Dopamine Function After Prenatal Ethanol Exposure

描述（由申请人提供）：孕期饮酒会导致胎儿酒精谱系障碍（FASD）。FASD最突出的行为症状之一是注意缺陷/多动障碍（ADHD）。大量的临床和动物研究表明ADHD与中边缘/皮质多巴胺能（DA）系统的异常功能之间存在联系，该系统起源于腹侧被盖区（VTA）的DA神经元。产前乙醇暴露大鼠也存在注意问题和DA功能异常，表明这些大鼠可以作为动物模型来研究DA功能异常如何导致FASD个体的ADHD症状。在过去的几年中，我们发现产前乙醇暴露会导致表达自发电活动（DA神经元群体活动）的VTA DA神经元数量持续减少。这种影响不是由于永久性细胞损失，可以通过DA激动剂（包括治疗ADHD有效的精神兴奋剂）使其正常化。DA激动剂的作用还表明，产前乙醇暴露动物的VTA DA神经元群活性降低是由于处于去极化失活状态的静止VTA DA神经元数量增加所致。也就是说，这些神经元由于过度兴奋而不能产生动作电位。我们的假设认为VTA DA神经元群活动的减少是去极化失活的结果，也预测了中边缘/皮层DA系统的整体功能发生了改变，使得VTA DA神经元对输入信号的反应以及终端区域的脉冲依赖性DA释放将与对照组有质的不同。在本研究中，我们将对上述假设进行检验。在Aim 1中，我们将使用体内细胞内记录技术直接验证产前乙醇暴露诱导的VTA DA神经元群活性降低是由于去极化失活的假设。在Aim 2中，我们将研究导致产前乙醇暴露动物VTA DA神经元群活性降低的细胞机制。在Aim 3中，我们将研究产前乙醇暴露动物的VTA DA神经元对输入信号和DA释放的反应是否有质的变化。这些研究的结果将使我们了解产前乙醇暴露如何改变中边缘/皮质DA系统的功能，该系统在许多行为功能（如注意力）中起着重要作用。从所提出的研究中获得的信息可能有助于我们阐明在许多FASD患者中观察到的ADHD症状的病因和治疗选择。

DESCRIPTION (provided by applicant): Drinking alcohol during pregnancy leads to fetal alcohol spectrum disorder (FASD). One of the most prominent behavioral symptoms of FASD is attention deficit/hyperactivity disorder (ADHD). Numerous clinical and animal studies have shown a link between ADHD and abnormal functions of the mesolimbic/cortical dopaminergic (DA) system, which originates from DA neurons in the ventral tegmental area (VTA). Attention problems and abnormal DA function are also present in prenatal ethanol exposed rats, indicating the these rats can be used as an animal model to study how abnormal DA functions could lead to ADHD symptoms in individuals with FASD. In the past few years, we have found that prenatal ethanol exposure produces a persistent reduction in the number of VTA DA neurons expressing spontaneous electrical activity (DA neuron population activity). This effect is not due to permanent cell loss and can be normalized by DA agonists, including psychostimulants that are effective in treating ADHD. The effect of DA agonists also suggests that reduced VTA DA neuron population activity in prenatal ethanol exposed animals is caused by increased number of quiescent VTA DA neurons in a state of depolarization inactivation. Namely, these neurons cannot generate action potentials due to excessive excitation. Our hypothesis that reduced VTA DA neuron population activity is a result of depolarization inactivation, also predicts that the overall function of the mesolimbic/cortical DA system is altered in such a way that responses of VTA DA neurons to input signals as well as impulse-dependent DA release in terminal regions will be qualitatively different from that in controls. In the proposed studies, we will test the above hypotheses. Under Aim 1, we will directly test the hypothesis that prenatal ethanol exposure-induced reduction in VTA DA neuron population activity is due to depolarization inactivation using the in vivo intracellular recording technique. Under Aim 2, we will investigate the cellular mechanism that leads to reduced VTA DA neuron population activity in prenatal ethanol exposed animals. Under Aim 3, we will investigate if there is a qualitative change in the responses of VTA DA neurons to input signals and DA release in prenatal ethanol exposed animals. The results from the proposed studies will allow us to understand how prenatal ethanol exposure alters the function of the mesolimbic/cortical DA system, which plays an important role in many behavioral functions such as attention. The information obtained from the proposed studies may help us to elucidate the etiology and treatment options of ADHD symptoms observed in many individuals with FASD.