Central Amygdala Kappa Opioid Receptor Mechanisms Underlying Effects of Ethanol

中央杏仁核 Kappa 阿片受体机制是乙醇作用的基础

• 批准号: 8058761
• 负责人: Scott D. Moore
• 金额: $ 18.53万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-10 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8058761
• 关键词: Acute; Agonist; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcohols; Amygdaloid structure; Animal Feed; Animals; Anxiety; Behavior; Behavioral; Brain; Brain region; Cell Nucleus; Cells; Chronic; Chronic Disease; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Development; Diet; Drug Addiction; Dynorphins; Enkephalins; Ethanol; Ethanol dependence; Exhibits; Heavy Drinking; Human Genetics; In Vitro; Intervention; Lateral; Ligands; Measures; Medial; Mediating; Mediation; Membrane Potentials; Neurons; Neuropeptides; Opiates; Opioid; Opioid Peptide; Outcome; Pathway interactions; Peptide Receptor; Play; Presynaptic Terminals; Receptor Activation; Reporting; Rest; Rodent; Role; Site; Slice; Stress; Synaptic Transmission; System; Techniques; Testing; Therapeutic; Walkers; Withdrawal; alcohol effect; biological adaptation to stress; drug of abuse; electric impedance; kappa opioid receptors; neuronal cell body; neurotransmission; patch clamp; presynaptic; public health relevance; release factor 3; research study; therapeutic development; voltage

DESCRIPTION (provided by applicant): The kappa opioid receptor (KOR) and its endogenous agonist, dynorphin, have been identified as critical for alcohol abuse and dependence. Human genetic studies have shown that the KOR system is associated with alcohol dependence (Xuei et al., 2006). In addition, behavioral studies using animals reported that KOR agonists decrease voluntary ethanol intake (Lindholm et al., 2001), while KOR antagonists decrease ethanol intake in chronically ethanol-treated animals (Walker and Koob, 2008). The KOR system has been suggested to mediate dysphoric effects of drugs of abuse including ethanol, and it has recently suggested that KOR system plays a role downstream of the corticotrophin releasing factor (CRF) system (Land et al., 2008). This proposal will test the hypothesis that the KOR system in the central amygdala nucleus (CeA), a critical brain region involved in stress and anxiety behavior as well as drug addiction, mediates acute ethanol effects and that the KOR system in CeA is dysregulated following chronic ethanol treatment. A second hypothesis to be tested is that KORs mediate ethanol effects through the CRF system in CeA. This study will examine the KOR system and its interaction with the CRF system using whole cell patch clamp electrophysiological techniques. We will investigate the role of these systems in mediating ethanol effects in the CeA in rodent brain slices taken from naove and chronically ethanol-treated animals. We will examine tonic effects of the KOR system as well as effects of acute activation of the KOR system on spontaneous excitatory and inhibitory neurotransmission in the CeA network. Studies will be performed in two subregions of central amygdala, lateral and medial divisions, as these divisions exhibit differential distribution of dynorphin (the putative endogenous KOR ligand) (Marchant et al., 2007). We will examine the effect of KOR antagonism and activation in four different conditions including (1) control conditions, (2) acute in vitro pretreatment with CRF, (3) acute in vitro pretreatment with ethanol, and (4) in brain slices from chronic ethanol treated animals and pair-fed animals with an equicaloric control diet. To investigate whether the KOR effect is dependent on CRF receptor activation, we will repeat experiments in the presence of CRF receptor antagonists. Understanding the role of the kappa opioid system in mediating alcohol actions in CeA should facilitate development of therapeutic alternatives to ameliorate alcohol dependence and abuse. PUBLIC HEALTH RELEVANCE: Alcohol dependence is a chronic disease characterized by uncontrollable excessive consumption of alcohol. Currently available pharmacological interventions have limited beneficial effects. This project will be investigating a candidate mechanism underlying alcohol dependence, a kappa opioid system in the amygdala. The outcome of this project will contribute to develop more effective pharmacological therapeutics to ameliorate and/or treat alcohol dependence.

描述(申请人提供)：kappa阿片受体(KOR)及其内源性激动剂强啡肽已被确定为酒精滥用和依赖的关键因素。人类遗传学研究表明，KOR系统与酒精依赖有关(薛等人，2006年)。此外，动物行为学研究报告说，KOR激动剂减少了自愿的乙醇摄入量(Lindholm等人，2001年)，而KOR拮抗剂减少了长期使用乙醇的动物的乙醇摄入量(Walker和Koob，2008)。KOR系统被建议用来调节包括乙醇在内的滥用药物的烦躁效应，最近有人建议KOR系统在促肾上腺皮质激素释放因子(CRF)系统的下游发挥作用(Land等人，2008年)。这项提议将检验这样的假设，即杏仁中央核(CEA)的KOR系统介导了急性乙醇效应，并且CEA中的KOR系统在慢性乙醇治疗后调节失调。CEA是参与应激和焦虑行为以及药物成瘾的关键脑区。需要检验的第二个假设是，Kors通过CEA中的CRF系统调节乙醇效应。本研究将利用全细胞膜片钳电生理技术研究KOR系统及其与CRF系统的相互作用。我们将研究这些系统在从NAOVE和长期酒精处理的动物的啮齿动物脑片中介导乙醇对CEA的影响中的作用。我们将研究KOR系统的紧张性效应，以及KOR系统的急性激活对CEA网络中自发兴奋性和抑制性神经传递的影响。研究将在杏仁中央核的两个亚区，即外侧和内侧分区进行，因为这些分区显示强啡肽(假定的内源性KOR配体)的不同分布(Marchant等人，2007年)。我们将研究KOR在四种不同条件下的拮抗和激活作用，包括(1)对照条件，(2)CRF的急性体外预处理，(3)乙醇的急性体外预处理，(4)在慢性乙醇处理动物和配对喂养的等热量对照饲料动物的脑片中。为了研究KOR效应是否依赖于CRF受体的激活，我们将在CRF受体拮抗剂存在的情况下重复实验。了解kappa阿片系统在调节CEA中酒精行为中的作用应有助于开发治疗替代方案来缓解酒精依赖和滥用。 与公共卫生相关：酒精依赖是一种慢性疾病，其特征是无法控制地过度饮酒。目前可用的药理干预措施有益效果有限。该项目将研究酒精依赖的候选机制，即杏仁核中的kappa阿片系统。该项目的成果将有助于开发更有效的药物疗法来缓解和/或治疗酒精依赖。