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

描述(申请人提供)：与前额叶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。慢性应激是这些疾病的一个风险因素，与5-羟色胺能功能的改变相互作用；阻止5-羟色胺再摄取的药物(SSRI)被用于治疗这些疾病。然而，目前尚不清楚慢性应激如何影响前额叶皮质的5-羟色胺能活动，也不知道这可能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，将使用注意集转移测试(AST)来评估5-羟色胺(5-HT)在慢性应激诱导的大鼠认知灵活性障碍中的作用。两周的慢性应激导致了AST的选择性逆转学习障碍，AST与眼眶前额叶皮质有关，可能受到5-羟色胺的特异性调节。目标1将描述这种认知缺陷的持续时间，以及在两周的慢性压力后的焦虑样行为，并评估5周的压力后的缺陷。这将决定用于Aim 3的慢性药物治疗研究的设计。Aim 2将测试这一假设，即应激诱导的AST反转学习中的认知缺陷与眶前皮质5-羟色胺活性降低有关。行为测试中5-羟色胺释放的变化将使用微透析来测量，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来测量。目的3将测试渗透压小泵给药的SSRI艾司匹林慢性治疗在缓解应激诱导的认知功能障碍方面的疗效。首先，将通过在为期两周的治疗期间给予药物来测试艾司西妥兰预防认知障碍的能力。接下来，将根据目标1的结果，通过两种设计之一测试艾司西普兰逆转认知缺陷的能力。药物将在治疗完成后开始给药，持续3周直到测试，或者在压力两周后开始给药，继续药物和压力治疗，直到测试。这个项目的结果将增加我们对慢性应激诱导的精神病理学的神经机制的理解，以及治疗药物发挥作用的机制。他们有望最终得出一个更全面的建议，以探索不同应激源导致特定认知障碍的机制，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叶皮层的子区域，并可能预测对不同类别治疗药物的优先反应。与公共健康相关：这个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，以及抗抑郁药物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，因为这表明，对患者表现出的特定认知缺陷进行更仔细和准确的评估，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.