Effect Of Drugs of Abuse On Synaptic Transmission In Nucleus Accumbens

滥用药物对伏核突触传递的影响

• 批准号: 8933812
• 负责人: Carl R. Lupica
• 金额: $ 17.64万
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8933812
• 关键词: Addictive Behavior; Address; Affect; Area; Axon; Behavior; Brain; Brain region; Cell Nucleus; Cocaine; Data; Dependovirus; Designer Drugs; Development; Dopamine; Drug Addiction; Drug abuse; Excitatory Synapse; Glutamate Receptor; Glutamates; Goals; Habenula; Kinetics; Lateral; Learning; Light; Marijuana; Mediating; Mental disorders; Molecular; Molecular Genetics; Monitor; Moods; Motivation; Neurodegenerative Disorders; Neurons; Nucleus Accumbens; Opiates; Opioid; Output; Parkinson Disease; Pharmaceutical Preparations; Physiology; Play; Process; Property; Proteins; Rattus; Rewards; Rodent; Role; Scanning; Signal Transduction; Site; Slice; Source; Synapses; Synaptic Transmission; Synaptic plasticity; System; Techniques; Transgenic Organisms; Translating; Tyrosine 3-Monooxygenase; base; dopaminergic neuron; drug of abuse; interest; learned behavior; motor learning; nerve supply; neurochemistry; promoter; recombinase; research study; selective expression; transmission process; vesicular glutamate transporter 2

The nucleus accumbens (NAc) represents a critical site for the rewarding and addictive properties of several classes of abused drugs. Therefore, it is necessary to understand the actions of abused drugs such as marijuana, cocaine, opioids, and designer drugs on physiology of this system, as well as to understand the important brain circuits that connect with the NAc. In addition, this brain nucleus is known to mediate motivational aspects of behavior. For this reason the NAc has been implicated in a variety of psychiatric disorders that involve alterations in mood and motivation, as well as in the process of drug addiction. The NAc medium spiny GABAergic output neurons (MSNs) receive innervation from other intrinsic MSNs, and glutamatergic innervation from extrinsic sources. Both GABAergic and glutamatergic synapses onto MSNs are inhibited by abused drugs, suggesting that this action may contribute to their rewarding properties. In addition, abused drugs are known to increase the release of dopamine (DA)in the NAc. One role of DA in regulating NAc activity may be to contribute to the long-term changes in excitatory transmission observed following repetitive activation of glutamatergic afferents. However, the precise mechanisms through which such synaptic plasticity develops, and how drugs of abuse alter such synaptic plasticity, remain poorly understood. To investigate the actions of abused drugs in the NAc, we are utilizing both electrophysiological and fast scan cyclic voltammetry (FSCV) recording techniques in brain slices obrained from transgenic and normal rodents. By combining these approaches, we hope to be able to simultaneously monitor changes in DA levels and the development of synaptic plasticity. Our most recent experiments have involved examining the synaptic properties of excitatory synapses arising from ventral tegmental (VTA)DA neurons in transgenic rats in which cre recombinase is under control of the tyrosine hydroxylase promoter (TH-Cre rats). Therefore, we selectively expressed the light-activated protein, channelrhodopsin-2 (ChR-2), using an adeno-associated virus containing the ChR-2 construct (AAV-DIO-ChR2). 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, as well as to other brain areas targeted by the VTA. In experiments with brain slices, we find that FSCV can detect DA release in the NAc during light-activation (473 nm) of TH+ axons, but not in the lateral habenula (LHb), another brain area receiving TH+ inputs from VTA. However, in contrast to these experiments, we also find that light-activated, glutamate-mediated synaptic EPSCs are readily detected in both brain regions. This suggestes that the mechanisms of DA release in the LHb differ from those in the NAc, whereas the control of glutamate release is distinct. Subsequent experiments examining the properties of glutamatergic EPSCs in both the NAc and LHb demonstrate that the biophysical kinetics of these light-activated synaptic currents differ significantly, with those in the NAc demonstrating much slower decay kinetic than those in the NAc. These data suggest that the ionotropic glutamate receptors targeted by these same TH+ neurons differ in these distinct brain regions. Planned experiments will elucidate the molecular basis for this difference.

伏隔核（NAC）代表了几类滥用药物的奖励和成瘾性能的关键位置。因此，有必要了解滥用药物的作用，例如大麻，可卡因，阿片类药物和设计师药物对该系统的生理学，以及了解与NAC相关的重要脑电路。另外，已知该脑核可以介导行为的动机方面。 因此，NAC与涉及情绪和动机改变以及吸毒过程的各种精神疾病有关。 NAC培养基GABA能神经元（MSN）从其他固有的MSN接收神经，并从外部源来获得谷氨酸能神经支配。滥用药物抑制了GABA能和谷氨酸能突触，这表明此作用可能有助于其奖励性能。 此外，已知滥用药物会增加NAC中多巴胺（DA）的释放。 DA在调节NAC活性中的作用之一可能是在重复激活谷氨酸能传递体后观察到的兴奋性传播的长期变化。 但是，这种突触可塑性发展的确切机制以及滥用药物如何改变这种突触可塑性，仍然对这种突触可塑性保持不足。 为了研究NAC中滥用药物的作用，我们正在利用电生理和快速扫描环状伏安法（FSCV）记录技术在从转基因和正常啮齿动物中屈服的脑切片中的记录技术。 通过结合这些方法，我们希望能够同时监测DA水平的变化和突触可塑性的发展。 我们最近的实验涉及研究由转基因大鼠中腹侧盖（VTA）DA神经元引起的兴奋性突触的突触特性，在这些大鼠中，CRE重组酶在酪氨酸羟化酶启动子（TH-CRE大鼠）的控制下。 因此，我们使用含有CHR-2构建体的腺相关病毒（AAV-DIO-CHR2）选择性地表达了光激活的蛋白通道Ropopsin-2（ChR-2）。由于许多酪氨酸羟化酶阳性（Th+）VTA神经元也表达了囊泡谷氨酸-2转运蛋白（VGLUT-2），因此它们能够将DA和谷氨酸信号共转移到NAC以及VTA靶向的其他大脑区域。 在使用脑切片的实验中，我们发现FSCV可以在TH+轴突的光激活（473 nm）期间检测NAC中的DA释放，而在侧向Habenula（LHB）中不能检测到来自VTA的TH+输入的另一个大脑区域。 但是，与这些实验相反，我们还发现在两个大脑区域都很容易检测到光激活，谷氨酸介导的突触EPSC。 这表明LHB中DA释放的机制与NAC中的机制不同，而谷氨酸释放的控制是不同的。 随后研究了NAC和LHB中谷氨酸能EPSC的性质的实验表明，这些光激活突触电流的生物物理动力学有很大差异，NAC中的NAC中的生物物理动力学比NAC中的NAC较慢。 这些数据表明，在这些不同的大脑区域中，由这些相同的TH+神经元靶向的离子型谷氨酸受体不同。 计划的实验将阐明这种差异的分子基础。