Neonatal Methamphetamine Effects on Adult Cholinergic and Cognitive Function

新生儿甲基苯丙胺对成人胆碱能和认知功能的影响

• 批准号: 7612304
• 负责人: Jessica A Siegel
• 金额: $ 4.12万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-26 至 2011-06-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7612304
• 关键词: Acetylcholine; Acetylcholinesterase Inhibitors; Adult; Affect; Affinity; Agonist; Animals; Basal Nucleus of Meynert; Biological Assay; Brain; Carbachol; Cell Count; Cells; Cerebrospinal Fluid; Child; Choline O-Acetyltransferase; Cholinergic Receptors; Cognition; Cognitive; Cognitive deficits; Confocal Microscopy; Data; Densitometry; Development; Drug abuse; Exposure to; Fiber; Financial compensation; Goals; Health; Hippocampus (Brain); Human; Immunohistochemistry; Impaired cognition; Impairment; Infant; Injection of therapeutic agent; Laboratory Finding; Life; Long-Term Effects; Measures; Medial; Methamphetamine; Modeling; Mus; Muscarinic Acetylcholine Receptor; Muscarinic Agonists; Muscarinic M2 Receptor; Muscarinics; Neonatal; Neurobiology; Neurodegenerative Disorders; Neurologic; Nicotinic Receptors; Pregnant Women; Problem behavior; Process; Public Health; Rodent; Saline; Schools; Societies; Stereotaxic Techniques; System; Techniques; Testing; Third Pregnancy Trimester; Training; basal forebrain; cholinergic; cognitive function; density; fetal methamphetamine exposure; fiber cell; immunoreactivity; improved; in utero; insight; lateral ventricle; methamphetamine exposure; neurobiological mechanism; postnatal; public health relevance; receptor binding; rivastigmine; skills; therapy development

DESCRIPTION (provided by applicant): The number of pregnant women using methamphetamine (MA) is increasing. Exposure to MA in utero leads to neurological and cognitive deficits in infants that persist into adulthood. Yet, the neurobiology underlying these deficits is not known. Understanding the neurobiological mechanisms behind MA-induced neurological and cognitive impairments will advance our understanding of MA's actions in the brain and offer insights into developing therapies for children exposed to MA in utero. MA administration in adults impairs the cholinergic system. However, little is known about the effects of fetal MA exposure on cholinergic function. One of NIDA's goals is to improve treatment for drug abuse and the objective of this project is in line with this goal, as the objective is to explore the long-term effects of in utero MA exposure on the cholinergic system and to investigate potential cholinergic therapies that may reverse MA-induced cognitive deficits in adulthood. This objective will be achieved by administering MA to mice during hippocampal development, which occurs during the first 3 postnatal weeks and mimics human hippocampal development during the third trimester. The specific aims of this proposal are: 1) determine the effects of neonatal MA on choline acetyltransferase positive cells in the basal forebrain and fiber densities innervating the hippocampus and cortex in adulthood. This will be achieved using immunohistochemistry and confocal microscopy with densitometry and unbiased stereological techniques; 2) determine the effects of neonatal MA on the number and affinity of M1 and M2 muscarinic receptors in the hippocampus and cortex in adulthood using muscarinic acetylcholine receptor binding assays; and 3) determine the ability of the acetylcholinesterase inhibitor rivastigmine or the muscarinic receptor agonist carbachol, injected directly into the lateral ventricle, to reverse cognitive impairments resulting from neonatal MA in adulthood. PUBLIC HEALTH RELEVANCE: As children exposed to MA in utero display impairments on a variety of cognitive tasks, it is imperative that the underlying neurobiology of these impairments is delineated and that treatments for these children are developed. Thus, this proposal will impact public health by increasing the possibility that these treatments will be discovered. The number of children exposed to MA in utero is increasing. Exposure to MA in utero leads to long-term cognitive and behavioral problems in children that affect our school systems and our society. This proposal will investigate the changes in neurobiology that result from in utero MA exposure and explore potential therapies to treat children that have cognitive impairments as a result of in utero MA exposure.

描述(申请人提供)：使用甲基苯丙胺(MA)的孕妇人数正在增加。在宫内暴露于MA会导致婴儿的神经和认知障碍，并持续到成年。然而，这些缺陷背后的神经生物学尚不清楚。了解MA引起的神经和认知损害背后的神经生物学机制将促进我们对MA在大脑中的作用的理解，并为开发针对宫内暴露于MA的儿童的治疗方法提供见解。成人服用MA会损害胆碱能系统。然而，关于胎儿接触MA对胆碱能功能的影响还知之甚少。NIDA的目标之一是改善药物滥用的治疗，该项目的目标与这一目标一致，因为该项目的目标是探索宫内MA暴露对胆碱能系统的长期影响，并研究可能扭转MA导致的成年认知障碍的潜在胆碱能疗法。这一目标将通过在小鼠的海马体发育期间给予MA来实现，海马体发育发生在出生后的前3周，并模拟人类海马体在第三个三个月的发育。这项建议的具体目的是：1)确定新生儿MA对成年期基底前脑胆碱乙酰转移酶阳性细胞和支配海马和皮质的纤维密度的影响。这将通过免疫组织化学和共聚焦显微镜结合密度测量和无偏向体视学技术来实现；2)通过M受体结合分析，确定新生儿MA对成年时海马和皮质中M1和M2受体数量和亲和力的影响；以及3)确定直接注入侧脑室的乙酰胆碱酯酶抑制剂里瓦斯替格明或M受体激动剂卡巴胆碱逆转新生儿MA导致的成年后认知障碍的能力。公共卫生相关性：由于宫内暴露于MA的儿童在各种认知任务中表现出损害，迫切需要描述这些损害的潜在神经生物学，并开发针对这些儿童的治疗方法。因此，这项提议将增加这些治疗方法被发现的可能性，从而影响公众健康。在宫内接触MA的儿童数量正在增加。在子宫中接触MA会导致儿童长期的认知和行为问题，影响我们的学校系统和我们的社会。这项建议将调查子宫内MA暴露导致的神经生物学变化，并探索治疗因子宫内MA暴露而有认知障碍的儿童的潜在疗法。