Opiates and Adult Neurogenesis

阿片类药物和成人神经发生

• 批准号: 8038861
• 负责人: AMELIA J EISCH
• 金额: $ 23.78万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2012-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8038861
• 关键词: Opiates; Adult; Neurogenesis

DESCRIPTION (provided by applicant): Revision: Drug dependence is linked to diminished hippocampal structure and function, and the hippocampus is involved in drug reward and relapse to drug seeking. Thus, our understanding and treatment of addiction will be greatly improved if we can clarify the time course, extent, and cause of drug-induced hippocampal neuroadaptations and identify if and how hippocampal neuroadaptations impact addictive behaviors. A notable aspect of the hippocampus is its ability to generate new neurons throughout life. Adult-generated neurons are functionally integrated into hippocampal circuitry and are involved in some types of learning. Drugs of abuse, like morphine, decrease neurogenesis in the hippocampal dentate gyrus subgranular zone (SGZ), raising the possibility that opiate-induced alteration in neurogenesis leads to cognitive deficits, continued drug taking or relapse, or otherwise impedes recovery. The parent grant application, DA 016765, has three aims to test this possibility: Aim 1) Determine how morphine self-administration and withdrawal alter discrete stages of adult hippocampal neurogenesis. Aim 2) Assess how altered adult hippocampal neurogenesis relates to drug seeking. Aim 3) Evaluate the involvement of adult-generated hippocampal neurons in drug/context association. For this competitive revision, we propose a new aim to be completed in one year: Aim 4) Evaluate the involvement of adult-generated hippocampal neurogenesis in the vulnerability to morphine addiction. Based on our recent publication (Noonan et al., J Neuroscience, 2010), we hypothesize that ablation of adult neurogenesis via cranial radiation will enhance vulnerability to self-administration in an animal model of opiate addiction without disrupting response to non-drug rewards. The extensive analysis of behavior in this new aim will reveal how adult-generated neurons contribute to basal and reward-based behavior, and makes this aim perfectly-suited for consideration through the NIH Basic Behavioral and Social Sciences Opportunity Network. By providing insight into the relationship among adult neurogenesis, opiates, and behavior, these studies will provide much-needed information relevant to our understanding of the addicted and the non-addicted brain and may indicate novel avenues to treat and prevent addiction and improve brain health in general. PUBLIC HEALTH RELEVANCE: Drug addiction is a devastating disorder marked by compulsive drug use, high propensity to relapse to drug taking, and cognitive deficits. Drugs of abuse, including morphine, lead to a decrease in the number of new neurons in the hippocampus, a brain region important for learning and memory. We will explore the potentially reciprocal relationship between opiate addiction and adult hippocampal neurogenesis, thus providing much- needed insight into the structure and function of the addicted brain as well as the function of adult-generated neurons in the non-addicted brain.

描述（由申请人提供）：修订：药物依赖性与海马结构和功能的减少有关，海马参与药物奖励并复发到寻求药物。因此，如果我们能够阐明药物诱导的海马神经适应的时间，程度和原因，并确定海马神经适应是否影响成瘾行为，我们对成瘾的理解和治疗将得到很大改善。海马的一个显着方面是它在一生中产生新神经元的能力。成人生成的神经元在功能上将其整合到海马电路中，并参与某些类型的学习。滥用药物（例如吗啡）降低了海马齿状回和粒状区（SGZ）中的神经发生，从而增加了鸦片诱导的神经发生变化的可能性会导致认知缺陷，持续吸毒或恢复药物或重新丧失或以其他方式阻碍了恢复。父母赠款应用DA 016765具有三个目的是测试这种可能性：目标1）确定吗啡自我给药和戒断如何改变成人海马神经发生的离散阶段。目标2）评估成年海马神经发生与寻求药物的关系。目标3）评估成人产生的海马神经元参与药物/情境关联。对于这项竞争性修订，我们提出了一个新的目标，要在一年内完成：目标4）评估成人生成的海马神经发生的参与与吗啡成瘾的脆弱性。根据我们最近的出版物（Noonan等人，J Neuroscience，2010年），我们假设通过颅辐射消融成人神经发生将增强在阿片类动物成瘾模型中的自我管理的脆弱性，而不会破坏对非毒品奖励的反应。对这个新目标的行为的广泛分析将揭示成人生成的神经元如何促进基于基础和奖励的行为，并使此目标非常适合通过NIH基本的行为和社会科学机会网络考虑。通过提供有关成人神经发生，阿片类药物和行为之间关系的洞察力，这些研究将提供与我们对上瘾和未成瘾的大脑的理解相关的急需信息，并可能表明新颖的途径可以治疗和预防成瘾和改善大脑健康。 公共卫生相关性：药物成瘾是一种具有强迫毒品使用的毁灭性疾病，高倾向于复发到药物服用和认知缺陷。包括吗啡在内的滥用药物，导致海马中新神经元的数量减少，这是一个对学习和记忆重要的大脑区域。我们将探讨阿片类成瘾与成人海马神经发生之间的潜在相互关系，从而为上瘾的大脑的结构和功能以及非成年大脑中成人生成的神经元的功能提供了急需的见解。