Chronic Stress or Psychostimulants on Central and Autonomic Nervous Systems

慢性压力或精神兴奋剂对中枢和自主神经系统的影响

• 批准号: 7835613
• 负责人: MARK M KNUEPFER
• 金额: $ 20.77万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7835613
• 关键词: Acute; Amygdaloid structure; Angiotensin II; Animals; Apoptosis; Attenuated; Autonomic nervous system; Behavioral; Blood Vessels; Cardiac; Cardiac Output; Cardiomyopathies; Cardiovascular Diseases; Cardiovascular system; Cell Nucleus; Chronic; Chronic stress; Cocaine; Conscious; Corticotropin-Releasing Hormone; Data; Development; Exposure to; Genetic Models; Heart Diseases; Human; Hypertension; Hypothalamic structure; Illicit Drugs; Incidence; Individual; Kidney; Life; Limbic System; Long-Term Effects; Mediating; Microinjections; Modeling; Nerve; Neuropeptide Receptor; Neuropeptides; Neurosecretory Systems; Neurotensin; Neurotransmitters; Oxytocin; Pathway interactions; Pattern; Peptides; Peripheral Resistance; Pharmaceutical Preparations; Predisposition; Rat Strains; Rattus; Research Personnel; Resistance; Role; Shock; Site; Societies; Sprague-Dawley Rats; Stimulus; Stress; Testing; Toxic effect; acute stress; cocaine use; design; genetic strain; hemodynamics; hypothalamic pituitary axis; indexing; neurochemistry; neuronal circuitry; preoptic nucleus; prevent; psychostimulant; receptor; relating to nervous system; response; restraint

DESCRIPTION (provided by applicant): Behavioral stress is unavoidable in our society. Unfortunately, some individuals do not respond appropriately to stressful situations. A number of those seek relief by using illegal psychostimulants. In many regards, these drugs have very similar effects on the body as acute exposure to behavioral stress. Therefore, it is likely that many of the factors that condition individuals to stress may also be activated by the use of illicit drugs. This proposal is designed to determine the long-term effects and interactions between stress and psychostimulant use. In some conscious Sprague-Dawley rats, cocaine or startle evoke substantial increases in systemic vascular resistance (SVR) and renal sympathetic nerve activity concurrent with reductions in cardiac output (CO). We have designated these animals vascular responders. In contrast, rats we identify to be mixed responders have smaller increases in SVR and, instead, an increase in CO in response to cocaine or startle. Vascular responders are more susceptible to cocaine induced cardiomyopathies and hypertension compared to mixed responders. Our data suggest that the primary difference between these groups is that vascular responders have greater CNS-mediated sympathoexcitation in response to stress or psychostimulants. We propose to study the effects of chronic behavioral stress, using the resident-intruder paradigm, or chronic psychostimulants, using cocaine, on acute responses to startle and to cocaine. We hypothesize that repeated exposure to stress or psychostimulants will initially enhance then attenuate autonomic and hypothalamic-pituitary axis (HPA) responsiveness to acute stress or psychostimulants to a greater extent in vascular responders than mixed responders. Moreover, we propose that the differences in responsiveness will be reflected in changes in hypothalamic and limbic neuropeptide receptor or peptide expression and cardiac apoptosis. Finally, we propose that the CNS changes associated with repeated stress will resemble those elicited by repeated psychostimulant administration. We will compare the effects of chronic stress and/or psychostimulants and determine whether there is cross-tolerance regarding the autonomic, neuroendocrine and neurochemical responses to these stimuli. In addition, we have identified two inbred sub-strains of rats that resemble vascular and mixed responders. We propose to study them in a similar manner as the outbred Sprague-Dawley rats. In other words, we propose that greater alterations in neurotransmitter expression will be apparent in the vascular responder sub-strain. These studies will combine the expertise of investigators studying hemodynamic and autonomic responsivity, neuroendocrine indices and central neuronal circuitry to determine the long-term effects of stress or psychostimulant use in models known to be sensitive or resistant to cardiovascular disease. The results will illuminate the similarities and differences in central autonomic and neuroendocrine responsiveness to stress and psychostimulants.

描述（由申请人提供）：在我们的社会中，行为压力是不可避免的。 不幸的是，有些人对压力的情况没有适当反应。 其中许多人通过使用非法精神刺激剂寻求救济。 在许多方面，这些药物对人体具有非常相似的影响，因为急性暴露于行为应力。 因此，可能会通过使用非法药物来激活个人压力的许多因素。 该建议旨在确定压力和精神刺激使用之间的长期影响和相互作用。 在某些有意识的Sprague-Dawley大鼠中，可卡因或惊吓引起了全身血管抗性（SVR）和肾交感神经活动的实质性增加，并同时减少心脏输出（CO）。 我们已经指定了这些动物血管反应者。 相反，我们确定的大鼠是混合响应者的SVR增加较小，而CO则响应可卡因或惊吓而增加。 与混合反应者相比，血管反应者更容易受到可卡因诱导的心肌病和高血压。 我们的数据表明，这些组之间的主要区别在于血管反应者对压力或精神刺激物的CNS介导的交感神经兴趣更大。 我们建议使用可卡因对慢性行为应力的影响，或使用可卡因对惊吓和可卡因的急性反应，研究慢性行为应力。 我们假设反复暴露于压力或心理刺激因素最初会增强，然后减轻对急性应激或心理刺激物在血管反应者中对急性应激或心理刺激物的响应能力的衰减，而比混合响应者更大程度上。 此外，我们提出，反应性的差异将反映在下丘脑和边缘神经肽受体或肽表达以及心脏凋亡的变化中。 最后，我们建议与重复应力相关的中枢神经系统变化类似于反复的心理刺激施用引起的变化。 我们将比较慢性应激和/或精神刺激剂的影响，并确定对这些刺激的自主神经，神经内分泌和神经化学反应是否存在跨耐受性。 此外，我们已经确定了两种类似于血管和混合反应者的大鼠的近交亚菌属。 我们建议以类似于Sprague-Dawley大鼠的方式研究它们。 换句话说，我们建议在血管响应子材料中显而易见神经递质表达的改变。 这些研究将结合研究血液动力学和自主神经反应，神经内分泌指数和中央神经元回路的专业知识，以确定已知对心血管疾病敏感或抗性的模型中压力或心理刺激性使用的长期影响。 结果将阐明中心自主神经和神经内分泌对压力和精神刺激物的反应性的相似性和差异。

项目成果

Fos-activation of FoxP2 and Lmx1b neurons in the parabrachial nucleus evoked by hypotension and hypertension in conscious rats.

• DOI: 10.1016/j.neuroscience.2012.05.049
• 发表时间: 2012-08-30
• 期刊: NEUROSCIENCE
• 影响因子: 3.3
• 作者: Miller, R. L.;Knuepfer, M. M.;Wang, M. H.;Denny, G. O.;Gray, P. A.;Loewy, A. D.
• 通讯作者: Loewy, A. D.

CNS sites activated by renal pelvic epithelial sodium channels (ENaCs) in response to hypertonic saline in awake rats.

清醒大鼠中肾盂上皮钠通道 (ENaC) 对高渗盐水的反应激活中枢神经系统部位。

• DOI: 10.1016/j.autneu.2016.09.015
• 发表时间: 2017
• 期刊: Autonomic neuroscience : basic & clinical
• 作者: Goodwill,VanessaS;Terrill,Christopher;Hopewood,Ian;Loewy,ArthurD;Knuepfer,MarkM
• 通讯作者: Knuepfer,MarkM