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

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 众所周知，急性酒精暴露会增加纹状体中神经调节剂多巴胺的水平，其中伏核(NAC)/腹侧纹状体和背内侧(联合)纹状体(DMS)的影响最大。这种急性酒精效应在很大程度上归因于中脑多巴胺能神经元活动增强，这些神经元投射到纹状体，在那里释放多巴胺。NAC中多巴胺的增加可能与药物的奖赏作用有关。此外，酒精对NAC终末释放多巴胺的抑制作用较弱。人们对长期饮酒和经常酗酒如何改变多巴胺能系统也很感兴趣。为了解决后一个问题，重点放在相关的大脑电路上，我们使用电刺激和快速扫描循环伏安法测量了C57BL6/J小鼠在慢性酒精暴露后DMS中的多巴胺释放。我们使用了两种酒精暴露范例，慢性间歇性强迫吸入乙醇(CIE)和在黑暗中饮酒(DID)自愿摄入程序。两个范例都进行了4周，然后至少6天强制禁欲。 从强制禁欲6天开始，从CIE和DID暴露的小鼠和适当的对照组制备含有DMS的脑片。DMS中的伏安记录显示，与仅暴露在空气中的对照组相比，CIE处理的小鼠的多巴胺释放增加，释放时间延长。在DID暴露的小鼠中没有观察到这样的变化。当检测急性乙醇处理对多巴胺释放的影响时，我们在酒精未成熟的小鼠中没有观察到抑制，但在CIE和DID暴露的小鼠中，40 mM乙醇对DMS中的多巴胺释放都有抑制作用。这一发现表明，这种急性酒精行为背后的机制在长期接触后变得更强。这种适应可以解释为什么在反复大量饮酒后，急性酒精产生的正常多巴胺增加会受到抑制。我们目前正在研究可能导致急性酒精抑制和慢性接触后酒精增加的机制。 这些实验是作为一项更大的研究的一部分进行的，该研究考察了酒精对小鼠睡眠的影响。我们使用多导睡眠图和我们定制的非监督睡眠评分系统来检查CIE对20只小鼠睡眠的影响，其中包括酒精处理的动物和对照组。有些令人惊讶的是，我们发现CIE对睡眠几乎没有影响，但确实增加了觉醒，减少了非快速眼动(NREM)睡眠，尽管CIE范式中的血液酒精浓度更高。这一发现提供了一个有趣的机会，可以将多巴胺释放的变化与在DID小鼠中观察到的睡眠变化联系起来。我们还开始探索其他可能导致这些小鼠睡眠变化的神经机制。

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.