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) 是几类滥用药物产生奖赏性和成瘾性的关键部位。因此，有必要了解大麻、可卡因、阿片类药物和设计药物等滥用药物对该系统生理学的作用，并了解与 NAc 连接的重要大脑回路。此外，众所周知，该脑核可以调节行为的动机方面。 因此，NAc 与多种精神疾病有关，这些精神疾病涉及情绪和动机的改变，以及毒瘾的过程。 NAc 中型多刺 GABA 能输出神经元 (MSN) 接受来自其他内在 MSN 的神经支配，以及来自外在来源的谷氨酸能神经支配。 MSN 上的 GABA 能和谷氨酸能突触都会受到滥用药物的抑制，这表明这种作用可能有助于它们的奖励特性。 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促进谷氨酸能传入神经重复激活后观察到的兴奋性传递的长期变化。 然而，人们对这种突触可塑性发展的精确机制以及滥用药物如何改变这种突触可塑性仍然知之甚少。 为了研究滥用药物在 NAc 中的作用，我们利用电生理学和快速扫描循环伏安法 (FSCV) 记录技术对从转基因和正常啮齿动物获得的脑切片进行记录。 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检查转基因大鼠腹侧被盖（VTA）DA神经元产生的兴奋性突触的突触特性，其中cre重组酶受到酪氨酸羟化酶启动子（TH-Cre大鼠）的控制。 因此，我们使用含有 ChR-2 构建体的腺相关病毒 (AAV-DIO-ChR2) 选择性表达光激活蛋白通道视紫红质-2 (ChR-2)。由于许多酪氨酸羟化酶阳性 (TH+) VTA 神经元也表达囊泡谷氨酸 2 转运蛋白 (VGlut-2)，因此它们能够将 DA 和谷氨酸信号共同传递至 NAc 以及 VTA 靶向的其他大脑区域。 在脑切片实验中，我们发现 FSCV 可以检测到 TH+ 轴突光激活（473 nm）期间 NAc 中 DA 的释放，但不能检测到侧缰核 (LHb)（另一个从 VTA 接收 TH+ 输入的大脑区域）中的 DA 释放。 然而，与这些实验相反，我们还发现光激活、谷氨酸介导的突触 EPSC 在两个大脑区域都很容易检测到。 这表明 LHb 中 DA 释放的机制与 NAc 中不同，而谷氨酸释放的控制是不同的。 随后的实验检查了 NAc 和 LHb 中谷氨酸能 EPSC 的特性，结果表明这些光激活突触电流的生物物理动力学存在显着差异，NAc 中的突触电流的衰减动力学比 NAc 中的衰减动力学慢得多。 这些数据表明，这些相同的 TH+ 神经元针对的离子型谷氨酸受体在这些不同的大脑区域中有所不同。 计划中的实验将阐明这种差异的分子基础。