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

描述(申请人提供)：患有创伤后应激障碍(PTSD)的人滥用精神刺激剂的可能性是普通人群的3倍。这令人担忧，因为据估计，8%的成年人一生中都曾滥用兴奋剂。确定创伤后应激障碍和药物成瘾的共同底物可以为创伤后应激障碍患者的药物滥用治疗提供一个有用的视角。早期生活应激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来在啮齿动物身上模拟。根据抑郁和焦虑的动物模型评估，隔离增加了对压力相关病理的敏感性，并增加了对刺激性自我管理的易感性。相反，发育过程中的环境丰富可以缓冲焦虑和刺激性自我管理。虽然应激轴的改变可能参与了隔离对药物自我给药的影响，但社会隔离导致的药物滥用易感性中应激的不同神经行为机制在很大程度上是未知的。通过增强自我管理的获得来衡量，急性应激能够增加寻求药物的能力，并且也会导致寻求药物的恢复。因此，相对于富含可卡因的大鼠，假设隔离饲养并受到急性应激源的大鼠将更快地获得可卡因自我给药，并由于敏化应激轴而表现出更大的应激诱导恢复。具体目标1将衡量可卡因自我给药的获得 在急性应激源后，测量在隔离条件(IC)、标准条件(SC)或强化条件(EC)中饲养的大鼠应激诱导的自我给药恢复。一种适应的单一延长应激模型(SPS)被认为是一种急性应激源，将被用于模拟创伤后应激障碍。啮齿动物的主要应激激素皮质酮及其受体糖皮质激素受体(GR)与应激诱导的习得和恢复有关。皮质酮或GR水平的差异可能是成瘾和焦虑相关病理(如创伤后应激障碍)的基础。鉴于GR和皮质酮在应激和药物滥用中的重要性，特定目标2将确定IC、SC和EC大鼠的这种激素/受体系统是否因急性应激而改变。在IC、SC和EC大鼠给予SPS后，GR在涉及药物滥用的脑区的表达水平将被量化。这些区域将包括杏仁核、内侧前额叶皮质、眶前叶皮质、伏隔核和背侧纹状体。此外，还将测量在这些不同居住条件下饲养的大鼠对SPS的反应中的游离皮质酮水平。这些实验很重要，因为创伤后应激障碍和兴奋剂成瘾的并存是一个严重的社会和健康问题。了解早期生活压力这一常见风险因素的神经生物学基础，有助于制定针对这一高危群体的成瘾治疗策略，并有助于设计改善过度敏感的压力轴的心理社会和药物干预措施。

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.