LTPGABA in the VTA and its Modulation by Opioids

VTA 中的 LTPGABA 及其阿片类药物的调节

• 批准号: 7423923
• 负责人: Fereshteh S Nugent
• 金额: $ 4.05万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7423923
• 关键词: Affect; Amphetamines; Area; Attention; Behavioral; Brain; Cell physiology; Cells; Chromosome Pairing; Class; Cocaine; Dopamine; Dopaminergic Cell; Drug Addiction; Drug Exposure; Ethanol; Excitatory Synapse; Exposure to; Fire - disasters; Frequencies; Glutamates; In Vitro; Inhibitory Synapse; Learning; Long-Term Potentiation; Midbrain structure; Molecular; Morphine; Neuraxis; Neurons; Nicotine; Nucleus Accumbens; Opiates; Opioid; Pharmaceutical Preparations; Physiological; Play; Population Heterogeneity; Prefrontal Cortex; Presynaptic Terminals; Prosencephalon; Rattus; Reporting; Research; Rewards; Role; Signal Transduction; Slice; Societies; Synapses; Synaptic Transmission; Synaptic plasticity; Travel; Ventral Tegmental Area; addiction; dopaminergic neuron; drug of abuse; gamma-Aminobutyric Acid; in vivo; interest; mesolimbic system; novel; patch clamp; postsynaptic; research study; response; transmission process

DESCRIPTION (provided by applicant): My primary area of interest is in the ventral tegmental area (VTA). This brain area consists of a heterogeneous population of neurons, plays a role in endogenous reward and is affected by many drugs of abuse. My colleague and I have found a novel long-term potentiation (LTP) of GABAergic synapses onto VTA dopaminergic neurons which can be altered by opioids in vitro. My project focuses on the characterization of this inhibitory LTP, and its underlying mechanisms. Additionally, I am interested in defining the molecular mechanisms by which opioids modify the excitability of the VTA neurons through the alterations of GABAergic transmission; and plasticity in the VTA. All experiments will be conducted in midbrain slices of rats using visualized patch clamp recording.Aim 1:To characterize the cellular postsynaptic mechanisms underlying the induction of LTPGABA. Aim 2:To determine the retrograde signal that travels from the postsynaptic initiating neuron to direct the presynaptic terminal to release more GABA during LTP.Aim 3: To explore the effects of opioids on this LTPGABA in vivo. Considering the enormous burden of drug addiction on society, the focus of this research is highly important. Studies such as this will provide a better understanding of how drugs of abuse modulate brain circuitry in a way causing an addict to manifest long-term unwanted behavioral changes. This study could also provide the potential targets for anti-addiction drugs.

描述（由申请人提供）：我感兴趣的主要区域是腹侧被盖区（VTA）。这个大脑区域由异质的神经元群体组成，在内源性奖励中发挥作用，并受到许多滥用药物的影响。我的同事和我发现了一种新的GABA能突触长时程增强（LTP）到腹侧被盖区多巴胺能神经元，这可以被阿片类药物在体外改变。我的项目集中在这种抑制性LTP的特征，及其潜在的机制。此外，我感兴趣的是确定阿片类药物通过改变GABA能传递和VTA可塑性来改变VTA神经元兴奋性的分子机制。所有实验均采用可视化膜片钳技术在大鼠中脑脑片上进行。目的1：探讨LTPGABA诱导的突触后机制。目的2：确定LTP过程中突触后起始神经元是否有逆行信号引导突触前末梢释放更多的GABA。目的3：探讨阿片类药物对LTP过程中LPGABA的影响。考虑到吸毒成瘾给社会带来的巨大负担，这项研究的重点非常重要。像这样的研究将提供一个更好的理解滥用药物如何调节大脑回路的方式，导致成瘾者表现出长期不必要的行为变化。该研究也为抗成瘾药物提供了潜在的靶点。