A Neural Mechanism Underlying Alcohol Consumption and Its Increase with Stress

描述(由申请人提供)：我们建议研究饮酒倾向背后的神经机制。这一机制最初被研究为在压力诱导的抑郁中很重要，现在似乎也显著地调节了饮酒的倾向。我们将集中讨论大脑中主要的去甲肾上腺素能细胞体蓝斑(LC)神经元的活动与代表中皮质边缘多巴胺系统胞体的腹侧被盖多巴胺神经元(VTA-DA神经元)的活动之间的关系。具体地说，我们将研究，最重要的是，这里将提出证据表明，饮酒意愿(或倾向)源于酒精深刻地抑制LC神经元的爆发式放电，从而减少对VTA-DA神经元的抑制影响，从而使乙醇能够显著增加VTA-DA神经元的放电，从而支持(促进)酒精消费。在这些研究中，我们将使用我们最初通过选择性育种培育的一种老鼠品系，以检测其应激敏感性(称为“易感”或“SUS”大鼠)。随后，我们发现这一品系的大鼠表现出明显的饮酒倾向，不同于我们的任何其他品系的选择性繁殖品系或正常的Spraogue-Dawley(SD)大鼠，后者不会自愿饮酒。事实上，SUS大鼠的饮酒量与专门为其饮酒倾向而培育的大鼠品系一样多，SUS大鼠自愿摄入的酒精量显然具有药理作用。此外，这些动物显示了一种现象，研究人员多年来一直试图在啮齿动物身上证明这一现象，甚至在喜欢饮酒的啮齿动物身上也是如此，这可能与SUS大鼠的应激敏感性有关--即SUS大鼠在暴露于压力时会增加酒精消耗量，从而显示出应激诱导的酒精消耗量增加。我们将研究上面描述的神经关系如何受到压力的影响，以及对这种关系的影响如何解释压力导致的酒精消耗量增加。在目标1中，我们通过选择性地增加或降低SUS大鼠的LC活性，然后测量(A)酒精摄入量和(B)乙醇注射诱导的条件性位置偏爱(CPP)来测试所提出的机制。乙醇摄入量和CPP随着LC活性的增加而降低，反之亦然。在目标2中，我们将记录VTA-DA神经元对酒精的反应，同时通过实验增加或降低LC活动，如目标1。最后，目标3将确定应激诱导的SUS大鼠酒精摄入量增加是否伴随着(A)对LC猝发放电的更大抑制，以及(B)酒精对VTA-DA更大的兴奋。 公共卫生相关性：在我们的实验室培育了一系列对压力表现出明显敏感的大鼠(称为游泳测试易感大鼠，或SUS大鼠)后，我们随后观察到，与正常大鼠相比，SUS大鼠表现出明确的饮酒倾向，在此，重要的是，暴露在应激条件下后，酒精消耗量增加。我们提出并计划测试一种潜在的神经生物学机制，该机制可能是SUS大鼠先天和压力诱导的大量饮酒倾向增强的基础，可能与其他类型的偏爱酒精的啮齿动物和人类酗酒者有关。

DESCRIPTION (provided by applicant): We propose to investigate a neural mechanism underlying propensity to consume alcohol. This mechanism was initially studied as being important in stress-induced depression, and now appears to prominently regulate the propensity to consume alcohol as well. We will focus on the relationship between activity of locus coeruleus (LC) neurons, the major noradrenergic cell body group in the brain, and dopamine neurons in the ventral tegmentum (VTA-DA neurons) that represent the cell bodies of the mesocorticolimbic dopaminergic system. Specifically, we will study, and, most importantly, will herein present evidence indicating that willingness (or propensity) to consume alcohol derives from ethanol profoundly inhibiting the burst firing of LC neurons, which, by so doing, reduces an inhibitory influence on VTA-DA neurons, thereby enabling ethanol to markedly increase firing of VTA-DA neurons that will support (promote) alcohol consumption. For these studies, we will use a rat line that we initially developed, through selective breeding, for its stress susceptibility (called "Susceptible" or "SUS" rats). Subsequently, we found that rats of this line show a pronounced propensity to consume alcohol, unlike any of our other lines of selectively-bred lines or normal Sprague-Dawley (SD) rats which will not voluntarily consume alcohol. SUS rats in fact drink as much alcohol as rat lines that have been specifically developed for their propensity to consume alcohol, and the amount of alcohol that SUS rats voluntarily consume clearly has pharmacological effects. Additionally, and perhaps related to stress-susceptibility of SUS rats, these animals show a phenomenon that researchers have attempted for many years to demonstrate in rodents, and even in alcohol-preferring rodents - namely, SUS rats increase their alcohol consumption when exposed to stress, and thereby show stress-induced increases in alcohol consumption. We will study how the neural relationship described above is affected by stress, and how effects on this relationship may explain stress-induced increases in alcohol consumption. In Aim 1, we test the proposed mechanism by selectively increasing or decreasing LC activity in SUS rats and then measuring (a) intake of alcohol and (b) conditioned place preference (CPP) induced by ethanol injections. Ethanol intake and CPP should decrease when LC activity is increased, and vice versa. In Aim 2, we will record the response of VTA-DA neurons to alcohol while experimentally increasing or decreasing LC activity as in Aim 1. Lastly, Aim 3 will determine if stress-induced increases in alcohol intake of SUS rats are accompanied by (a) greater inhibition of LC burst firing, and (b) larger VTA-DA excitation by alcohol. PUBLIC HEALTH RELEVANCE: Having developed in our laboratory a line of rats that shows a marked sensitivity to stress (called the Swim-test Susceptible, or SUS rat), we subsequently observed that SUS rats, in contrast to normal rats, show a decided propensity to consume alcohol and, important here, an increase in alcohol consumption after exposure to stressful conditions. We propose, and plan to test, a potential neurobiological mechanism that may underlie both the innate and stress-induced enhancement of the propensity to consume large amounts of alcohol by SUS rats, possibly relevant to other lines of alcohol-preferring rodents and human alcoholics as well.