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: 7795995
• 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 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7795995
• 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

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Recent survey data indicate that heavy drinking is more prevalent in young military recruits (age 18-20) than in the general young adult population, and early adolescent onset of alcohol use/dependence is correlated with increased risk of mental disorders including posttraumatic stress disorder (PTSD). The goal of this project is to identify in an animal model any causal link between a adolescent alcohol exposure and increased risk of PTSD-like symptoms upon subsequent exposure to traumatic stress. Confirmation of such a causal link has translational implications for a potential environmental risk factor (prior alcohol abuse) in the etiology of PTSD for a significant percentage of OEF/OIF military personnel and returning veterans. Additional translational benefits for the VA patient population are expected to emerge from proposed pharmacological validation of the animal model as a preclinical tool for identification of a) novel treatments for PTSD; and b) screening tools for predicting increased PTSD risk resulting from alcohol abuse.

描述（由申请人提供）： 虽然创伤后应激障碍（PTSD）是美国一般人群中第四大最常见的精神疾病，但最近的一项研究报告说，PTSD代表了持久自由运营（OEF）和伊拉克自由行动（OIF）的所有精神障碍的一半。军事人员中的大多数饮酒者的年龄不到25年，据报道，相同的年龄段的PTSD风险和其他40岁以上退伍军人的心理健康并发症的风险增加。最近对海军，海军和空军招募18-20岁的海军调查报告，相对于美国普通的早期青少年使用物质使用的重量/风险饮酒的发病率增加与其他疾病中PTSD的风险增加有关。由于从酒精中退出的饮酒伴随着PTSD中看到的许多相同的使人衰弱的情绪症状，因此我们假设，在青春期期间，先前反复的酒精中毒和戒断病史可能会直接增加因脑回旋的脑电路变化而导致介导压力的变化而导致创伤后PTSD发作的脆弱性。在特定的目标1中，年轻的成年男性雄性Wistar大鼠将在有独特的气味提示的情况下暴露于社会失败压力的几种条件之一（非屈服控制，3倍，6倍或9倍失败的情节）之一，然后测试持续的PTSD PTSD型行为和内分泌的迹象，使用以下ptsistement-PTSD样的行为和内分泌变化，使用以下帕拉迪姆（Paradigms：1）高度的行为： 2）声学惊吓反应性（夸张的惊吓）； 2）颅内自刺激（ICS）奖励阈值缺陷（Anhedonia）； 4）血浆皮质酮（低皮质醇）。还将评估与创伤相关的气味提示的避免和惊吓反应性。具体的目标2将探究任何持久的后果对年轻的成年后的任何持续后果，以探测间歇性乙醇蒸气的历史（每天10小时暴露在1、3或5天/周，靶向200-300 mg/dl的靶向血液酒精含量为200-300 mg/dl），使用这些相同的行为上的行为和内部分泌点，在周期期间（28-56））。然后，AIM 2中的其他实验将将精选的周围乙醇暴露条件与AIM 1的精选失败参数相结合，以测试我们对周围乙醇引起的社会失败创伤后果的增强的假设。预测是，随着青少年酒精暴露量的增加，导致持久的行为和内分泌改变需要更少的失败情节，并且/或给定数量的失败情节的变化幅度更大。一个进一步的预测是，中枢神经系统中的皮质激素释放因子（CRF）和/或去甲肾上腺素（NE）系统对于乙醇暴露和退出对PTSD脆弱性的增强作用至关重要。特定目标3将检查是否可以在AIM 1中完善的社会失败创伤模型中逆转类似PTSD的后果（例如，MPZP）和NE（例如Prazosin）的拮抗剂（例如，prazosin）的拮抗剂，任何观察到的酒精饮酒脆弱性，以及任何对AIM 2的社会失败的易受性创伤的易受启发性的态度。系统（带有Yohimbine）和/或CRF受体（带有CRF）。如果所有目标都产生了预期的结果，则该项目将：1）确定OEF/OIF军事人员和返回退伍军人的PTSD病因中普遍的假定环境风险因素（即青春期酒精）； 2）确定PTSD和酒精受体调节PTSD症状的可能的关键CNS底物（CRF，NE）； 3）开发和药理验证（MPZP，prazosin）是一个临床前平台，用于测试用于治疗PTSD和酒精饮食性PTSD症状的潜在药物治疗干预措施； 4）开发和验证（CRF，Yohimbine）一种临床前模型，用于识别潜在的筛查工具，以增强因先前酒精暴露而导致的创伤性压力脆弱性。 公共卫生相关性： 最近的调查数据表明，在年轻的军事新兵（18-20岁）中，大量饮酒比在一般年轻人人口中更普遍，并且早期的饮酒/依赖性青少年发作与包括创伤后应激障碍（PTSD）在内的精神障碍风险增加有关。该项目的目的是在动物模型中确定青少年酒精暴露与随后暴露于创伤性压力后患有PTSD样症状的风险之间的任何因果关系。对这种因果关系的确认对PTSD病因的潜在环境危险因素（先前的酗酒）具有转化的影响，其中很大一部分OEF/OIF/OIF军事人员和返回的退伍军人。预计VA患者人群的其他翻译益处将从提议的药物学验证作为动物模型的临床前工具中出现，以鉴定a）PTSD的新型治疗方法； b）筛选工具可预测酗酒导致的PTSD风险增加。