Alcohol and Dopamine Release: Cellular and Synaptic Mechanisms

酒精和多巴胺的释放：细胞和突触机制

• 批准号: 8111307
• 负责人: NEIL L. HARRISON
• 金额: $ 36.75万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8111307
• 关键词: Acute; Alcohol abuse; Alcohol consumption; Alcoholism; Alcohols; Behavior; Behavioral; Brain; Brain Part; Cells; Chemicals; Cholinergic Receptors; Chronic; Cocaine; Consensus; DRD2 gene; Data; Dependence; Development; Disinhibition; Dopamine; Dose; Ethanol; Health; Human; Image; In Vitro; Individual; Interneurons; Intoxication; Laboratories; Lasers; Lead; Mediating; Microscope; Morphine; Mus; Nerve Endings; Neurons; Neurotransmitters; Nucleus Accumbens; Opiates; Pharmaceutical Preparations; Physiological; Population; Preparation; Process; Property; Public Health; Rattus; Rewards; Site; Slice; Specialist; Synapses; System; Technology; Testing; United States; Ventral Striatum; Ventral Tegmental Area; alcohol and other drug; alcohol effect; alcohol exposure; behavioral sensitization; brain cell; cholinergic; cholinergic neuron; design; dopamine system; dopamine transporter; dopaminergic neuron; drug of abuse; in vivo; presynaptic; public health relevance; reward circuitry; sedative; social; transmission process

DESCRIPTION (provided by applicant): Drinking alcohol results in short-term behavioral changes and longer-term adaptations that lead to abuse and dependence. These adaptations are not understood, but a consensus suggests that, in accordance with the mechanism of all addictive drugs, an increase in the release of dopamine (DA) is associated with behavioral sensitization to alcohol and is related to the abuse liability of the drug. Although alcohol is known to enhance DA release in the nucleus accumbens (nAc), the mechanism is not known. In this proposal we will evaluate competing hypotheses for the action of alcohol on the DA system. The Specific Aims are: 1) to investigate the effects of alcohol on dopaminergic and GABAergic neurons in the VTA. The release of DA in the nucleus accumbens is activated by acute alcohol exposure in vivo. One possible explanation for this is that alcohol directly or indirectly increases the firing rate of DAergic neurons within the VTA, as is the case with other drugs of abuse, such as the opiates. We will investigate the effects of alcohol on identified populations of DAergic projection neurons and local GABAergic neurons in the VTA using GAD67-GFP and TH-GFP mice. The hypothesis to be tested is that acute alcohol activates the VTA, either by disinhibition (as with opiates) or by direct activation of DA neurons, which subsequently results in increased release of DA within the nAc. 2) To study the interactions between alcohol and dopamine release in the nucleus accumbens (nAc) We will use the newly developed technology of fluorescent false neurotransmitters (FFNs) to image individual DAergic terminals, and combined with the use of physiologically relevant stimulation parameters, compare these results with those using conventional cyclic voltammetry. The hypothesis to be tested is that alcohol increases DA release from a subset of DAergic neurons terminating within the nAc, possibly due to the differential presence of presynaptic GABAergic and/or cholinergic receptors. 3) To study the effects of alcohol on the activity of a population of cholinergic interneurons the in nAc and medium spiny neurons in the nAc. More than 90% of the cells in the ventral striatum are medium spiny neurons (MSNs), but several classes of interneurons also exist, including a population of cholinergic neurons, the activity of which strongly regulates evoked DA release in the nAc. The hypothesis to be tested is that alcohol enhances cholinergic neuron activity in the nAc. PUBLIC HEALTH RELEVANCE: Alcoholism is a major public health problem in the United States. Drinking alcohol results in changes in behavior in the short-term that are reversible, but in the long-term chronic abuse of alcohol results in physiological changes that are detrimental to human health and have societal consequences. We know that a brain chemical called dopamine is released from nerve endings in the brain when we drink alcohol, and that this is associated with the addictive properties of alcohol and other drugs. This process is not well understood, but could be a result of effects of alcohol in two parts of the brain's reward circuitry, the ventral tegmental area (VTA) or the nucleus accumbens (nAc). In this proposal we will study alcohol effects to see whether it acts in the VTA (like morphine) or in the nAc (like cocaine) in order to change the activity of brain cells. This will be done using state-of-the-art electrical recording and a laser confocal microscope.

描述（由申请人提供）： 饮酒会导致短期的行为变化和长期的适应，从而导致滥用和依赖。这些适应尚不清楚，但共识表明，根据所有成瘾药物的机制，多巴胺（DA）释放的增加与对酒精的行为敏感化有关，并与药物的滥用倾向有关。虽然已知酒精可增强多巴胺在丘脑核（nAc）中的释放，但其机制尚不清楚。在这个建议中，我们将评估竞争的假设，酒精的DA系统的行动。具体目的：1）研究酒精对腹侧被盖区多巴胺能神经元和γ-氨基丁酸能神经元的影响。在体急性酒精暴露可激活中脑延髓核DA的释放。一种可能的解释是，酒精直接或间接增加腹侧被盖区DA能神经元的放电率，就像其他滥用药物（如阿片类药物）一样。我们将使用GAD 67-GFP和TH-GFP小鼠研究酒精对腹侧被盖区DA能投射神经元和局部GABA能神经元的影响。有待检验的假设是，急性酒精激活腹侧被盖区，无论是通过去抑制（与阿片类药物）或通过直接激活DA神经元，随后导致增加释放的DA内的nAc。2)为了研究乙醇与多巴胺在丘脑腹外侧核（nAc）释放的相互作用，我们将利用新发展的荧光假神经递质（FFNs）技术对单个DA能末梢进行成像，并结合生理相关的刺激参数，将这些结果与传统的循环伏安法进行比较。要测试的假设是，酒精增加DA释放从DA能神经元的一个子集内终止的nAc，可能是由于突触前GABA能和/或胆碱能受体的差异存在。3)目的：研究酒精对nAc胆碱能中间神经元和nAc中棘神经元活动的影响。腹侧纹状体中超过90%的细胞是中等多刺神经元（MSN），但也存在几类中间神经元，包括一群胆碱能神经元，其活性强烈调节nAc中诱发的DA释放。待检验的假设是，酒精增强nAc中胆碱能神经元的活性。 公共卫生相关性： 酗酒是美国的一个主要公共卫生问题。饮酒会导致短期内可逆的行为变化，但长期慢性滥用酒精会导致对人类健康有害的生理变化，并产生社会后果。我们知道，当我们喝酒时，大脑中的神经末梢会释放出一种叫做多巴胺的化学物质，这与酒精和其他药物的成瘾特性有关。这个过程还没有被很好地理解，但可能是酒精对大脑奖励回路的两个部分的影响的结果，腹侧被盖区（VTA）或丘脑核（nAc）。在这个建议中，我们将研究酒精的影响，看看它是否作用于腹侧被盖区（如吗啡）或nAc（如可卡因），以改变脑细胞的活动。这将使用最先进的电子记录和激光共聚焦显微镜来完成。