DOES EXERCISE AMELIORATE THE EFFECTS OF EARLY LIFE STRESS ON DRUG REWARD?

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 我们研究的长期目标是更好地了解儿童期虐待和创伤幸存者对药物滥用和依赖的脆弱性增强的神经基础。这个项目的目标是检查一个特定的干预措施的效果  自愿运动  在早期生活压力的大鼠模型中对精神兴奋剂药物的行为反应和神经适应。我们的中心假设是，自愿运动在青春期将正常化改变精神兴奋剂的敏感性，以前观察到大鼠暴露于慢性压力在出生后早期的发展。 新生儿母亲分离，一种早期生活压力的大鼠模型，已知会产生压力高反应性和对精神兴奋剂的敏感性增强，并持续到成年。从断奶时开始，我们将先前分离的大鼠圈养在笼中，并在有或没有转轮的情况下短暂处理对照品三周。在三周的运动操作后，我们将用不同的大鼠队列进行两个实验。在实验1中，我们将测试大鼠的敏感性，在条件性位置偏好范式的精神刺激和可卡因的强化效果。在实验2中，我们将测试大鼠重复注射可卡因后的精神敏化。我们还将测量多巴胺转运蛋白（DAT）和脑源性神经营养因子（BDNF）在边缘脑区域的表达与药物滥用有关。之所以选择这些蛋白质，是因为两者都是在边缘脑区域受到母亲分离和重复可卡因暴露的调节。 我们希望定期锻炼可以使母亲分离引起的精神兴奋剂敏感性和相关神经适应性的改变正常化。拟议的研究将增进对早年压力和体力活动相互作用影响药物滥用脆弱性的机制的了解。这些结果可以为新的行为干预提供科学依据，以预防或减少高危人群的药物滥用。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The long-term objective of our research is to better understand the neural underpinnings of enhanced vulnerability to substance abuse and dependence in survivors of childhood maltreatment and trauma. The goal of this project is to examine the effects of a specific intervention  voluntary exercise  on behavioral responses and neural adaptations to psychostimulant drugs in a rat model of early life stress. Our central hypothesis is that voluntary exercise during adolescence will normalize the altered psychostimulant sensitivity previously observed in rats exposed to chronic stress during early postnatal development. Neonatal maternal separation, a rat model of early life stress, is known to produce stress hyper-responsiveness and enhanced sensitivity to psychostimulants that persist into adulthood. Starting at the time of weaning, we will house previously-separated rats and briefly handled controls in cages with or without access to running wheels for three weeks. After the three-week exercise manipulation, we will carry out two experiments with separate cohorts of rats. In experiment 1, we will test rats for their sensitivity to the psychomotor stimulant and reinforcing effects of cocaine in a conditioned-place preference paradigm. In experiment 2, we will test rats for psychomotor sensitization after repeated cocaine injection. We will also measure expression of the dopamine transporter (DAT) and brain-derived neurotrophic factor (BDNF) in limbic brain regions implicated in drug abuse. These proteins were chosen because both are regulated in limbic brain regions by maternal separation and repeated cocaine exposure. We expect that regular exercise will normalize the altered psychostimulant sensitivity and associated neural adaptations induced by maternal separation. The proposed studies will enhance understanding of the mechanisms by which early life stress and physical activity interact to impact substance abuse vulnerability. The outcomes could provide the scientific basis for novel behavioral interventions to prevent or reduce substance abuse in high-risk individuals.