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。这种机制最初被认为在压力诱发的抑郁症中很重要，现在似乎也显著地调节了饮酒的倾向。我们将重点关注蓝斑（LC）神经元（大脑中主要的去肾上腺素能细胞体群）与代表中皮质边缘多巴胺能系统细胞体的腹侧被盖多巴胺神经元（VTA-DA神经元）的活性之间的关系。具体来说，我们将研究，最重要的是，我们将在此提出证据，表明饮酒的意愿（或倾向）源于乙醇对LC神经元爆发放电的深刻抑制，通过这样做，减少了对VTA-DA神经元的抑制影响，从而使乙醇显著增加VTA-DA神经元的放电，从而支持（促进）饮酒。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系，用于其应激敏感性（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，不像我们的任何其他选择性繁殖品系或正常的Sprague-Dawley （SD）大鼠不会自愿饮酒。事实上，SUS大鼠的饮酒量与专门为其饮酒倾向而开发的大鼠品系一样多，SUS大鼠自愿饮酒的数量显然具有药理作用。此外，也许与SUS大鼠的压力易感性有关，这些动物表现出一种现象，研究人员多年来一直试图在啮齿动物，甚至是偏爱酒精的啮齿动物中证明，即SUS大鼠在暴露于压力时增加酒精摄入量，从而表现出压力引起的酒精摄入量增加。我们将研究上述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引起的饮酒增加。在Aim 1中，我们通过选择性地增加或降低SUS大鼠的LC活性来测试所提出的机制，然后测量(a)酒精摄入量和(b)乙醇注射诱导的条件位置偏好（CPP）。乙醇摄入量和CPP随LC活性的增加而降低，反之亦然。在Aim 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减少LC活性，如Aim 1中所示。最后，Aim 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.