摘要
大麻是世界上最易于滥用的精神药物,其活性成分大麻素(THC)可以对包括人类在内灵长类产生奖赏效应。但是到目前为止,还没有有效的治疗大麻素成瘾的手段,很大程度上是因为对大麻素成瘾的确切机制还不明了。近年来,相当多的证据表明,成瘾效应导致的中枢神经系统适应性变化与学习记忆功能有共同的谷氨酸依赖的细胞分子机制,这使得突触传递的长时程增强(LTP)和长时程减弱(LTD)成为研究成瘾效应的细胞分子机制的焦点。而且,大多数具有强化效应或奖赏效应并易于滥用的精神依赖性药物都可以升高伏隔核(NAc)内的多巴胺水平,表明成瘾药物使得中脑多巴胺系统的多巴胺神经元活性增强。人们进一步发现,许多成瘾药物包括尼古丁、可卡因、安非他命、吗啡和酒精等,都可以使得腹侧背盖区(VTA)多巴胺神经元产生LTP效应,说明VTA多巴胺神经通路的LTP在药物成瘾效应的发生过程中有至关重要的作用。但是,到目前为止,还不清楚大麻素能否在VTA诱导出LTP或LTD,更重要的是如果大麻素可以引起VTA的突触可塑性改变,那么这种改变是否与大麻素成瘾行为表现密切相关还没有答案。
本研究采取对大鼠脑片场电位记录(年幼和成年鼠)和DA与GABA神经元全细胞膜片钳记录(年幼鼠)的手段,并结合分子生物学技术、生物化学技术和免疫组化技术,研究大麻素慢性作用对VTA突触可塑性的影响。目的是获得大麻素成瘾过程中VTA DA神经元的谷氨酸能传入突触强度长时程变化的特征和可能的细胞分子机制,并为大麻素成瘾问题的治疗措施提供新思路。本研究首先观察到大麻素(THC和HU210)慢性作用易化了VTA LTD的诱导。接着,发现大麻素通过激活星形胶质细胞上的CB1R以及通过DA神经元AMPARI的内吞作用诱导VTA DA神经元在体产生LTD。具体结果如下：
1大麻素通过激活VTA CB1R易化DA神经元LTD的诱导
空白对照组和安慰剂组在不阻断抑制性GABA中间神经元下,无论是LFS还是HFS都不能诱导出VTA脑片的LTP或LTD。相反,大麻素慢性作用5天的24小时后,HFS依然不能诱导出LTP,而LFS则可以诱导出LTD。大麻素慢性作用易化VTA LFS诱导LTD的现象可以被CBIR的特异性阻断剂AM281阻断。通过全细胞膜片钳记录表明大麻素易化LTD的诱导现象产生于DA神经元,而非GABA神经元。
2大麻素是通过活化VTA DA神经元突触后NMDAR易化LTD的诱导,并需要APMAR的内吞过程
PPR记录发现HU210作用并不改变突触前谷氨酸递质的释放概率,表明突触后机制介导了大麻素易化VTA LTD的诱导。这种突触后依赖的LTD可以被NMDAR的阻滞剂所阻断,而mGluR阻滞剂却没有作用,说明大麻素易化VTA LTD的诱导效应是突触后NMDAR依赖的。
干扰GluR2内吞过程的TAT-GluR2干扰肽可以消除HU210易化VTA LTD的诱导效应。免疫荧光双标记实验表明,GluR2阳性神经元与TH标记的DA神经元可以共染色,而与GABA神经元无共染色,提示GluR2内吞过程可能主要发生在DA神经元而非GABA神经元。免疫荧光的结果,进一步证明大麻素易化VTA LTD的诱导效应是发生于DA神经元。
3大麻素可能诱导VTA DA神经元产生在体LTD
与上述的HU210慢性作用,最后一次注射24小时后的大鼠脑片相比,最后一次注射30分钟后的脑片LFS不能诱导出LTD,提示LTD的诱导可能被阻滞(occlusion);且30分钟后的细胞膜表面的GluR2表达量较24小时明显降低；30分钟后VTA DA神经元的AMPAR/NMDAR电流比率较24小时后组和空白对照组明显下降；HU210慢性作用后DA神经元的NR2B/NR2A电流比率较空白对照组明显升高。所有这些证据表明大麻素可能诱导VTA DA神经元产生在体LTD。
4星形胶质细胞在大麻素诱导的VTA DA神经元生成LTD中的作用
星形胶质细胞可以表达CB1R,本研究接下来观察特异性下调星形胶质细胞CB1R的表达量对大麻素诱导的在体LTD的影响。通过免疫印迹手段,我们首先确定了双侧颅内VTA定位微量注射构建的CB1R-shRNA腺病毒能明显抑制VTA CB1R的表达,并观察到CB1R-shRNA腺病毒主要转染VTA的星形胶质细胞,说明腺病毒能较特异地下调星形胶质细胞CB1R的表达量。接下来发现,腺病毒注射能明显抑制HU210慢性作用易化LFS诱导的LTD。另外,VTA定位注射能抑制突触前谷氨酸释放和增强星形胶质细胞对谷氨酸清除的的药物riluzole,可以抑制HU210作用后LFS对LTD的诱导。
众所周知,含NR2B亚基的NMDAR可以诱导GluR2的内吞,进而产生LTD效应。我们发现大麻素慢性作用,最后一次注射24小时后NR2B/NR2A电流比率明显增强；免疫荧光标记结果表明,VTA中包含NR2B亚基的NMDAR主要位于旁突触,而包含NR2A亚基的NMDAR主要位于突触,提示由突触附近星形胶质细胞释放的谷氨酸作用到位于旁突触的NR2B,从而介导大麻素对LTD的诱导。
5大麻素和尼古丁的中和作用
以上所有结果表明,大麻素可以诱导VTA DA神经环路产生在体LTD效应。与此不同的是,大多数成瘾药物包括尼古丁、可卡因、吗啡、安非他命和酒精等均可以诱导DA神经元的LTP。这就产生一个疑问,对突触可塑性作用相反的成瘾药物是否可以产生中和作用。
本研究提供两条证据以回答以上问题,一是慢性尼古丁作用后,HFS能诱导出VTALTP,而LFS不能诱导LTD。其次,尼古丁和大麻素联合作用后,HFS不能诱导出LTP,而LFS也不能诱导LTD。说明尼古丁和大麻素对VTA DA神经元的突触可塑性的影响产生了中和作用。
根据以上结果,得出如下结论：
大麻素注射可以诱导VTA产生在体LTD,且该效应的维持少于24小时。停止大麻素注射24小时后,易化了LFS诱导VTA的DA神经元LTD的生成。大麻素诱导的LTD是NMDAR和AMPAR依赖的,其途径是首先激活VTA星形胶质细胞的CBIR,使其分泌谷氨酸,谷氨酸活化旁突触的NR2B亚基,进而引起GluR2的内吞效应。大麻素诱导的LTD和尼古丁诱导的LTP可以产生中和作用。
Cannabis is the most commonly abused illegal drug in the world and its main psychoactive ingredient, delta-9-tetrahydrocannabinol (THC), produces rewarding effects in humans and non-human primates. However, there is no effective treatment for cannabis addiction in humans, largely due to our poor understanding of its underlying mechanisms. Recently, considerable evidence suggests that neuroadaptations leading to addiction involve the same glutamate-dependent cellular mechanisms that enable learning and memory. Long-term potentiation (LTP) and long-term depression (LTD) have therefore become an important focus of addiction research. In addition, most psychoactive drugs that have reinforcing or rewarding effects in experimental animals and are abused by humans increase dopamine levels in the nucleus accumbens shell, indicating VTA DA neurons are activated during drug exposure. LTP induction in VTA dopamine neurons following exposure to most drug (nicotine, cocaine, amphetamine, morphine and ethanol), indicated an essential contribution of LTP induction in the VTA dopamine circuitry to the development of drug addiction. It is entirely unknown, however, whether cannabinoids are able to induce LTP or LTD in the VTA.More importantly, whether such alterations in VTA synaptic plasticity causatively contribute to drug addictive behavior has not previously been addressed.
In present study, we employed a combination of field potential recordings from both young and adult rats, whole cell recordings of the EPSCs from both dopamine and GABA neurons in the young rat VTA, and molecular biological, biochemical, immunohistochemica to exhibit the changes of VTA synaptic plasticity following chronic cannabinoid exposure. The purposes of this study are to describe the change of synaptic plasticity in VTA following cannobinoid exposure and underlying molecular and cellular mechanisms, and to provide candidate therapeutic strategies for treating cannabis addiction. We first observed that chronic cannabinoid (THC and HU210) exposure in vivo facilitated LTD induction in the VTA. Then, we provide the first evidence suggesting that cannabinoids induce in vivo LTD in VTA dopamine neurons via cannabinoid CB1 receptors (CB1R) probably on VTA astrocytes and AMPAR on VTA dopamine neurons. The results are as followings:
1 Cannabinoids act on VTA CB1R to facilitate LTD induction in the DA neuron
Without blocking inhibitory GABA neurons, neither HFS nor LFS of excitatory afferents induced LTP or LTD in the field EPSPs recording in the VTA of both naive rats and vehicle-treated rats. In contrast, LFS induced LTD, but HFS still failed to induce LTP, from in midbrain slices prepared at 24 hours after 5 days chronic cannabinoid exposure. The selective CB1R antagonist AM281 prevented cannabinoid-facilitated LTD induction. Whole cell recording identified that this LTD was expressed in VTA dopamine neurons but not GABA neurons.
2 Cannabinoid facilitates LTD induction in the VTA via post-synaptic NMDAR and requiring AMPAR endocytosis
The paired pulse ratio (PPR) recording shows that the in vivo HU210 exposure did not cause a change in probability of glutamate transmitter release, indicating a postsynaptic mechanism for the induction of cannabinoid-facilitated LTD in the VTA. This postsynaptic LTD was blocked by the NMDAR antagonist, but not mGluR antagonists, suggesting that cannabinoid facilitates LTD induction in the VTA via post-synaptic NMDAR.
TAT-GluR2 peptide, the blocker of GluR2 endocytosis procedure, abolished LTD induction in HU210-treated rats. GluR2 endocytosis likely occurs in the post-synaptic membrane of VTA dopamine neurons, but not VTA GABA neurons, because GluR2-positive neurons were doubly stained with the dopamine-synthesizing enzyme tyrosine hydroxylase (TH), but not with the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD) 65/67. These results further strongly support the idea that the expression of cannabinoid-facilitated LTD in the VTA occurs in VTA dopamine neurons but not GABA neurons.
3 Cannabinoid induces in vivo LTD in VTA dopamine neurons
Compared with the slices prepared at 24 hours after chronic HU210 injection, LFS failed to induce LTD at the slices prepared at 30 minutes after the last HU210 injection, but not at 24 hours, by a preceding HU210-induced LTD in vivo, indicating the occlusion of LFS-induced LTD in vitro at 30 minutes. Cell surface levels of GluR2 in the VTA significantly reduced at 30 minutes, but not at 24 hours, after the fifth HU210 injection. The AMPAR/NMDAR current ratio of glutamatergic synaptic currents in VTA dopamine neurons was significantly smaller at 30 minutes than both that at 24 hours after the fifth HU210 injection and that in naive rats. NR2B/NR2A EPSC ratio of VTA dopamine neurons was significantly larger in HU210-treated rats than that in naive rats. All these evidences support that cannabinoid likely induces in vivo LTD in VTA dopamine neurons.
4 Role of VTA astrocytes in cannabinoid-induced in vivo LTD in VTA dopamine neurons
It were reported that astrocytes express CB1R. So we if selective knocking down of CB1R expression in the VTA using CB1R shRNA expressed by adenoviral vectors could disturb cannabinoid-induced in vivo LTD. Through immunoblotting method, we firstly confirmed that bilateral injection of CB1R shRNA expressed by adenoviral vectors into the VTA significantly suppressed CB1R expression; then we show that VTA astrocytes are the major targets of intra-VTA injection of the vectors by double staining technology; finally, we found that LFS-induced LTD in HU210-treated rats was inhibited after vectors intra-VTA microinjection. Furthermore, we observed that riluzole, a drug can inhibit pre-synaptic glutamate release and enhance glutamate uptake into astrocytes, daily intra-VTA infusion before systemic HU210 injection prevented LFS-induced LTD in the VTA.
It is generally agreed that NR2B-containing NMDAR induces GluR2 endocytosis and subsequent LTD induction. Here we show that an increase in NR2B/NR2A EPSC ratio of VTA dopamine neurons at 24 hours after the fifth HU210 injection. Immunofluorescent staining results show that the majority of NR2B-and NR2A-containing NMDARs in the VTA are located in extra-synaptic and synaptic zones, respectively, indicating that the extra-synaptic NR2B activation by glutamate released from nearby astrocytes is response to cannabinoid-induced LTD.
5 Counteractive effects of cannabinoid and nicotine
While we show evidence here strongly suggesting that cannabinoid exposure in vivo induces LTD in vivo in VTA dopamine circuitry, previous studies show that many other drugs of abuse including nicotine, cocaine, amphetamine, morphine and ethanol may induce LTP in vivo in these neurons(10-12).It would be of interest to examine co-administration of cannabinoid and one of these drugs of abuse may neutralize their opposite effects on VTA synaptic plasticity.
We obtained two lines of evidence to support this hypothesis. First, HFS, but not LFS, induced VTA LTP from rats receiving chronic nicotine injection. Second, neither HFS nor LFS induced VTA LTP or LTD from rats receiving chronic co-administration of HU210 and nicotine.
Conclusion
Cannabinoid exposure in vivo induced in vivo LTD in the VTA that lasts for less than 24 hr, and facilitated LTD induction in the DA neuron 24 hours later. The signaling process of this LTD induction in the VTA is that cannabinoid via CB1R on astrocytes activate post-extrasynaptic NR2B subunits of NMDAR and then lead GluR2 subunits of AMPAR endocytosis. Furthermore, LTD induced by cannabinoid and TLP induced by nicotine could be neutralized each other.
引文
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