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Synaptic Transmission: Modulation, Plasticity And Effects Of Drugs Of Abuse

突触传递：调节、可塑性和滥用药物的影响

基本信息

批准号：
10922444
负责人：
David M Lovinger
金额：
$ 230.75万
依托单位：
NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10922444
关键词：
Abstinence Acute Address Air Alcohol consumption Alcoholic Intoxication Alcohols Animals Behavior Behavior Control Blood alcohol level measurement Brain Chronic Cognition Corpus striatum structure Custom Darkness Decision Making Dependence Dopamine Drug Exposure Electric Stimulation Elements Ethanol Ganglia Goals Habits Inhalation Exposure Intake Intoxication Investigation Laboratories Lobular Neoplasia Measures Mediating Midbrain structure Mus Neuromodulator Neurons Neurosciences Nucleus Accumbens Periodicity Pharmaceutical Preparations Physiological Play Polysomnography Procedures Process Prosencephalon Research Research Personnel Rewards Role Scanning Sleep Slice Synapses Synaptic Transmission System Technology Ventral Striatum alcohol and other drug alcohol behavior alcohol effect alcohol exposure alcohol misuse alcohol seeking behavior alcohol use disorder brain circuitry cohort design dopaminergic neuron drinking drug action drug misuse drug of abuse experimental study interest neural neural circuit neuroadaptation neuromechanism neuronal circuitry non rapid eye movement response

项目摘要

Chronic Alcohol Exposure Alters Acute Alcohol Effects on Dopamine Release: Potential Role in Alcohol Effects on Sleep Acute alcohol exposure is known to produce increases levels of the neuromodulator dopamine in the striatum, with the largest effects in the Nucleus accumbens (NAc)/ventral striatum and the dorsomedial (associative) striatum (DMS). This acute alcohol effect is largely attributed to enhanced activity of midbrain dopaminergic neurons that project to striatum where they release dopamine. The dopamine increase in NAc may contribute to the rewarding effects of the drug. In addition, alcohol has a less potent inhibitory action on dopamine release from terminals in the NAC. There is also considerable interest in how chronic alcohol exposure and regular binge-like alcohol drinking alter the dopaminergic system. To address this latter question with an emphasis on the associative brain circuitry we measured dopamine release following chronic alcohol exposure in the DMS using electrical stimulation and fast-scan cyclic voltammetry in C57Bl6/J mice. We used two alcohol exposure paradigms, chronic intermittent forced inhalational exposure to ethanol (CIE) and the drinking in the dark (DID) voluntary intake procedure. Both paradigms were conducted for 4 weeks, followed by a minimum 6 day forced abstinence period. Brain slices containing DMS were prepared from CIE and DID-exposed mice and appropriate controls beginning 6 days into forced abstinence. Voltammetric recordings in DMS revealed increased dopamine release and prolonged release in CIE-treated mice relative to air-only exposed controls. No such changes were observed in the DID-exposed mice. When acute ethanol application effects on dopamine release were examined, we observed no inhibition in alcohol naive mice, but inhibition by 40 mM ethanol in DMS in both CIE and DID-exposed mice. This finding indicates that the mechanisms underlying this acute alcohol action become stronger after chronic exposure. Such an adaptation could explain how the normal increase in dopamine produced by acute alcohol could be dampened following repeated heavy alcohol intake. We are currently investigating mechanisms that potentially contribute to the acute alcohol inhibition and the increase following chronic exposure. These experiments were carried out as part of a larger study examining alcohol effects on mouse sleep. We used polysomnography and our custom-designed unsupervised sleep scoring system to examine effects of CIE and DID on sleep in cohorts of 20 mice that contained both alcohol-treated animals and controls. Somewhat surprisingly we found that CIE had little effect on sleep, while DID produced increased wake and decreased non-rapid eye movement (NREM) sleep, despite the fact that blood alcohol concentrations were higher in the CIE paradigm. This finding provides an intriguing opportunity to relate the changes in dopamine release to sleep alterations observed in the DID mice. We are also beginning to explore other neural mechanisms that may contribute to the changes in sleep in these mice.

慢性酒精暴露改变急性酒精对多巴胺释放的影响：酒精对睡眠影响的潜在作用已知急性酒精暴露会增加纹状体中神经调质多巴胺的水平，其中在延髓核（NAc）/腹侧纹状体和背内侧（联合）纹状体（DMS）中的影响最大。这种急性酒精效应主要归因于中脑多巴胺能神经元的活性增强，这些神经元投射到纹状体，在那里它们释放多巴胺。NAc中多巴胺的增加可能有助于药物的奖励作用。此外，酒精对NAC末梢释放多巴胺的抑制作用较弱。还有相当大的兴趣是如何慢性酒精暴露和定期酗酒，如饮酒改变多巴胺能系统。为了解决后一个问题，重点是关联的脑回路，我们测量了多巴胺释放后，慢性酒精暴露在DMS中使用电刺激和快速扫描循环伏安法在C57 B16/J小鼠。我们使用了两种酒精暴露模式，慢性间歇性强迫吸入暴露于乙醇（CIE）和在黑暗中饮酒（DID）自愿摄入程序。两种模式都进行了4周，然后是至少6天的强制禁欲期。从CIE和DID暴露的小鼠和适当的对照组制备含有DMS的脑切片，开始强制戒断6天。DMS中的伏安记录显示，与仅暴露于空气的对照组相比，CIE处理的小鼠中多巴胺释放增加且释放时间延长。在DID暴露小鼠中未观察到此类变化。当研究急性乙醇应用对多巴胺释放的影响时，我们在未接触过酒精的小鼠中没有观察到抑制作用，但在CIE和DID暴露的小鼠中，40 mM乙醇在DMS中的抑制作用。这一发现表明，这种急性酒精作用的机制在慢性暴露后变得更强。这种适应可以解释急性酒精产生的多巴胺的正常增加如何在反复大量饮酒后受到抑制。我们目前正在研究可能导致急性酒精抑制和慢性暴露后增加的机制。这些实验是作为一项更大规模的研究的一部分进行的，该研究旨在研究酒精对小鼠睡眠的影响。我们使用多导睡眠图和我们定制设计的无监督睡眠评分系统来检查CIE和DID对20只小鼠的睡眠的影响，这些小鼠包括酒精治疗的动物和对照组。令人惊讶的是，我们发现CIE对睡眠几乎没有影响，而DID则增加了觉醒，减少了非快速眼动（NREM）睡眠，尽管血液酒精浓度在CIE范式中更高。这一发现提供了一个有趣的机会，将多巴胺释放的变化与在DID小鼠中观察到的睡眠改变联系起来。我们也开始探索可能导致这些小鼠睡眠变化的其他神经机制。