Effect Of Drugs of Abuse On Synaptic Transmission In Nucleus Accumbens

伏隔核(NAC)是参与动机的大脑关键区域，参与调节几类滥用药物的奖赏和成瘾特性。此外，由于它在激励过程中的作用，NAC还与涉及情绪和动机变化的精神障碍有关。因此，有必要了解这一脑区的基本功能，以及大麻、可卡因、阿片类药物和设计师药物等滥用药物对这一系统的作用。NAC主要由中等带刺的GABA能输出神经元(MSN)组成，MSN接受来自其他MSN的神经支配，许多额外的脑区接受谷氨酸支配，以及来自腹侧中脑的多巴胺神经支配。严重的是，GABA和谷氨酸突触到MSN上都被几类滥用药物抑制，这表明这一作用可能有助于它们的奖赏特性，长期接触药物会改变内在回路和外部输入的功能。此外，已知滥用药物会增加NAC中多巴胺(DA)的释放，这可能有助于重复激活谷氨酸能传入后观察到的兴奋性传递的长期变化。虽然关于NAC对行为的贡献已经知道很多，但这种突触可塑性对行为的确切机制，以及滥用药物如何改变突触过程，仍然知之甚少。为了研究滥用药物在NAC中的作用，我们利用电生理学和行为分析，结合光遗传技术，在转基因和正常啮齿动物中进行研究。目前的实验包括考察特定的NAC输入和输出通路对行为的影响，以及通过自我给药或实验者递送的方式暴露于滥用药物后这些通路的变化。当使用腺相关病毒(AAV)时，光遗传学允许选择性地表达光激活蛋白，如通道视紫红质-2(ChR2)或卤视紫质(HALO)。由于许多酪氨酸羟化酶阳性(TH)的VTA神经元也表达囊泡型谷氨酸-2转运体(VGlut-2)，它们能够将DA和谷氨酸信号共同传递给NAC。我们发现，ChR2的光激活在病毒注射到向NAC发送轴突的几个大脑区域后，在NAC壳中唤起谷氨酸介导的突触EPSCs。然后将这些EPSP特性在针对NAC的通路中进行比较，如腹侧海马体、杏仁基底外侧核和内侧前额叶皮质，并可以比较这些通路中每一条通路在暴露于大麻精神活性成分β-9-四氢大麻酚(THC)后功能的变化。具体地说，我们最近的工作表明，暴露于THC超过2周会导致NAC壳的前额叶皮质输入显著减弱，并极大地增强来自腹侧海马和杏仁基底外侧核的输入。在NAC的输入中观察到的变化模式与在人类大麻使用者中进行的脑成像研究的报告一致，并表明随着长期使用THC，NAC失去了皮质控制，皮质下控制增加。这对人类的认知和情绪处理有重要的影响，我们假设我们确定的变化与被诊断为大麻使用障碍的人类的行为和精神变化有关。其他工作包括检查NAC的输出通路与与人类吸毒和复发有关的冲动行为的相关性。在这方面，我们正在将逆行追踪研究与免疫组织化学相结合，以确定NAC靶向参与抑制不想要的行为的通路。这些正在进行的研究已经开发出冲动行为的行为分析，这种行为分析会因干扰NAC的输出而增加。这些最近的研究表明，来自NAC的输出对于控制涉及有效奖励寻求策略的操作者行为以及寻求可卡因等药物的冲动非常重要。

The nucleus accumbens (NAc) is a critical brain area involved in motivation that mediates the rewarding and addictive properties of several classes of abused drugs. Additionally, because of its role in motivational processes, the NAc is also implicated in psychiatric disorders that involve alterations in mood, and motivation. Therefore, it is necessary to understand the basic function of this brain region, as well as the actions of abused drugs such as marijuana, cocaine, opioids, and designer drugs on this system. The NAc is largely comprised of medium spiny, GABAergic output neurons (MSNs) that receive innervation from other MSNs, glutamate innervation from many additional brain areas, and dopamine innervation from the ventral midbrain. Acutely, both GABA and glutamate synapses onto MSNs are inhibited by several classes of abused drugs, suggesting that this action may contribute to their rewarding properties, and long-term exposure to drugs alters the function of both intrinsic circuits and extrinsic inputs. In addition, abused drugs are known to increase the release of dopamine (DA) in the NAc, and this likely contributes to long-term changes in excitatory transmission observed following repetitive activation of glutamatergic afferents. Although much is known about the contributions of the NAc to behavior, the precise mechanisms in which such synaptic plasticity contributes to behavior, and how abused drugs alter synaptic processes remains poorly understood. To investigate the actions of abused drugs in the NAc, we are utilizing electrophysiology and behavioral analyses combined with optogenetic techniques in transgenic and normal rodents. Current experiments involve examining the influence of specific NAc input and output pathways on behavior and changes in these pathways after exposure to abused drugs by self-administration or through experimenter delivery. Optogenetics permits selective expression of the light-activated proteins, such as channelrhodopsin-2 (ChR2), or halorhodopsin (Halo) when an adeno-associated virus (AAV) containing these constructs are used. As many tyrosine hydroxylase positive (TH+) VTA neurons also express the vesicular glutamate-2 transporter (VGlut-2) they are capable of co-transmitting DA and glutamate signals to the NAc. We find that light-activation of ChR2 evokes glutamate-mediated synaptic EPSCs in the NAc shell following virus injections into several brain regions that send axons to the NAc. These EPSP properties are then compared among pathways targeting the NAc, such as the ventral hippocampus, basolateral amygdala and medial prefrontal cortex, and alterations in their function following exposure to the psychoactive component of marijuana, delta-9-tetrahydrocannabinol (THC), on each of these pathways can be compared. Specifically, our recent work shows that exposure to THC over 2 weeks causes a significant weakening of prefrontal cortical inputs to the NAc shell, and greatly strengthens inputs arising from the ventral hippocampus and basolateral amygdala. The pattern of changes observed in the inputs to the NAc are consistent with reports in brain imaging studies conducted in human marijuana users, and suggest a loss of cortical control over the NAc and an increase in subcortical control with chronic THC use. This has important implications for cognition and emotional processing in humans, and we hypothesize that the changes we have identified are related to behavioral and psychiatric changes seen in humans that are diagnosed with cannabis use disorder. Additional work includes an examination of the relevance of output pathways of the NAc to impulsive behaviors that are linked to drug use and relapse to drug seeking in humans. In this regard, we are combining retrograde tracing studies with immunohistochemistry to identify pathways targeted by the NAc that are involved in suppression of unwanted behavior. These ongoing studies have developed behavioral assays of impulsive behavior that are increased by disruption of NAc output. These more recent studies are indicating that outputs from the NAc are important for controlling operant behavior involving efficient reward seeking strategies, and in the impulse to seek drugs like cocaine.