Alcohol and Dopamine Release: Cellular and Synaptic Mechanisms

酒精和多巴胺的释放：细胞和突触机制

基本信息

批准号：
8660010
负责人：
NEIL L. HARRISON
金额：
$ 35.65万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
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/8660010
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 reward circuitry sedative social transmission process

项目摘要

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.

描述（由申请人提供）：饮酒会导致短期行为变化和长期适应，从而导致滥用和依赖。这些适应尚不清楚，但共识表明，根据所有成瘾性药物的机制，多巴胺（DA）的释放增加与行为对酒精的敏感有关，并且与该药物的滥用责任有关。尽管已知酒精可以增强伏隔核（NAC）中的DA释放，但该机制尚不清楚。在此提案中，我们将评估酒精对DA系统作用的竞争假设。具体目的是：1）研究酒精对VTA中多巴胺能和GABA能神经元的影响。 DA在伏隔核中的释放是通过体内急性酒精暴露激活的。对此的一种可能解释是，酒精直接或间接增加了VTA内的Daergic神经元的发射速率，就像其他滥用药物一样，例如阿片类药物。我们将使用GAD67-GFP和TH-GFP小鼠研究酒精对VTA中鉴定出的Daergic投射神经元和局部GABA能神经元的影响。要检验的假设是，急性酒精通过抑制（与阿片类药物一样）或直接激活DA神经元激活VTA，这随后导致NAC内DA的释放增加。 2）为了研究伏隔核（NAC）中酒精和多巴胺释放之间的相互作用，我们将使用新开发的荧光假神经递质（FFN）技术来对单个DAERGIC终末进行图像，并与生理上相关的刺激参数的使用结合，将这些结果与使用常规的cyclit cytalmetsmetry进行比较。要测试的假设是，酒精会增加从NAC内终止的DAERMER元组的DA释放，这可能是由于存在突触前GABA能和/或胆碱能受体的差异所致。 3）研究酒精对NAC中NAC和中刺神经元中胆碱能中间神经元的活性的影响。腹侧纹状体中超过90％的细胞是中刺神经元（MSN），但也存在几类神经元的中间神经元，包括胆碱能神经元的群体，其活性强烈调节NAC中唤起的DA释放。要检验的假设是酒精会增强NAC中的胆碱能神经元活性。