Maternal Separation: Rat Model of Opioid Vulnerability

母体分离：阿片类药物脆弱性的大鼠模型

• 批准号: 6616785
• 负责人: STEPHEN G HOLTZMAN
• 金额: $ 30.66万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6616785
• 关键词: behavioral /social science research tag; behavioral habituation /sensitization; conditioning; early experience; endogenous opioid; gender difference; laboratory rat; microarray technology; mother deprivation; neural plasticity; pain threshold; psychological models; psychomotor function; psychopharmacology; self stimulation; solution hybridization; stress

Results of studies on rodents indicate links among reactivity to stress, mesolimbic dopamine system activity, behavioral and neurochemical responses to psychomotor stimulant and opioid drugs, and drug-seeking behaviors. Male rats separated from their mother for 3 hr/day on postnatal days 2-14, as adults, are more reactive to stress than are rats from control rearing groups and have behavioral traits consistent with proposed models of drug vulnerability. They also have altered sensitivity to effects of acute and chronic morphine on pain threshold and motor activity. The principal aim of this project is to characterize further the influence of early maternal separation on opioid sensitivity by extending observations to additional procedures and drugs (e.g., kappa opioids), and to female offspring. We will address the interrelated hypotheses that mother-infant separation results in enduring changes in the functional state of endogenous opioid systems, in their plasticity, and in brain markers of opioid systems. Experiments will focus on phenomena associated with drug-induced neuronal plasticity-tolerance, physical dependence, sensitization-and on measures of drug reinforcement and abuse potential-intracranial self-stimulation, place conditioning, IV drug self- administration. Morphine and other prototypic drugs will be tested over a range of doses in adult rats that, on postnatal days 2-14, had underwent either a) 3-hr maternal separation, b) 15-min separation, or c) no separation. To identify cellular correlates of rearing-induced alterations in behavior and sensitivity to opioid drugs, opioid-related mRNAs will be measured in selected brain regions by solution hybridization and gene chip microarrays. Early mother-infant separation impacts the subsequent behavior and opioid sensitivity of the dams, too. Thus, dams will be tested in some of the same procedures as the offspring. The maternal separation paradigm affords unique animal models that can give new insights into pharmacological, behavioral, environmental, and cellular variables that affect sensitivity to opioid drugs and vulnerability to drug abuse.

啮齿动物的研究结果表明对压力的反应性，中断多巴胺系统活性，行为和神经化学反应对精神运动刺激剂和阿片类药物的反应以及寻求药物的行为。 与对照组的大鼠相比，在产后第2-14天与母亲分离的雄性大鼠对压力的压力更为反应，并且具有与拟议的药物脆弱性模型一致的行为特征。 它们还改变了对急性和慢性吗啡对疼痛阈值和运动活动的影响的敏感性。 该项目的主要目的是通过将观察结果扩展到其他程序和药物（例如Kappa阿片类药物）以及对女性后代来进一步表征早期产妇分离对阿片类药物敏感性的影响。 我们将解决相互关联的假设，即母亲分离会导致内源性阿片类系统功能状态的变化，其可塑性以及阿片类药物系统的脑标志物。 实验将集中于与药物诱导的神经元可塑性，身体依赖性，敏感性以及药物增强和滥用潜在的颅内自我刺激，位置调节，IV药物自我给药相关的现象。 吗啡和其他原型药物将在成年大鼠的一系列剂量上进行测试，这些大鼠在产后2-14天接受了a）3小时母体分离，b）15分钟分离或c）无分离。 为了鉴定饲养引起的行为改变和对阿片类药物的敏感性的细胞相关性，将通过溶液杂交和基因芯片微阵列在选定的大脑区域中测量与阿片类药物相关的mRNA。 早期的母亲分离也会影响大坝的随后行为和阿片类药物敏感性。因此，将在与后代的某些程序中进行测试。 孕产妇的分离范式提供了独特的动物模型，可以为影响对阿片类药物敏感的药理，行为，环境和细胞变量提供新的见解，并为阿片类药物的敏感性以及对药物滥用的脆弱性。