Adolescent Alcohol,Dysregulated Stress System, and PTSD Vulnerability

青少年酒精、压力系统失调和创伤后应激障碍 (PTSD) 脆弱性

• 批准号: 8195909
• 负责人: GERHARD H SCHULTEIS
• 金额: --
• 依托单位: VA SAN DIEGO HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8195909
• 关键词: 11 year old; Acoustics; Adolescence; Adolescent; Adult; Affect; Age; Air; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohol or Other Drugs use; Alcohol withdrawal syndrome; Alcoholic Intoxication; Alcoholic beverage heavy drinker; Alcohols; Amino Acids; Anhedonia; Animal Model; Animals; Anxiety; Anxiety Disorders; Behavior; Behavioral; Blood alcohol level measurement; Brain; Chemosensitization; Chronic; Chronic stress; Corticosterone; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Country; Cues; DSM-IV; Data; Dependence; Development; Diagnosis; Diagnostic and Statistical Manual of Mental Disorders; Disease; Dose; Emotional; Endocrine; Environmental Risk Factor; Ethanol; Etiology; Event; Exposure to; Freedom; Goals; Heavy Drinking; Hormonal; Hypothalamic structure; Incidence; Individual; Intervention; Intoxication; Iraq; Laboratories; Link; Marines; Mediating; Mediator of activation protein; Medical center; Mental Depression; Mental Health; Mental disorders; Military Personnel; Modeling; Mood Disorders; Moods; Names; Neuraxis; Norepinephrine; Norepinephrine Receptors; Odors; Outcome; Pharmaceutical Preparations; Pituitary-Adrenal System; Plasma; Play; Population; Post-Traumatic Stress Disorders; Prazosin; Pre-Clinical Model; Predisposing Factor; Rattus; Recording of previous events; Recruitment Activity; Relative (related person); Reporting; Rewards; Risk; Role; Screening procedure; Self Stimulation; Social Conditions; Stress; Substance Use Disorder; Surveys; Symptoms; System; Teenagers; Testing; Trauma; Traumatic Stress Disorders; Validation; Veterans; Wistar Rats; Withdrawal; Work; Yohimbine; acute stress; addiction; adolescent alcohol; adolescent alcohol exposure; adverse outcome; age group; alcohol exposure; binge drinking; biological adaptation to stress; combat; disorder risk; drinking; experience; high risk drinking; lifetime risk; male; neuroadaptation; noradrenergic; norepinephrine system; novel; operation; patient population; polypeptide; postnatal; pre-clinical; preclinical study; public health relevance; receptor; research study; response; social; tool; twelfth grade; underage drinking; vapor; young adult

While posttraumatic stress disorder (PTSD) is the fourth most common psychiatric disorder in the general U.S. population, a recent study reported that PTSD represents nearly half of all mental disorders for veterans of Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF). Most heavy drinkers among military personnel are less than 25 years old, and this same age group is reported to be at increased risk for PTSD and other mental health complications from combat deployment relative to veterans 40 years or older. Recent surveys of Naval, Marine, and Air Force recruits ages 18-20 report increased incidence of heavy/risky drinking during adolescence relative to the general U.S. Early adolescent onset of substance use is associated with increased risk of PTSD among other disorders. Because withdrawal from alcohol is accompanied by many of the same debilitating emotional symptoms seen in PTSD, we hypothesize that prior history of repeated alcohol intoxication and withdrawal during adolescence may directly increase vulnerability to onset of PTSD upon exposure to trauma due to alcohol-induced changes in brain circuits that mediate responses to stress. In Specific Aim 1, young adult male Wistar rats will be exposed to one of several conditions of social defeat stress (Nondefeat Control, 3x, 6x, or 9x defeat episodes) in the presence of a unique odor cue, followed by testing for signs of persistent PTSD-like behavioral and endocrine changes using the following paradigms: 1) elevated plus maze (anxiety-like behavior); 2) acoustic startle reactivity (exaggerated startle); 2) intracranial self-stimulation (ICSS) reward threshold deficits (anhedonia); 4) plasma corticosterone (hypocortisolism). Avoidance of, and startle reactivity to, the trauma-associated odor cue also will be assessed. Specific Aim 2 will probe for any lasting consequences into young adulthood of varying history of intermittent ethanol vapor exposure (10 hr exposure per day on 1, 3 or 5 days/week, target blood alcohol levels of 200-300 mg/dL) during the periadolescent period (postnatal day 28-56), using these same behavioral and endocrine endpoints. Additional experiments in Aim 2 will then combine select periadolescent ethanol exposure conditions with select defeat parameters from Aim 1 to test our hypothesis of periadolescent ethanol-induced potentiation of the consequences of social defeat trauma. The prediction is that with increasing amount of adolescent alcohol exposure, fewer defeat episodes will be required to engender lasting behavioral and endocrine alterations, and/or the magnitude of alterations for a given number of defeat episodes will be greater. A further prediction is that corticotropin releasing factor (CRF) and/or norepinephrine (NE) systems in the CNS are central to the potentiative effects of ethanol exposure and withdrawal on PTSD vulnerability. Specific Aim 3 will examine whether systemically active CRF (e.g. MPZP) and NE (e.g. prazosin) antagonists can reverse PTSD-like consequences in the social defeat trauma model refined in Aim 1, and any observed alcohol-potentiated vulnerability to social defeat trauma from Aim 2. Further experiments in Aim 3 will explore whether prior alcohol history can potentiate the dose-response function for stress-like responses to stimulation of NE systems (with yohimbine) and/or CRF receptors (with CRF). If all Aims yield the expected results, this project will: 1) identify a prevalent putative environmental risk factor in the etiology of PTSD for OEF/OIF military personnel and returning veterans (i.e. adolescent alcohol); 2) identify possible key CNS substrates (CRF, NE) of PTSD and alcohol-potentiated PTSD symptoms; 3) develop and pharmacologically validate (MPZP, prazosin) a preclinical platform for testing potential pharmacotherapeutic interventions for treatment of PTSD and alcohol-potentiated PTSD symptoms; and 4) develop and validate (CRF, yohimbine) a preclinical model for identifying potential screening tools for enhanced traumatic stress vulnerability resulting from prior alcohol exposure.

虽然创伤后应激障碍（PTSD）是普通中第四大最常见的精神障碍 美国人口最近的一项研究报告说，PTSD占所有精神障碍的一半 持久自由（OEF）和伊拉克自由行动（OIF）行动的退伍军人。大多数饮酒者 在军事人员中，不到25岁，据报道，同一年龄段的人数正在增加 PTSD和其他心理健康并发症的风险，从战斗部署到40年的退伍军人 或年龄较大。最近对海军，海军陆战队和空军招募18-20岁报告的调查增加了 相对于美国一般早期的物质发作，青春期中的大量饮酒 使用与其他疾病的风险增加有关。因为从酒精中提取 伴随着许多相同的使人衰弱的情绪症状，我们假设 在青春期中反复饮酒和戒断的先前历史可能直接 由于酒精引起的变化而导致创伤后，增加了PTSD发作的脆弱性 介导对压力的反应的脑电路。在特定的目标1中，年轻的成年雄性Wistar大鼠将是 暴露于社会失败压力的几种条件之一（非遭受控制，3倍，6倍或9倍失败 情节）在存在独特的气味提示的情况下，然后测试持续的PTSD样迹象 使用以下范例的行为和内分泌变化：1）升高的迷宫（焦虑样） 行为）; 2）声学惊吓反应性（夸张的惊吓）； 2）颅内自刺激（ICS）奖励 阈值赤字（Anhedonia）； 4）血浆皮质酮（低皮质醇）。避免和惊吓 对创伤相关的气味提示的反应性也将被评估。特定的目标2将探测任何持久的 间歇性乙醇蒸气暴露史的年轻成年后的后果（10小时 在1、3或5天/周的每天暴露，目标血液酒精水平为200-300 mg/dl） 使用这些相同的行为和内分泌终点，会周期（产后第28-56天）。 然后 从AIM 1中选择打败参数，以检验我们对周围乙醇诱导的增强的假设 社会失败创伤的后果。预测是，随着青少年的增加 酒精暴露，失败情节较少才能产生持久的行为和内分泌 给定数量的失败情节的变化和/或变化的幅度将更大。一个 进一步的预测是CNS中的皮质激素释放因子（CRF）和/或去甲肾上腺素（NE）系统 是乙醇暴露和退出对PTSD脆弱性的增强作用的核心。具体的 AIM 3将检查系统活跃的CRF（例如MPZP）和NE（例如prazosin）拮抗剂是否可以 在AIM 1中完善的社会失败创伤模型中的类似PTSD的后果，任何观察到的 AIM 2的酒精注入社会失败创伤的脆弱性。目标3将进行进一步的实验 探索先前的酒精病史是否可以增强剂量反应功能，以表明应力样的反应 刺激NE系统（Yohimbine）和/或CRF受体（带有CRF）。如果所有目标都产生了预期的 结果，该项目将：1）确定PTSD病因的普遍推定环境风险因素 OEF/OIF军事人员和退伍军人（即青春期酒精）； 2）确定可能的密钥中枢神经系统 PTSD和酒精赋予PTSD症状的底物（CRF，NE）； 3）开发和药理 验证（MPZP，prazosin）一个用于测试潜在药物治疗干预措施的临床前平台 治疗PTSD和酒精感染的PTSD症状； 4）开发和验证（CRF，Yohimbine） 临床前模型，用于识别潜在的筛查工具，以增强创伤性压力脆弱性 先前的酒精暴露导致。