A Neural Mechanism Underlying Alcohol Consumption and Its Increase with Stress

描述（由申请人提供）：我们建议调查消费酒精倾向的神经机制。这种机制最初被研究为在压力诱导的抑郁症中很重要，现在似乎也显著地调节了饮酒的倾向。我们将专注于蓝斑（LC）神经元，在大脑中的主要去甲肾上腺素能细胞体组，和多巴胺神经元在腹侧被盖（VTA-DA神经元），代表的细胞体的mesocorticolimbic多巴胺能系统的活动之间的关系。具体地说，我们将研究，并且最重要的是，将在本文中提出证据表明，消费酒精的意愿（或倾向）源于乙醇深刻地抑制LC神经元的爆发放电，通过这样做，减少了对VTA-DA神经元的抑制影响，从而使乙醇能够显着增加VTA-DA神经元的放电，这将支持（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开发的大鼠品系（称为“易感”或“SUS”大鼠）。随后，我们发现这一品系的大鼠显示出明显的饮酒倾向，不像我们的任何其他品系的选择性繁殖品系或正常的Sprague-Dawley（SD）大鼠，它们不会自愿饮酒。事实上，SUS大鼠的饮酒量与专门针对其饮酒倾向开发的大鼠品系一样多，SUS大鼠自愿摄入的酒精量显然具有药理作用。此外，也许与SUS大鼠的应激敏感性有关，这些动物显示了研究人员多年来试图在啮齿动物中证明的现象，甚至在嗜酒精的啮齿动物中-即SUS大鼠在暴露于应激时增加其酒精消耗，从而显示应激诱导的酒精消耗增加。我们将研究上述神经关系如何受到压力的影响，以及这种关系的影响如何解释压力引起的饮酒量增加。在目的1中，我们通过选择性地增加或减少SUS大鼠的LC活性，然后测量（a）酒精摄入量和（B）由乙醇注射诱导的条件性位置偏爱（CPP）来测试所提出的机制。当LC活性增加时，乙醇摄入量和CPP应减少，反之亦然。在目标2中，我们将记录腹侧被盖区DA神经元对酒精的反应，同时实验性地增加或减少LC活性，如目标1中所述。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有（a）对LC爆发放电的更大抑制，以及（B）酒精对VTA-DA的更大兴奋。

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.