Antidepressants - same effect on mesolimbic DA activity?

描述(由申请人提供)：本项目(MH65737)前期收集的数据继续表明，所有有效的抗抑郁药物(AD)治疗都会降低蓝斑(LC)神经元的活动，蓝斑(LC)神经元是大脑中主要的去甲肾上腺素能细胞体。这一结论现在得到了临床和基础研究的支持。在这一更新申请中建议进行研究，以检查LC活性的减少如何改变被认为是神经回路的“效应臂”，从而导致抑郁症状的改善。这项工作源于AD诱导的LC活性降低将导致多巴胺(DA)能神经元活性增加而产生治疗效果的想法。因此，我们建议通过测量腹侧被盖区(VTA)(中皮质边缘系统的细胞体起源)中DA神经元的电生理活动，来确定有效的AD治疗是否增加了它们的活动，从而推进到假想的神经事件级联的下一个水平。利用单单位电生理记录技术，本项目下一阶段提出的实验将检查一系列AD治疗对VTA-DA神经元活动的影响。要测试的治疗方法是我们测试的对LC神经元的影响，包括长期使用两种三环类药物、四种选择性5-羟色胺再摄取抑制剂、一种单胺氧化酶抑制剂、三种非典型AD药物，以及电惊厥。在特定的目标I下，我们将使用一个已被发现对迄今测试的所有AD有效治疗都有反应的动物模型，检查对电生理鉴定的VTA-DA神经元活动的影响。我们的实验数据显示，在这种模型的动物中，VTA-DA神经元的放电减少，正如假设在抑郁症中发生的那样。因此，特定的目标I确定AD治疗是否会抵消与抑郁相关的VTA-DA活性下降。在特定的目标2下，我们将测试三种药物的效果，每种药物都有一系列的剂量，也是在目标1中使用的相同的剂量，但在目标2中，这些研究将在正常的“幼稚”大鼠身上进行。因此，目标2可以比较抑郁症动物模型(目标I)和“正常”大鼠的剂量-反应效应；这是为了确定“抑郁”是如何转移(升高？)阿尔茨海默病有效所需的治疗剂量。最后，在特定的目标3下，我们将研究AD药物在LC和VTA-DA神经元中的起效时间过程，这可能与这些药物治疗效果的延迟起效现象有关。综上所述，这个项目建立在先前对LC的研究结果的基础上，进入下一步研究对中脑DA系统的影响，该区域长期以来一直与抑郁症有关，但就电生理学研究而言，迄今为止研究相对较少。

DESCRIPTION (provided by applicant): Data gathered in the previous period of this project (MH65737) continue to indicate that activity of locus coeruleus (LC) neurons, the major noradrenergic cell-body group of the brain, is reduced by all effective antidepressant (AD) treatments. This conclusion is now supported by both clinical and basic research. Proposed in this renewal application are studies to examine how this reduction in LC activity may alter what is envisioned to be the "effecter arm" of the neural circuit to thereby lead to amelioration of depressive symptoms. The work proposed here arises from the idea that AD-induced decreased LC activity will result in an increase in the activity of dopaminergic (DA) neurons to produce therapeutic effects. Thus, we propose to advance to that next level of the hypothesized cascade of neural events by measuring electrophysiological activity of DA neurons in the ventral tegmental area (VTA), the cell-body origin of the mesocorticolimbic system, to determine whether their activity is increased by effective AD treatments. Using single-unit electrophysiological recording techniques, the experiments proposed for the next period of this project will examine the effects of a range of AD treatments on activity of VTA-DA neurons. Treatments to be tested are those that we have tested for effects on LC neurons, which include chronic administration of two tricyclics, four selective serotonin reuptake inhibitors, one monoamine oxidase inhibitor, three atypical AD drugs, and also electroconvulsive shock. Under Specific Aim i, using an animal model that has been found to respond to all AD effective treatments tested thus far, we will examine effects on activity of VTA-DA neurons identified electrophysiologically. We show pilot data indicating that firing of VTA-DA neurons is decreased in animals of this model, as is hypothesized to occur in depression. Thus, Specific Aim i determines if AD treatments will counteract the decreased VTA-DA activity associated with depression. Under Specific Aim 2, we then will test effects of three drugs, each drug across a series of doses and also at the same series of doses as used within Aim i, but in Aim 2 these studies will be done on normal, "naive" rats. Aim 2 thus makes possible comparison of dose-response effects obtained in an animal model of depression (Aim i) with those in "normal" rats; this is done to determine how "depression" shifts (elevates?) the therapeutic dose of an AD drug that is required for effect. Finally, under Specific Aim 3, we will investigate the time course for the onset of effects of AD drugs in both LC and VTA-DA neurons, which is suspected to be related to the well-known phenomenon of delayed onset for the therapeutic effectiveness of these drugs. In summary, this project builds on previous findings for LC by progressing to the next step of studying the effects on the midbrain DA system, an area long implicated in depression but, in terms of electrophysiological study, relatively little studied to date.