Electrophysiology of alcohol in extended amygdela

扩展杏仁核中酒精的电生理学

• 批准号: 7490550
• 负责人: GEORGE Robert SIGGINS
• 金额: $ 30.74万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-27 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7490550
• 关键词: Acute; Agonist; Alcohol consumption; Alcohol dependence; Alcoholic Intoxication; Alcoholism; Alcohols; Amygdaloid structure; Animal Model; Animals; Anxiety; Area; Behavior; Behavioral; Biological; Boutos; Brain; Brain region; Breeding; CRF receptor type 2; Cell Nucleus; Cell physiology; Cells; Chromosome Pairing; Chronic; Cocaine; Collaborations; Communication; Complex; Data; Dependence; Disease; Drug Addiction; Dynorphins; Electrodes; Electrophysiology (science); Enkephalins; Epilepsy; Ethanol; Ethanol dependence; Figs - dietary; Frequencies; Future; Galanin; Genetic; Genotype; Glutamates; Heavy Drinking; Hippocampus (Brain); Hypothalamic structure; Investigation; Ion Channel; Knock-out; Knockout Mice; Knowledge; Laboratories; Ligands; Maps; Measures; Mediating; Membrane; Mental Depression; Messenger RNA; Methods; Modeling; Molecular; Morphine; Mouse Strains; Mus; Mutation; Neurons; Neuropeptides; Norepinephrine; Nucleus Accumbens; Opioid; Opioid Receptor; Oral; Peptides; Pharmaceutical Preparations; Physiologic pulse; Physiological; Play; Polymerase Chain Reaction; Preparation; Process; Property; Psychological reinforcement; Publishing; Pulse taking; Radioimmunoassay; Rattus; Reporting; Research; Research Personnel; Rewards; Role; Schedule; Science; Self Administration; Self-Administered; Site; Slice; Standards of Weights and Measures; Stress; Structure of terminal stria nuclei of preoptic region; Synapses; Synaptic Potentials; Synaptic Transmission; System; Testing; Tetrodotoxin; Thinking; Time; Withdrawal; Work; alcohol behavior; alcohol effect; alcohol exposure; alcohol sensitivity; base; biological adaptation to stress; conditioning; delta opioid receptor; drinking; drug of abuse; endogenous opioids; galanin receptor; gamma-Aminobutyric Acid; interest; kappa opioid receptors; locus ceruleus structure; motivated behavior; mouse model; neuroadaptation; neurochemistry; nociceptin; paired stimuli; patch clamp; postsynaptic; presynaptic; receptor; receptor binding; release factor; research study; response; size; transmission process

This project is based on behavioral findings that the central amygdala nucleus (CeA) and locus coeruleus (LC) are key brain areas involved in stress reactions and the reinforcing properties of abused drugs, and that these behaviors may involve several transmitters (GABA, glutamate, norepinephrine) and neuropeptides (CRF, opioids and galanin). Both regions are implicated in motivated behaviors and anxiety states, and we hypothesize that these same neurochemical systems within the CeA and LC are involved in the excessive ethanol drinking seen in dependent animals. Therefore, we propose several sets of experiments: 1) To assess the role of CRF receptors in excessive drinking, by comparing the CeA cellular and network function in brain slices from control and excessively drinking mice (WID model) mice, with respect to the ethanol augmentation of GABAergic IPSCs or inhibition of glutamatergic EPSPs, combined with cytochemical localization of CRF and CRF receptors. 2) To determine the role of kappa opiate receptors (KORs) in excessive drinking, for comparison to our mu and delta receptor data, by examining CeA cellular function in brain slices from WID mice with a knockout (KO) for brain KORs. 3) To determine the role of galanin and its receptors in excessive drinking, by examining CeA and LC cellular in slices from WID mice and those with KOs for brain Gall and Gal2 receptors and with galanin over-expression, and by neurochemical and molecular biological measures in CeA and LC neurons. 4) To determine the effects on the largest WID- induced changes from the results of Specific Aims 1-3, in the HDID mice selectively bred by the Crabbe and Finn groups for high drinking in the dark versus their controls, and for SHAG vs.SLAG lines, selected for scheduled high and low alcohol consumption.The electrophysiological studies will use CeA and LC brain slices and involve standard intracellular and whole-cell clamp methods. We will use a battery of measures to assess the pre- versus postsynaptic sites of action of ethanol and peptide effects. RIA, real-time PCR and receptor binding studies will be used in the galanin studies. This project should provide important new ¿ information on the possible sequelae of ethanol intoxication at the cellular level, and, by comparisons of ethanol and peptide actions in control, excessively drinking, and knockout models, will also provide clues as to the synaptic, cellular and ion channel correlates of ethanol dependence.

该项目是基于行为学的发现，中央杏仁核（CeA）和蓝斑 (LC)是参与压力反应和滥用药物强化特性的关键大脑区域，并且 这些行为可能涉及几种递质（GABA、谷氨酸、去甲肾上腺素）和神经肽 (CRF阿片类药物和甘丙肽）。这两个区域都与动机行为和焦虑状态有关， 假设CeA和LC中的这些相同的神经化学系统参与了过度的 依赖性动物中的乙醇饮用。因此，我们提出了几组实验：1） 评估CRF受体在过量饮酒中的作用，通过比较CeA细胞和网络功能， 在来自对照和过度饮酒小鼠（WID模型）的脑切片中，关于乙醇 增强GABA能IPSC或抑制GABA能EPSP，结合细胞化学 CRF和CRF受体的定位。2)为了确定κ阿片受体（KOR）在 过量饮酒，与我们的mu和delta受体数据进行比较，通过检查 来自具有脑KOR敲除（KO）的WID小鼠的脑切片。3)为了确定甘丙肽的作用及其 受体在过量饮酒中的作用，通过检查WID小鼠和那些 脑Gal 1和Gal 2受体以及甘丙肽过表达的科斯，以及神经化学和 CeA和LC神经元的分子生物学测量。4)为了确定对最大WID的影响- 在Crabbe选择性饲养的HDID小鼠中，根据特异性目的1-3的结果诱导变化， Finn组在黑暗中大量饮酒与对照组相比，SHAG与SLAG系，选择 预定的高和低酒精消费。电生理研究将使用CeA和LC脑 切片，并涉及标准的细胞内和全细胞钳方法。我们将采取一系列措施， 评估乙醇和肽作用的突触前和突触后作用部位。RIA、实时PCR和 受体结合研究将用于甘丙肽研究。该项目将提供重要的新？ 关于乙醇中毒在细胞水平上可能的后遗症的信息， 乙醇和肽在控制，过度饮酒和敲除模型中的作用，也将提供线索， 与乙醇依赖性的突触、细胞和离子通道相关。