BRAIN MONOAMINES AND CONDITIONED BEHAVIOR

描述（改编自申请人的摘要）： 单相抑郁症是当今最常见的心理健康问题。的 低速率72秒强化计划（DRL）的差异强化 72-s时间表）是一种敏感和选择性的行为筛选， 抗抑郁（AD）药物。5-羟色胺-1A（5 HT 1A）受体激动剂等药物 和5 HT 2A受体拮抗剂，以及选择性5 HT再摄取抑制剂 （SSRIs），在DRL 72-s任务中具有抗抑郁药样特征。大鼠 选择性繁殖，以增加对低温效应的敏感性， 5-HT 1A受体激动剂8-OH-DPAT，高DPAT敏感性（HDS）大鼠，不同于 他们的选择性繁殖的同行，低DPAT敏感（LDS）大鼠，在基线 性能和响应DRL上的5 HT特异性AD。的 选择性饲养的大鼠在强迫游泳中也有不同的不动时间 测试（FST），另一个行为任务，以前已被证明是 对AD敏感本建议的总体目标是更充分地 了解抑郁症的5 HT机制和AD的作用， 使用HDS和LDS大鼠系。第一组研究的目的是 比较和检查几种药物类别的AD对DRL和FST的影响 行为;此外，我们建议检查全脑和 在这两种行为模式中局部5 HT耗竭，以及研究 5-HT耗竭如何改变AD的作用。第二组的目的是 实验的目的是确定突触前和突触后神经元之间是否存在差异。 使用体外微透析在HDS和LDS大鼠之间的受体功能， 5 HT 1A和5 HT 2A/C受体的放射性配体结合，以及5 HT转运蛋白， 和第二信使测定。综合起来，这些研究将决定 这些行为差异是否受到5-HT系统的调节， 确定哪些组件的能量系统负责 HDS和LDS系大鼠之间的功能差异。的结果 这些研究将有助于我们进一步了解病因和底物 潜在的抑郁症

DESCRIPTION (Adapted From The Applicant's Abstract): Unipolar depression is the most common mental health problem today. The differential reinforcement of low rate 72-second schedule of reinforcement (DRL 72-s schedule) is a sensitive and selective behavioral screen for antidepressant (AD) drugs. Drugs such as serotonin-1A (5HT1A) receptor agonists and 5HT2A receptor antagonists, as well as selective 5HT reuptake inhibitors (SSRIs), have antidepressant-like profiles on the DRL 72-s task. Rats selectively-bred for increased sensitivity to the hypothermic effects of the 5HT1A receptor agonist 8-OH-DPAT, high DPAT sensitive (HDS) rats, differ from their selectively-bred counterparts, low DPAT sensitive (LDS) rats, in baseline performance and in response to 5HT- specific ADs on the DRL. The selectively-bred rats also have different immobility times in the forced swim test (FST), another behavioral task that has been previously shown to be sensitive to ADs. The overall objective of this proposal is to more fully understand 5HT mechanisms underlying depression and the action of ADs by making use of the HDS and LDS lines of rats. The aim of the first set of studies is to compare and examine the effects of ADs from several drug classes on DRL and FST behavior; additionally, we propose to examine the effects of whole-brain and local 5HT depletions in these two behavioral paradigms, as well as investigate how the action of ADs is modified by 5HT depletions. The aim of the second set of experiments is to determine if differences exist in pre- and postsynaptic receptor function between the HDS and LDS rats using in vitro microdialysis, radioligand binding for 5HT1A and 5HT2A/C receptors, and the 5HT transporter, and second messenger assays. Taken together, these studies will determine whether these behavioral differences are regulated by the 5HT system, and will determine which components of the serotonergic system are responsible for the functional differences between the HDS and LDS lines of rats. The results of these studies will help us further understand the etiology and substrates underlying depression.