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: 7849732
• 负责人: Jessica A Siegel
• 金额: $ 4.14万
• 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/7849732
• 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（由申请人提供）：使用甲基苯丙胺 (MA) 的孕妇数量正在增加。在子宫内接触 MA 会导致婴儿出现神经和认知缺陷，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 引起的神经和认知障碍背后的神经生物学机制将增进我们对 MA 在大脑中的作用的理解，并为开发针对子宫内接触 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 MA 暴露对胆碱能功能的影响知之甚少。 NIDA 的目标之一是改善药物滥用的治疗，该项目的目标与此目标一致，因为其目标是探索子宫内 MA 暴露对胆碱能系统的长期影响，并研究可能逆转 MA 引起的成年认知缺陷的潜在胆碱能疗法。这一目标将通过在小鼠海马体发育期间给予 MA 来实现，海马体发育发生在出生后前 3 周，模仿人类妊娠晚期海马体的发育。该提案的具体目标是：1）确定新生儿 MA 对基底前脑胆碱乙酰转移酶阳性细胞以及成年期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、光密度测定和无偏立体学技术来实现； 2) 使用毒蕈碱乙酰胆碱受体结合测定确定新生儿 MA 对成年期海马和皮质中 M1 和 M2 毒蕈碱受体的数量和亲和力的影响； 3) 确定直接注射到侧脑室的乙酰胆碱酯酶抑制剂卡巴拉汀或毒蕈碱受体激动剂卡巴胆碱逆转成年新生儿 MA 造成的认知障碍的能力。公共卫生相关性：由于在子宫内接触 MA 的儿童在各种认知任务上表现出障碍，因此必须描述这些障碍的潜在神经生物学并开发针对这些儿童的治疗方法。因此，该提案将通过增加发现这些治疗方法的可能性来影响公共健康。在子宫内接触 MA 的儿童数量正在增加。在子宫内接触 MA 会导致儿童出现长期的认知和行为问题，从而影响我们的学校系统和社会。该提案将调查子宫内 MA 暴露引起的神经生物学变化，并探索治疗因子宫内 MA 暴露而出现认知障碍的儿童的潜在疗法。