大鼠吗啡戒断大麻素信号对伏隔核突触传递调节功能的影响的研究
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摘要
奖赏通路在药物成瘾和戒断中发挥了重要的作用。伏隔核（NAc）是这条通路中的一个重要核团。已知，表达于突触前膜的大麻素1型受体（CB1Rs）广泛地分布于NAc上。并且，CB1Rs和NAc一样，也参与了对药物成瘾的调节。早先的研究发现，可卡因间断给药1周后，CB1Rs参与了对纹状体γ–氨基丁酸（GABA）突触的调节。受此启发，我们研究了大鼠在吗啡（MOR）戒断时，CB1Rs对NAc突触的传递调节功能的影响。在本研究中，7天的重复皮下给药（MOR）可以成功地诱导大鼠的条件性位置偏爱（CPP）模型。运用电生理学方法可以看到，CB1Rs激动剂WIN55,212–2对NAc神经元的自发抑制性突触后电流（sIPSC）、微小抑制性突触后电流（mIPSC）以及刺激诱发的抑制性突触后电流（eIPSC）的抑制作用在3天MOR组和3周MOR组中较同时间的生理盐水组（SAL组）明显增强，并且这个增强作用可以被预先灌流的CB1Rs抑制剂AM251阻断。而在5周MOR组和5周SAL组的比较中，这种抑制增强作用消失。用同样方法观察兴奋性突触后电流（EPSCs），结果显示，WIN55,212–2对NAc神经元的自发兴奋性突触后电流（sEPSC）、微小兴奋性突触后电流（mEPSC）以及刺激诱发的兴奋性突触后电流（eEPSC）的影响，与SAL组在3天、3周和5周时比较没有统计学差异（P>0.05）。根据以上结果，我们对比了MOR组和SAL组在3天、3周以及5周时的CPP变化，结果发现，3天MOR组和3周MOR组的大鼠保留了对MOR配对空间的偏爱，而在5周时这种现象消失。由此我们得出结论，在MOR戒断时，大鼠NAc中CB1Rs的含量增多和（或者）功能增强，并且GABA电流的敏化作用是逐渐可逆的。以上结果表明，调节CB1Rs对于治疗阿片类药物成瘾可能具有重要的理论和现实意义。本实验分为四个部分：
第一部分:大鼠吗啡戒断模型的建立以及WIN55,212–2实验浓度的确定
运用CPP方法，研究人员可以预测人类和动物对成瘾药物的依赖性和渴求性。因此CPP实验是一项被广泛应用于检测药物成瘾的行为学方法。在本研究中，我们应用此法观察7天皮下间断注射MOR是否可以成功诱导大鼠对MOR的偏爱，进而制成稳定的大鼠吗啡CPP模型。结果显示，反复的MOR注射可以成功地诱导大鼠的CPP形成（P <0.05），而用SAL处理的大鼠却没有形成对SAL的偏爱（P>0.05）。因此，通过CPP方法，我们可以成功地建立大鼠MOR戒断模型。
为了保证本研究的稳定性和可重复性，我们进行了剂量依赖性实验。我们发现，0.1μM的Win55,212–2对MOR组和SAL组较实验前没有统计学差异（P>0.05）。然而，0.3μM，1μM，2μM，4μM的Win55,212–2能够剂量性地抑制MOR组和SAL组的sIPSC的频率和eIPSC的幅度（P <0.05）。因此，为了保证实验的稳定性并且尽量避免药物的毒性作用，我们选择Win55,212–2的实验浓度为1μM。
第二部分：CB1Rs激动剂和抑制剂对NAc中的MSNs的EPSCs的影响
已知在NAc神经元中，突触前刺激CB1Rs可以减少谷氨酰胺能神经传递。因此，为了观察谷氨酰胺能传递是否参与了CB1Rs对药物成瘾和戒断的影响，在全细胞记录模式下，我们运用电压钳技术，首先给包含NAc结构的脑片灌流bicuculline，分离sEPSC。接着我们又加入河豚毒素（TTX），分离出mEPSC。而后，用电刺激包含NAc的脑片，检测了eEPSC的变化情况。
Win55,212–2对MOR组的sEPSC的频率和幅度、mEPSC的频率和幅度以及eEPSC的幅度与SAL组相比，没有统计学差异（P>0.05）。
第三部分:CB1Rs激动剂和抑制剂对于NAc中的MSNs的IPSCs的影响以及CPP留存情况
在全细胞记录模式下，我们运用电压钳技术，首先给包含NAc结构的脑片灌流NMDA受体拮抗剂APV和非NMDA受体拮抗剂CNQX，分离自发抑制性突触后电流（sIPSC），检测GABA突触的电生理活性。接着我们又加入TTX，分离出微小抑制性突触后电流（mIPSC）。而后，用电刺激含NAc的脑片，检测了刺激诱发的抑制性突触后电流（eIPSC）的变化情况。以上所有的电流均可被GABA受体阻断剂bicuculline阻断。
与SAL组相比，Win55,212–2可以显著地降低3天MOR组和3周MOR组的sIPSC的频率、mIPSC的频率和eIPSC的幅度（P <0.05），而这些效果可以被预先灌流的AM251阻断（P <0.05），这意味着GABA能突触对CB1Rs刺激反应性的增加。但是，Win55,212–2对5周MOR组的sIPSC的频率、mIPSC的频率和eIPSC的幅度的抑制作用，与SAL组相比，没有统计学差异（P>0.05）。
我们根据实验分组中的时间指标检查了SD大鼠的CPP留存情况。结果显示，3天MOR组和3周MOR组大鼠依旧保留了对造模时MOR配对空间的偏爱（P <0.05）。而5周MOR组的这种现象消失（P>0.05）。
第四部分：CB1Rs激动剂对双脉冲比（PPR）的影响以及NAc中MSNs的形态学研究
我们运用PPR法确认CB1Rs对NAc的GABA能传递的刺激作用是否为突触前机制。在MOR组和SAL组的大鼠脑片上，将间隔刺激时间设为50ms，我们发现Win55,212–2对PPR的反应显著增强（eIPSC2eIPSC1）（P <0.05）。这个实验结果说明了CB1Rs的作用是突触前机制。
在本实验中，我们在倒置显微镜下，以大鼠脑解剖图谱为依据，在鼠脑的冠状位上找到并确认了NAc区域。我们通过前联合定位NAc。并且，在NAc的背侧和内侧可以发现大量的MSNs。
It is known that presynaptic cannabinoid CB1receptors (CB1Rs), which distributedwidely in nucleus accumbens (NAc), are involved in the natural reward pathway that playan important role in natural drugs (such as opioids or cocaine) addiction and withdrawal.Based on previous findings, in which CB1Rs were found to be involved in the process tomediate striatal GABA synapses one week after the discontinuation of cocaine, we want toknow how the CB1Rs are regulated after withdrawl from morphine (MOR) in NAcneurons of rats. In our study,7days repeated administration of MOR could induce stableMOR–conditioned place preference (CPP). Using electrophysiological experiments, theinhibition effects of CB1Rs agonist WIN55,212–2on spontaneous, miniature and evokedinhibitory postsynaptic currents (sIPSC, mIPSC, eIPSC) were enhanced in both the day3and the day21MOR–treated groups after last injection of MOR. And this effect of MOR exposure could be prevented by AM251, which was perfused before treated with WIN55,212–2. In contrast, the spontaneous, miniature and evoked excitatory postsynaptic currents(sEPSC, mEPSC, eEPSC) and the IPSCs of day35MOR–treated group to WIN55,212–2were unaltered compared with saline–(SAL–) treated rats. Then an experiment wasperformed to measure the retention of the CPP. And we found that the day3and the day21MOR treated–groups had maintained the preference for the MOR–paired compartment,whereas the day35MOR–treated group had extinguished its preference. So we concludedthat the content and/or the capability of CB1Rs were up–regulated and/or enhanced inMOR–treated rats during abstinence of MOR consumption, and the MOR sensitization toCB1Rs could be slowly reversible. The results indicated that regulateing CB1Rs is apromising strategy for the treatment of MOR addiction. The study is composed of fourparts.
Part1. The animal model of MOR withdrawal in rats, and determination of theworking concentration of Win55,212–2
CPP, which may predict the dependence liability in humans and animals in drugaddiction, is a widely used behavioral measure for the rewarding properties of abuseddrugs. In the present study, we used the CPP paradigm to investigate whether MORadministration produce addictive behavior by testing the rewarding properties at the timepoint of day7after last injection of MOR in rats. Data analysis revealed that repeatedMOR injections could produce significant CPP (P <0.05), whereas the SAL–treated ratsdid not show any significant CPP for either compartment (P>0.05). So, by CPP methods,we could successfully establish the animal model of MOR withdrawal in rats.
In the Dose–response relationship assay, we found that0.1μM Win55,212–2was noteffective in both MOR–and SAL–treated rats (P>0.05), while0.3,1,2,4μM Win55,212–2could dose–dependently inhibit the frequencies of sIPSC and the amplitudes ofeEPSC in MOR–and SAL–treated rats. Treatment with Win55,212–2at1μM resulted ina stable effect to rats. Hence, a working concentration of1μM was chosen for allsubsequent studies.
Part2. Effects of AM251and Win55,212–2on EPSCs of NAc in SAL–andMOR–treated rats
In the NAc, stimulation of CB1Rs presynaptically reduces glutamatergic transmission.Thus, to see whether the effects of CB1Rs on drug of addiction and withdrawl wereinvolved glutamate–mediated process, we performed whole–cell recordings to examinesEPSC, and then isolated mEPSC, following the application of tetrodotoxin (TTX), in thepresence of bicuculline. After that, following stimulation around NAc on other brain slices,we examined eEPSC in core region of NAc.
Compared with the neurons from SAL–treated rats at the time point of3days,21days and35days, no significant difference were found in frequencies and the amplitudesof sEPSC (P>0.05) and mEPSC (P>0.05), and the amplitudes of eEPSC (P>0.05) afterthe application of the CB1Rs agonist Win55,212–2.
Part3. Effects of AM251and Win55,212–2on IPSCs of NAc in SAL–andMOR–treated rats, and the condition of CPP retention
We measured sIPSC to examine the physiological activity of GABA synapses, and thenisolated mIPSC, following the application of TTX, a selective voltage–dependent sodiumchannel blocker in the NAc of both MOR–and SAL–treated rats, in the presence of APVplus CNQX. After that, following stimulation around NAc on other brain slices, weexamined eIPSC by whole–cell voltage clamp recordings in core region of NAc. All ofthese currents could be blocked by the GABA receptor antagonist, bicuculline.
Compared with the neurons from SAL–treated rats at the time point of3days and21days, application of Win55,212–2could significantly reduce the frequencies of sIPSC (P<0.05) and mIPSC (P <0.05), and the amplitudes of eIPSC (P <0.05), which indicatedincreased sensitivity of GABA synapses to cannabinoid receptor stimulation, and theenhanced effect could be prevented by preincubating the slice with the selective antagonistof CB1Rs AM251(P>0.05). But in NAc neurons from day35MOR treated–group,Win55,212–2produced similar effects on the frequencies of sIPSC and mIPSC, and theamplitudes of eIPSC than in the respective controls (P>0.05).
Then an experiment was performed to measure the retention of the CPP. And we foundthat the day3and the day21MOR–treated rats had maintained the preference for theMOR–paired compartment. But in day35MOR treated–group, the rewarding effects ofMOR were disappeared.
Part4. Effects of Win55,212–2on PPR, and the morphology of MSNs in NAc
To see whether the effects of CB1Rs stimulation on NAc GABA transmission werepresynaptic, PPR analysis was performed to predict the nature of synaptic plasticity. Inboth MOR–and SAL–treated rats, the depressant effect of Win55,212–2on eIPSC, withan interstimulus interval of50ms, was associated with a significant increase in PPR(eIPSC2eIPSC1), as expected for a presynaptic action of MOR (P <0.05for both theMOR–and SAL–groups).
The NAc was first identified in coronal slices with reference to the rat brain atlasusing an inverted microscope. By reference to the anterior commissure, we could find theNAc. The MSNs of NAc were found dorsal and medial to the anterior commissure.
第一部分:大鼠吗啡戒断模型的建立以及WIN55,212–2实验浓度的确定
运用CPP方法，研究人员可以预测人类和动物对成瘾药物的依赖性和渴求性。因此CPP实验是一项被广泛应用于检测药物成瘾的行为学方法。在本研究中，我们应用此法观察7天皮下间断注射MOR是否可以成功诱导大鼠对MOR的偏爱，进而制成稳定的大鼠吗啡CPP模型。结果显示，反复的MOR注射可以成功地诱导大鼠的CPP形成（P <0.05），而用SAL处理的大鼠却没有形成对SAL的偏爱（P>0.05）。因此，通过CPP方法，我们可以成功地建立大鼠MOR戒断模型。
为了保证本研究的稳定性和可重复性，我们进行了剂量依赖性实验。我们发现，0.1μM的Win55,212–2对MOR组和SAL组较实验前没有统计学差异（P>0.05）。然而，0.3μM，1μM，2μM，4μM的Win55,212–2能够剂量性地抑制MOR组和SAL组的sIPSC的频率和eIPSC的幅度（P <0.05）。因此，为了保证实验的稳定性并且尽量避免药物的毒性作用，我们选择Win55,212–2的实验浓度为1μM。
第二部分：CB1Rs激动剂和抑制剂对NAc中的MSNs的EPSCs的影响
已知在NAc神经元中，突触前刺激CB1Rs可以减少谷氨酰胺能神经传递。因此，为了观察谷氨酰胺能传递是否参与了CB1Rs对药物成瘾和戒断的影响，在全细胞记录模式下，我们运用电压钳技术，首先给包含NAc结构的脑片灌流bicuculline，分离sEPSC。接着我们又加入河豚毒素（TTX），分离出mEPSC。而后，用电刺激包含NAc的脑片，检测了eEPSC的变化情况。
Win55,212–2对MOR组的sEPSC的频率和幅度、mEPSC的频率和幅度以及eEPSC的幅度与SAL组相比，没有统计学差异（P>0.05）。
第三部分:CB1Rs激动剂和抑制剂对于NAc中的MSNs的IPSCs的影响以及CPP留存情况
在全细胞记录模式下，我们运用电压钳技术，首先给包含NAc结构的脑片灌流NMDA受体拮抗剂APV和非NMDA受体拮抗剂CNQX，分离自发抑制性突触后电流（sIPSC），检测GABA突触的电生理活性。接着我们又加入TTX，分离出微小抑制性突触后电流（mIPSC）。而后，用电刺激含NAc的脑片，检测了刺激诱发的抑制性突触后电流（eIPSC）的变化情况。以上所有的电流均可被GABA受体阻断剂bicuculline阻断。
与SAL组相比，Win55,212–2可以显著地降低3天MOR组和3周MOR组的sIPSC的频率、mIPSC的频率和eIPSC的幅度（P <0.05），而这些效果可以被预先灌流的AM251阻断（P <0.05），这意味着GABA能突触对CB1Rs刺激反应性的增加。但是，Win55,212–2对5周MOR组的sIPSC的频率、mIPSC的频率和eIPSC的幅度的抑制作用，与SAL组相比，没有统计学差异（P>0.05）。
我们根据实验分组中的时间指标检查了SD大鼠的CPP留存情况。结果显示，3天MOR组和3周MOR组大鼠依旧保留了对造模时MOR配对空间的偏爱（P <0.05）。而5周MOR组的这种现象消失（P>0.05）。
第四部分：CB1Rs激动剂对双脉冲比（PPR）的影响以及NAc中MSNs的形态学研究
我们运用PPR法确认CB1Rs对NAc的GABA能传递的刺激作用是否为突触前机制。在MOR组和SAL组的大鼠脑片上，将间隔刺激时间设为50ms，我们发现Win55,212–2对PPR的反应显著增强（eIPSC2eIPSC1）（P <0.05）。这个实验结果说明了CB1Rs的作用是突触前机制。
在本实验中，我们在倒置显微镜下，以大鼠脑解剖图谱为依据，在鼠脑的冠状位上找到并确认了NAc区域。我们通过前联合定位NAc。并且，在NAc的背侧和内侧可以发现大量的MSNs。
It is known that presynaptic cannabinoid CB1receptors (CB1Rs), which distributedwidely in nucleus accumbens (NAc), are involved in the natural reward pathway that playan important role in natural drugs (such as opioids or cocaine) addiction and withdrawal.Based on previous findings, in which CB1Rs were found to be involved in the process tomediate striatal GABA synapses one week after the discontinuation of cocaine, we want toknow how the CB1Rs are regulated after withdrawl from morphine (MOR) in NAcneurons of rats. In our study,7days repeated administration of MOR could induce stableMOR–conditioned place preference (CPP). Using electrophysiological experiments, theinhibition effects of CB1Rs agonist WIN55,212–2on spontaneous, miniature and evokedinhibitory postsynaptic currents (sIPSC, mIPSC, eIPSC) were enhanced in both the day3and the day21MOR–treated groups after last injection of MOR. And this effect of MOR exposure could be prevented by AM251, which was perfused before treated with WIN55,212–2. In contrast, the spontaneous, miniature and evoked excitatory postsynaptic currents(sEPSC, mEPSC, eEPSC) and the IPSCs of day35MOR–treated group to WIN55,212–2were unaltered compared with saline–(SAL–) treated rats. Then an experiment wasperformed to measure the retention of the CPP. And we found that the day3and the day21MOR treated–groups had maintained the preference for the MOR–paired compartment,whereas the day35MOR–treated group had extinguished its preference. So we concludedthat the content and/or the capability of CB1Rs were up–regulated and/or enhanced inMOR–treated rats during abstinence of MOR consumption, and the MOR sensitization toCB1Rs could be slowly reversible. The results indicated that regulateing CB1Rs is apromising strategy for the treatment of MOR addiction. The study is composed of fourparts.
Part1. The animal model of MOR withdrawal in rats, and determination of theworking concentration of Win55,212–2
CPP, which may predict the dependence liability in humans and animals in drugaddiction, is a widely used behavioral measure for the rewarding properties of abuseddrugs. In the present study, we used the CPP paradigm to investigate whether MORadministration produce addictive behavior by testing the rewarding properties at the timepoint of day7after last injection of MOR in rats. Data analysis revealed that repeatedMOR injections could produce significant CPP (P <0.05), whereas the SAL–treated ratsdid not show any significant CPP for either compartment (P>0.05). So, by CPP methods,we could successfully establish the animal model of MOR withdrawal in rats.
In the Dose–response relationship assay, we found that0.1μM Win55,212–2was noteffective in both MOR–and SAL–treated rats (P>0.05), while0.3,1,2,4μM Win55,212–2could dose–dependently inhibit the frequencies of sIPSC and the amplitudes ofeEPSC in MOR–and SAL–treated rats. Treatment with Win55,212–2at1μM resulted ina stable effect to rats. Hence, a working concentration of1μM was chosen for allsubsequent studies.
Part2. Effects of AM251and Win55,212–2on EPSCs of NAc in SAL–andMOR–treated rats
In the NAc, stimulation of CB1Rs presynaptically reduces glutamatergic transmission.Thus, to see whether the effects of CB1Rs on drug of addiction and withdrawl wereinvolved glutamate–mediated process, we performed whole–cell recordings to examinesEPSC, and then isolated mEPSC, following the application of tetrodotoxin (TTX), in thepresence of bicuculline. After that, following stimulation around NAc on other brain slices,we examined eEPSC in core region of NAc.
Compared with the neurons from SAL–treated rats at the time point of3days,21days and35days, no significant difference were found in frequencies and the amplitudesof sEPSC (P>0.05) and mEPSC (P>0.05), and the amplitudes of eEPSC (P>0.05) afterthe application of the CB1Rs agonist Win55,212–2.
Part3. Effects of AM251and Win55,212–2on IPSCs of NAc in SAL–andMOR–treated rats, and the condition of CPP retention
We measured sIPSC to examine the physiological activity of GABA synapses, and thenisolated mIPSC, following the application of TTX, a selective voltage–dependent sodiumchannel blocker in the NAc of both MOR–and SAL–treated rats, in the presence of APVplus CNQX. After that, following stimulation around NAc on other brain slices, weexamined eIPSC by whole–cell voltage clamp recordings in core region of NAc. All ofthese currents could be blocked by the GABA receptor antagonist, bicuculline.
Compared with the neurons from SAL–treated rats at the time point of3days and21days, application of Win55,212–2could significantly reduce the frequencies of sIPSC (P<0.05) and mIPSC (P <0.05), and the amplitudes of eIPSC (P <0.05), which indicatedincreased sensitivity of GABA synapses to cannabinoid receptor stimulation, and theenhanced effect could be prevented by preincubating the slice with the selective antagonistof CB1Rs AM251(P>0.05). But in NAc neurons from day35MOR treated–group,Win55,212–2produced similar effects on the frequencies of sIPSC and mIPSC, and theamplitudes of eIPSC than in the respective controls (P>0.05).
Then an experiment was performed to measure the retention of the CPP. And we foundthat the day3and the day21MOR–treated rats had maintained the preference for theMOR–paired compartment. But in day35MOR treated–group, the rewarding effects ofMOR were disappeared.
Part4. Effects of Win55,212–2on PPR, and the morphology of MSNs in NAc
To see whether the effects of CB1Rs stimulation on NAc GABA transmission werepresynaptic, PPR analysis was performed to predict the nature of synaptic plasticity. Inboth MOR–and SAL–treated rats, the depressant effect of Win55,212–2on eIPSC, withan interstimulus interval of50ms, was associated with a significant increase in PPR(eIPSC2eIPSC1), as expected for a presynaptic action of MOR (P <0.05for both theMOR–and SAL–groups).
The NAc was first identified in coronal slices with reference to the rat brain atlasusing an inverted microscope. By reference to the anterior commissure, we could find theNAc. The MSNs of NAc were found dorsal and medial to the anterior commissure.
引文
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