BRAIN MONOAMINES AND CONDITIONED BEHAVIOR

描述(改编自申请人的摘要)： 单相抑郁是当今最常见的心理健康问题。这个 低增强率的差别增援--72秒增援计划(DRL 72-S赛程)是一个敏感和选择性的行为筛选 抗抑郁(AD)药物。5-羟色胺-1A(5HT1A)受体激动剂等药物 和5HT2a受体拮抗剂，以及选择性5HT重摄取抑制剂 (SSRI)，在DRL 72-S任务中有抗抑郁药样资料。老鼠 选择性繁殖，以提高对低温效应的敏感性 5HT1a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对应物，低DPAT敏感(LDS)大鼠，在基线 性能和对DRL上特定于5HT的广告的响应。这个 选育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，以前已经被证明是 对广告敏感。这项提议的总体目标是更充分地 了解抑郁症的5-羟色胺机制和ADS的作用 利用大鼠的HDS和LDS系。第一组研究的目的是 比较和检验几类药物的ADS对DRL和FST的影响 行为；此外，我们建议检查全脑和 这两种行为范式中的局部5-羟色胺耗竭，以及调查 5-羟色胺耗竭如何改变ADS的作用。第二盘的目的是 实验的目的是确定突触前和突触后是否存在差异 用体外微透析技术研究HDS和LDS大鼠的受体功能， 5HT1A和5HT2A/C受体的放射性配基结合，以及5HT转运体， 第二信使分析。总而言之，这些研究将确定 这些行为差异是否受5HT系统的调节，以及是否会 确定5-羟色胺能系统的哪些成分负责 HDS和LDS系大鼠的功能差异。结果是 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.