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

基本信息

项目摘要

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):与前额叶皮层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一个危险因素,与肾上腺素能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多巴胺能活动,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,注意力定势转换测试(AST)将被用来评估5-羟色胺(5-HT)在慢性应激诱导的认知灵活性缺陷大鼠的作用。两周的慢性应激诱导AST的逆转学习的选择性缺陷,这与眶额皮质有关,并且可能由5-HT特异性调制。目的1将是描述这种认知缺陷的持续时间,以及焦虑样行为,两周的慢性压力,并评估5周的压力后的赤字。这将决定用于目标3的慢性药物治疗研究的设计。目的2将检验这一假设,即应激诱导的AST逆转学习中的认知缺陷与眶额皮质5-HT活性降低有关。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。目的3将测试SSRI艾司西酞普兰长期治疗的疗效,通过渗透压微型泵输送,在减轻应激诱导的认知缺陷。首先,将通过在2周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,依地普仑逆转认知缺陷的能力将在两种设计之一中进行测试,这取决于目标1的结果。药物将在治疗完成后开始给药,并持续3周直至测试,或药物将在应激2周后开始给药,继续药物和应激治疗直至测试。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。他们将有望最终导致一个更全面的建议,以探索不同压力源诱导的特定认知缺陷的机制,建模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别的治疗药物的优先反应。公共卫生关系:这个项目将增加我们对慢性压力如何与抑郁症或焦虑症等精神疾病相关的理解,以及抗抑郁药等治疗药物如何发挥作用。此外,这些结果可能会改善这些疾病的治疗,这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。

项目成果

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David A Morilak其他文献

David A Morilak的其他文献

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{{ truncateString('David A Morilak', 18)}}的其他基金

Therapy-induced cognitive impairment in a rat model of prostate cancer
前列腺癌大鼠模型中治疗引起的认知障碍
  • 批准号:
    10766874
  • 财政年份:
    2023
  • 资助金额:
    $ 7.41万
  • 项目类别:
Cognitive impairment associated with androgen deprivation therapy for prostate cancer
前列腺癌雄激素剥夺疗法相关的认知障碍
  • 批准号:
    10527354
  • 财政年份:
    2018
  • 资助金额:
    $ 7.41万
  • 项目类别:
Cognitive impairment associated with androgen deprivation therapy for prostate cancer
前列腺癌雄激素剥夺疗法相关的认知障碍
  • 批准号:
    10287767
  • 财政年份:
    2018
  • 资助金额:
    $ 7.41万
  • 项目类别:
Cognitive impairment associated with androgen deprivation therapy for prostate cancer
前列腺癌雄激素剥夺疗法相关的认知障碍
  • 批准号:
    10310426
  • 财政年份:
    2018
  • 资助金额:
    $ 7.41万
  • 项目类别:
Cognitive impairment associated with androgen deprivation therapy for prostate cancer
前列腺癌雄激素剥夺疗法相关的认知障碍
  • 批准号:
    10059183
  • 财政年份:
    2018
  • 资助金额:
    $ 7.41万
  • 项目类别:
Treating PTSD and depression: Mechanisms of pharmacotherapy and psychotherapy in rats
治疗 PTSD 和抑郁症:大鼠药物治疗和心理治疗的机制
  • 批准号:
    10250669
  • 财政年份:
    2017
  • 资助金额:
    $ 7.41万
  • 项目类别:
Treating PTSD and depression: Mechanisms of pharmacotherapy and psychotherapy in rats
治疗 PTSD 和抑郁症:大鼠药物治疗和心理治疗的机制
  • 批准号:
    10620164
  • 财政年份:
    2017
  • 资助金额:
    $ 7.41万
  • 项目类别:
Treating PTSD and depression: Mechanisms of pharmacotherapy and psychotherapy in rats
治疗 PTSD 和抑郁症:大鼠药物治疗和心理治疗的机制
  • 批准号:
    10392391
  • 财政年份:
    2017
  • 资助金额:
    $ 7.41万
  • 项目类别:
Integrated Graduate Training Program in Neuroscience, UTHSCSA
UTHSCSA 神经科学综合研究生培训计划
  • 批准号:
    10625662
  • 财政年份:
    2013
  • 资助金额:
    $ 7.41万
  • 项目类别:
Integrated Graduate Training Program in Neuroscience, UTHSCSA
UTHSCSA 神经科学综合研究生培训计划
  • 批准号:
    10430193
  • 财政年份:
    2013
  • 资助金额:
    $ 7.41万
  • 项目类别:

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