋白水平没有显著影响。这些结果提示中脑皮层边缘系统内的κ-阿片受体可能参与了药物依赖的过程。而VTA、NAc、mPFC中κ-阿片受体表达改变的区域差异性说明κ-受体在这些脑区的合成和降解受到不同方式的调节,提示这些脑区在调控药物依赖中可能处于不同的地位。
前人和我们的实验结果均表明VTA中的κ-受体可能参与了吗啡依赖的过程,同时VTA微注射κ-激动剂在正常动物可引起显著的行为改变,于是我们推测VTA微注射κ-激动剂U-50488有可能影响吗啡诱导的精神依赖。我们在两个动物行为模型上对此进行考察。在大鼠条件性位置偏爱实验中,VTA微注射U-50488,至少在所用剂量下并不产生显著的条件性位置厌恶(或偏爱),但却可以显著抑制吗啡所致的条件性位置偏爱;在大鼠行为敏化实验中,VTA微注射U-50488在并不影响动物自发活动的剂量下可显著抑制吗啡所致的行为敏化。这些结果表明,VTA微注射U-50488可以抑制吗啡诱导的精神依赖。
在进一步的实验中,我们对VTA微注射κ-激动剂影响吗啡依赖的机制进行了初步探讨。采用脑组织匀浆的实验方法,我们检测了mPFC和NAc中单胺类神经递质及其代谢产物浓度的改变。实验结果表明,吗啡急性给药使mPFC和NAc中DA转化率升高,表明这两个脑区中DA能神经传递加强。而VTA微注射U-50488可显著抑制吗啡引起的DA转化率的升高。在吗啡慢性给药情况下,各处理组间虽无显著性差异,但也表现出类似趋势。在清醒动物脑微透析实验中,VTA微注射U-50488还可显著抑制吗啡引起的NAc细胞外液中DA和5-HT代谢产物的升高。免疫组化实验的结果表明,形成行为敏化的大鼠,NAc(包括核部和壳部)和mPFC中的FosB阳性细胞显著增加,而VTA微注射U-50488显著抑制吗啡引起的变化。以上结果提示,VTA微注射U-50488影响吗啡依赖的机制可能包括抑制DA能神经传递,抑制转录因子FosB的表达。VTA微注射U-50488对投射靶区NAc和mPFC均可产生显著影响,提示VTA中κ-阿片受体的作用可能并无VTA-NAc或VTA-mPFC投射通路的选择性。
通过以上研究我们发现,吗啡急慢性给药可引起中脑皮层边缘系统中κ-阿片受体表达的改变,提示该系统中的κ-阿片受体可能参与了对吗啡依赖的调节。在中脑皮层边缘系统的核心区域VTA给予κ-激动剂可以抑制吗啡诱导的精神依赖,其作用可能与其对单胺类神经递质以及FosB基因表达的调节有关。而且VTA给予κ-激动剂可同时影响靶区NAc和mPFC,提示VTA中κ-阿片受体的作用并无投射通路的选择性。本研究对全面理解κ-受体对中脑DA能神经传递的调控作用以及κ-受体系统与药物依赖的关系有一定意义。
Opioid dependence remains a serious medical and social issue.Neurobiological and pharmacological studies have revealed that there is a direct correlation between the mesocorticolimbic system and opioid dependence.Opioids,such as morphine, disinhibit the dopaminergic neurons by activating theμ-opioid receptor on the GABAergic interneurons in ventral tegmental area(VTA).The subsequent DA efflux in the dopaminergic projecting targets(such as nucleus accumbens,medial prefrontal cortex) is believed to be initial events that trigger reward and dependence.In addition, exposure to opioids results in activation of some transcription factors,such as CREB and Fos family.ΔFosB,a truncated splice variant of full-length FosB,is considered to be a molecular switch of addiction.
Kappa-opioid receptor,as well as its endogenous ligand dynorphin,hss a wide distribution in central nervous system.Activation of theκ-receptor antagonizes variousμ-receptor-mediated actions in the brain.κ-agonists inhibit the DA neurons and DA release,whileμ-agonists activate the dopaminergic neurotransmission.μ-agonists produce euphoria and function as positive reinforcers.In contrast,κ-agonists produce dysphoria and function as negative reinforcers.Taking together,μ-andκ-receptor act as an opposing pair in opioid signaling in the brain.
Evidence is increasing to indicate that activation ofκ-opioid receptor suppress the morphine dependence.U-50488,a selectiveκ-agonist,abolishes the reinforcing effects of morphine in both self-administration and conditioned place preference paradigms.Without any effect by its self,selective-antagonist nor-BNI blocks the inhibitory effects of U-50488 on the morphine dependence.On the other hand,DA release stimulated by addictive drugs is exacerbated inκ-receptor knockout mice.The dual modulations of the midbrain dopaminergic system byμ- andκ-receptors may underlie the mechanism through whichκ-agonist inhibits the morphine dependence.
It has long been recognized that drug dependence processing relies heavily on mesocorticolimbic DA systems,comprising DA neurons in VTA and their projections to NAc,mPFC and other forebrain regions.Recently,major efforts have attempted to specify what functionκ-receptor contribute in VTA.Doesκ-receptor exist in VTA? Doesκ-receptor in VTA exert an inhibitory effect of DA neurotransmission? Does intra-VTA administration ofκ-agonist inhibit morphine dependence and what is the mechanism? We are now trying to explore these issues.
Using the real-time quantitative PCR and western blot tequniques,we measure theκ-receptor mRNA and protein levels in mPFC,NAc and VTA.Acute exposure to morphine increases the mRNA levels in all three regions,but have no significant effects on protein levels.After chronic exposure to morphine,whereasκ-receptor mRNA returns to basal level in NAc and VTA,the relatively modest induction in mPFC persists.Moreover,κ-receptor protein levels decrease in mPFC and VTA,but remain unchanged in NAc.These results suggest the involvement of mesocorticolimbicκ-receptors in the development of morphine dependence.
Given the findings metioned above,we speculate that intra-VTA administration ofκ-agonist might influence the morphine dependence.Thus,the effects of U-50488 following VTA microinjetion on the morphine dependence were evaluated in behavior models of conditioned place preference and locomotor sensitization.Intra-VTA administraion of U-50488,at the doses we tested,did not produce significant effects on place conditioning and locomotor activity in naive rats.However,the morphine-induced place preference and locomotor sensitization were attenuated in U-50488-treated rats,suggesting a VTAκ-receptor-mediated mechanism in the modulation of morphine depedence.
In further studies,we explored the neurochemical and neurobiological mechanisms through whichκ-agonist inhibit the morphine dependence.We found that acute exposure to morphine elevated the DA turnover in NAc and mPFC extracts. These elevations were significantly suppressed in extracts obtained from the rats treated with U-50488.A similar tendency was observed in animals received chronic drug administration,although there were no significant changes in DA turnover.In microdialysis study,U-50488,following microinjection into VTA,also attenuated the morphine-induced elevation of DA metabolite(HVA) and 5-HT metabolite(5-HIAA). In addition,the number of FosB-positive neurons significantly increased in mPFC and NAc during the development of locomotor sensitization.U-50488,following microinjection into VTA,reduced the number of FosB-positive neurons significantly, indicating that the inhibitory effects of intra-VTA U-50488 on morphine dependence might be related to its modulatory effects on expression of the transcription factor FosB.
In conclusion,κ-opioid receptor in VTA was found to be involved in the morphine dependence.Activation of theκ-opioid receptor in VTA exhibits inhibitory effects on morphine-induce place preference and locomotor sensitization.The mechanism is related to its modulation on DA release and FosB expression.
引文
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