Cognitive Effects of 5-HT and SSRIs in Rat Prefrontal Cortex

描述（由申请人提供）：与前额皮质变化相关的认知功能障碍在抑郁症和焦虑症中很普遍。慢性压力是这些疾病的一个危险因素，与血清素能功能的改变相互作用；阻断血清素再摄取的药物（SSRIs）被用于治疗这些疾病。然而，目前尚不清楚慢性压力如何影响前额皮质的血清素活性，也不知道这如何导致执行功能和认知灵活性的缺陷。在这个试点项目中，注意力集中转移测试（AST）将用于评估血清素（5-HT）在大鼠慢性应激性认知灵活性缺陷中的作用。两周的慢性应激导致AST的选择性逆转学习缺陷，这与眶额叶皮质有关，并可能由5-羟色胺特异性调节。目的1将描述这种认知缺陷的持续时间，以及类似焦虑的行为，在两周的慢性压力下，以及在5周的压力下评估缺陷。这将决定目标3中使用的慢性药物治疗研究的设计。目的2将验证AST上应激诱导的逆向学习认知缺陷与眶额叶皮层5-羟色胺活性降低相关的假设。行为测试期间5-羟色胺释放的变化将通过微透析测量，突触后5-羟色胺受体结合密度的变化将通过定量放射自显影测量。目的3将测试SSRI艾司西酞普兰慢性治疗的有效性，通过渗透微泵给药，减轻应激性认知缺陷。首先，艾司西酞普兰预防认知缺陷的能力将被测试，通过在2周的治疗期间给药。接下来，依第一个目标的结果，艾司西酞普兰逆转认知缺陷的能力将在两种设计中进行测试。治疗结束后开始用药，持续3周直到测试，或应激2周后开始用药，继续药物和应激治疗直到测试。该项目的结果将增加我们对慢性应激性精神病理的神经机制的理解，以及治疗药物可能发挥其作用的机制。他们希望最终能提出一个更全面的建议，探索由不同压力源引起的特定认知缺陷的潜在机制，模拟抑郁和焦虑的不同组成部分，可能涉及不同的神经递质系统和前额叶皮层的子区域，并可能预测对不同类型治疗药物的优先反应。公共卫生相关性：该项目将增加我们对慢性压力与抑郁症或焦虑症等精神疾病的关系的理解，以及抗抑郁药等治疗药物如何发挥作用。此外，研究结果可能会改善这些疾病的治疗，通过对患者表现出的特定认知缺陷进行更仔细和精确的评估，可能会更好地预测最有效的治疗策略。

DESCRIPTION (provided by applicant): Cognitive dysfunction related to changes in prefrontal cortex are prevalent in depression and anxiety disorders. Chronic stress is a risk factor in these illnesses, interacting with alterations in serotonergic function; and drugs that block the reuptake of serotonin (SSRIs) are used in the treatment of these disorders. However, it is not known how chronic stress affects serotonergic activity in prefrontal cortex, nor how that may contribute to deficits in executive function and cognitive flexibility. In this pilot project, an attentional set-shifting test (AST) will be used to assess a role for serotonin (5-HT) in chronic stress-induced deficits of cognitive flexibility in rats. Two weeks of chronic stress induced a selective deficit in reversal learning on the AST, which has been linked to orbitofrontal cortex, and which may be modulated specifically by 5-HT. Aim 1 will be to characterize the duration of this cognitive deficit, as well as anxiety-like behavior, following two weeks of chronic stress, and also to assess the deficit after 5 weeks of stress. This will determine the design of the chronic drug treatment studies to be used in aim 3. Aim 2 will test the hypothesis that stress-induced cognitive deficits in reversal learning on the AST are associated with reduced 5-HT activity in orbitofrontal cortex. Changes in 5-HT release during behavioral testing will be measured using microdialysis, and changes in post-synaptic 5-HT receptor binding density will be measured by quantitative autoradiography. Aim 3 will test the efficacy of chronic treatment with the SSRI escitalopram, delivered by osmotic minipump, in alleviating the stress- induced cognitive deficit. First, the ability of escitalopram to prevent the cognitive deficit will be tested, by administering drug during the 2-week treatment. Next, the ability of escitalopram to reverse the cognitive deficit will be tested in one of two designs, depending on the outcome of aim 1. Drug will be given beginning after treatment is complete and continued for 3 weeks until testing, or drug will be given beginning after 2 weeks of stress, continuing both drug and stress treatment until testing. The results of this project will add to our understanding of the neural mechanisms underlying chronic stress-induced psychopathology, and the mechanisms by which therapeutic drugs may exert their effects. They will hopefully lead ultimately to a more comprehensive proposal to explore the mechanisms underlying specific cognitive deficits induced by different stressors, modeling different components of depression and anxiety, possibly involving different neurotransmitter systems and sub-regions of prefrontal cortex, and perhaps predicting preferential response to different classes of therapeutic drugs. PUBLIC HEALTH RELEVANCE: This project will add to our understanding of how chronic stress is related to psychiatric illnesses such as depression or anxiety disorders, and how therapeutic drugs such as antidepressants may exert their effects. Further, the results may improve the treatment of these disorders, by suggesting that a more careful and precise evaluation of the specific cognitive deficits exhibited by a patient might better predict the most effective treatment strategy.