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

5-HT 和 SSRIs 对大鼠前额皮质的认知影响

• 批准号: 7577265
• 负责人: David A Morilak
• 金额: $ 7.41万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-05 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7577265
• 关键词: Address; Affect; Aftercare; Antidepressive Agents; Anxiety; Anxiety Disorders; Behavior; Chronic; Chronic stress; Clinical; Cognitive; Cognitive deficits; Data; Development; Dimensions; Disease; Escitalopram; Evaluation; Exhibits; Exposure to; Future; HTR2A gene; Human; Impaired cognition; Impairment; Lead; Lesion; Link; Measures; Medial; Mediating; Mental disorders; Microdialysis; Modeling; Nature; Neurotransmitters; Norepinephrine; Outcome; Patients; Pattern; Performance; Pharmaceutical Preparations; Pilot Projects; Prefrontal Cortex; Primates; Process; Psychopathology; Quantitative Autoradiography; Rattus; Reversal Learning; Risk Factors; Rodent; Role; Selective Serotonin Reuptake Inhibitor; Serotonin; Serotonin Receptor 5-HT2C; Sorting - Cell Movement; Specificity; Stress; System; Testing; Therapeutic; Time; Wisconsin; behavior test; density; depression; design; effective therapy; efficacy testing; executive function; flexibility; improved; monoamine; neuroimaging; neuromechanism; neurotransmission; noradrenergic; osmotic minipump; prevent; public health relevance; receptor; receptor binding; relating to nervous system; research study; response; reuptake; serotonin receptor; stressor; tool; treatment strategy

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.

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普遍存在。慢性压力是这些疾病的危险因素，与血清素功能的改变相互作用。阻断血清素再摄取的药物（SSRIs）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，注意力转移测试（AST）将用于评估血清素（5-HT）在大鼠慢性应激引起的认知灵活性缺陷中的作用。两周的慢性压力会导致 AST 逆转学习出现选择性缺陷，而 AST 与眶额皮层有关，并且可能受到 5-HT 的特异性调节。目标 1 是描述两周慢性压力后认知缺陷的持续时间以及类似焦虑的行为，并评估 5 周压力后的认知缺陷。这将决定目标 3 中使用的慢性药物治疗研究的设计。目标 2 将检验这样的假设：压力诱导的 AST 逆转学习认知缺陷与眶额皮层 5-HT 活性降低相关。将使用微透析测量行为测试期间 5-HT 释放的变化，并通过定量放射自显影测量突触后 5-HT 受体结合密度的变化。目标 3 将测试通过微型渗透泵输送的 SSRI 艾司西酞普兰长期治疗在缓解压力引起的认知缺陷方面的功效。首先，将通过在两周的治疗期间给药来测试艾司西酞普兰预防认知缺陷的能力。接下来，将根据目标 1 的结果，以两种设计之一测试艾司西酞普兰逆转认知缺陷的能力。治疗完成后开始给药，持续 3 周，直至测试，否则将给药两周压力后开始，继续药物和压力治疗直至测试。该项目的结果将增进我们对慢性压力诱发的精神病理学背后的神经机制以及治疗药物发挥作用的机制的理解。他们有望最终提出一个更全面的建议，探索不同压力源引起的特定认知缺陷的机制，对抑郁和焦虑的不同组成部分进行建模，可能涉及不同的神经递质系统和前额皮质子区域，并可能预测对不同应激源的偏好反应。不同类别的治疗药物。公共健康相关性：该项目将加深我们对慢性压力与抑郁症或焦虑症等精神疾病之间的关系，以及抗抑郁药等治疗药物如何发挥作用的理解。此外，这些结果可能会改善这些疾病的治疗，因为表明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。