Social isolation: effects on the stress axis and stimulant self-administration

社会隔离：对压力轴和兴奋剂自我管理的影响

• 批准号: 8783514
• 负责人: Rebecca Hofford
• 金额: $ 3.95万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-10 至 2015-09-03
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8783514
• 关键词: Acute; Adolescence; Adult; Amygdaloid structure; Animal Housing; Animal Model; Animals; Anxiety; Area; Behavior Therapy; Behavioral; Brain; Brain region; Buffers; Childhood; Cocaine; Corpus striatum structure; Corticosterone; Development; Disease; Dorsal; Drug Addiction; Drug abuse; Early-life trauma; Environment; Event; Extinction (Psychology); General Population; Glucocorticoid Receptor; Goals; Health; Hormone Receptor; Hormones; Housing; Human; Individual; Intervention; Laboratories; Life Stress; Measures; Medial; Mental Depression; Mental disorders; Modeling; Neurobiology; Nucleus Accumbens; Organism; Pathology; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Physiological; Plasma; Post-Traumatic Stress Disorders; Predisposition; Prefrontal Cortex; Protein Hormone Receptor; Rattus; Relative (related person); Research; Risk; Risk Factors; Rodent; Role; Self Administration; Social isolation; Staging; Stress; Substance Use Disorder; Syndrome; System; Testing; Time; Weaning; acute stress; addiction; base; comorbidity; design; drug reward; environmental enrichment for laboratory animals; experience; neurobehavioral; post-traumatic stress; preclinical study; psychosocial; public health relevance; receptor; receptor expression; research study; response; social; stimulant abuse; stimulant dependence; stressor; treatment strategy; young adult

DESCRIPTION (provided by applicant): People suffering from post-traumatic stress disorder (PTSD) are 3 times more likely to abuse psychostimulants than people in the general population. This is alarming, since estimates indicate that 8% of adults have abused stimulants in their lifetime. Identifying common substrates of both PTSD and drug addiction can provide a useful perspective on drug abuse treatment in patients with PTSD. Early life stress contributes to the development of both PTSD and drug addiction, and can be modeled in rodents by employing social isolation during the early post-weaning period. Isolation enhances susceptibility to stress-related pathologies as assessed by animal models of depression and anxiety, as well as increasing vulnerability to stimulant self- administration. Conversely, environmental enrichment during development buffers against both anxiety and stimulant self-administration. Although alterations in the stress axis are likely involved in the effect of isolaton on drug self-administration, the distinct neurobehavioral mechanisms of stress in drug abuse vulnerability induced by social isolation are largely unknown. Acute stress has the ability to increase drug seeking as measured by enhanced acquisition of self-administration, and also causes reinstatement of drug seeking. Therefore, relative to enriched rats, it is hypothesized that rats raised in isolation and subjected to an acute stressor will acquire cocaine self-administration more rapidly and will demonstrate greater stress-induced reinstatement due to a sensitized stress axis. Specific Aim 1 will measure the acquisition of cocaine self- administration after an acute stressor, and measure stress-induced reinstatement of self-administration in rats raised in an isolated condition (IC), standard condition (SC), or an enriched condition (EC). An adapted single prolonged stress model (SPS), considered a type of acute stressor, will be used to model PTSD. Corticosterone, the major stress hormone in rodents, and its receptor, the glucocorticoid receptor (GR), are implicated in stress-induced acquisition and reinstatement. Differences in levels of corticosterone or GR have the potential to underlie addiction and anxiety-related pathologies such as PTSD. Given the importance of GR and corticosterone in both stress and drug abuse, Specific Aim 2 will determine if this hormone/receptor system is altered by acute stress in IC, SC, and EC rats. GR expression levels will be quantified in brain areas involved in drug abuse after SPS administration in IC, SC, and EC rats. These areas will include the amygdala, medial prefrontal cortex, orbitofrontal cortex, nucleus accumbens, and dorsal striatum. Additionally, levels of free corticosterone will be measured in response to SPS in rats raised in these different housing conditions. These experiments are important because co-morbidity of PTSD and stimulant addiction is a serious social and health problem. Understanding the neurobiological basis of a common risk factor, early life stress, can aid in the development of addiction treatment strategies targeting this at-risk group and can help design both psychosocial and pharmaceutical interventions that ameliorate an overly sensitive stress axis.

描述（由申请人提供）：患有创伤后应激障碍（PTSD）的人滥用精神兴奋剂的可能性是普通人群的3倍。这是令人震惊的，因为估计表明，8%的成年人在其一生中滥用兴奋剂。确定PTSD和药物成瘾的共同底物可以为PTSD患者的药物滥用治疗提供有用的视角。早期生活压力有助于创伤后应激障碍和药物成瘾的发展，并且可以通过在断奶后早期采用社会隔离在啮齿动物中建模。如通过抑郁和焦虑的动物模型所评估的，隔离增强了对应激相关病理的易感性，以及增加了对刺激性自我施用的脆弱性。相反，在发展过程中丰富的环境缓冲对焦虑和兴奋剂自我管理。虽然压力轴的改变可能参与了隔离对药物自我管理的影响，但社会隔离引起的药物滥用脆弱性中压力的独特神经行为机制在很大程度上是未知的。急性应激有能力增加药物寻求，如通过增强自我管理的获得来测量的，并且还导致药物寻求的恢复。因此，相对于丰富的大鼠，据推测，大鼠提出了在隔离和受到急性应激源将获得可卡因自我管理更迅速，并会表现出更大的压力诱导的恢复，由于敏感的应力轴。具体目标1将测量可卡因自我给药的获得 在急性应激源后，并测量在隔离条件（IC）、标准条件（SC）或富集条件（EC）下饲养的大鼠中应激诱导的自我给药恢复。一个适应性的单一长期应激模型（SPS），被认为是一种急性应激源，将被用来模拟创伤后应激障碍。皮质酮是啮齿类动物中主要的应激激素，其受体糖皮质激素受体（GR）参与应激诱导的获得和恢复。皮质酮或GR水平的差异有可能成为成瘾和焦虑相关病理学（如PTSD）的基础。鉴于GR和皮质酮在应激和药物滥用中的重要性，具体目标2将确定该激素/受体系统是否因IC、SC和EC大鼠的急性应激而改变。在IC、SC和EC大鼠中，SPS给药后，将量化涉及药物滥用的脑区域中的GR表达水平。这些区域包括杏仁核、内侧前额叶皮质、眶额皮质、丘脑核和背侧纹状体。此外，将测量在这些不同饲养条件下饲养的大鼠对SPS的响应的游离皮质酮水平。这些实验很重要，因为PTSD和兴奋剂成瘾的共同发病率是一个严重的社会和健康问题。了解一个共同的风险因素，早期生活压力的神经生物学基础，可以帮助制定针对这一高危人群的成瘾治疗策略，并可以帮助设计心理和药物干预措施，改善过度敏感的压力轴。