Developmental Effects of Methamphetamine-like Stimulants

甲基苯丙胺类兴奋剂的发育影响

• 批准号: 7026522
• 负责人: Charles V Vorhees
• 金额: $ 29.1万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-08-05 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7026522
• 关键词: NMDA receptors; adrenal transplantation; adrenalectomy; animal developmental psychology; autoradiography; behavior test; behavioral /social science research tag; cognition; corticosterone; embryo /fetus toxicology; hippocampus; homologous transplantation; hormone biosynthesis; hypothalamic pituitary adrenal axis; immunocytochemistry; laboratory rat; malnutrition; memory; methamphetamine; metyrapone; neural information processing; neurochemistry; neurotoxicology; nitric oxide synthase; psychological stressor; psychopharmacology; receptor binding; synapsins; visual perception

DESCRIPTION (provided by applicant): This is a revised competing renewal. We found that d-methamphetamine (MA) induces spatial learning and memory (L&M) deficits in Morris water maze (MWM) after exposure on P11-20 but not P1-10, and increases corticosterone (CORT). During the most recent period we found that MA causes dose-dependent MWM spatial and 'strategies' but not cued deficits, reference but not working memory deficits and spares sequential learning. Spatial deficits generalize to Barnes maze to aversive, but were unclear for appetitive reinforcement. MA results in ~15% reductions in striatal DA, D2 receptors, PKA, and in dendritic spines and arbors. MWM deficits emerge by P40 and persist until at least P360. Fractionating P11-20 reveals MWM deficits after P11-15 but not P16-20. The stress hyporesponsive period (SHRP) is P4-14. We find a MA-related SHRP of P7-13 to single doses, but 5-day MA overrides this with a CORT rise at 24 hours. New hypotheses: (1) Developmental exposure to MA from P11-15 results in altered response to stressors and L&M. We will test this in offspring measuring CORT after stressor exposure or on hippocampally-mediated L&M; (2) Inhibition of CORT synthesis in MA exposed rats will reduce CORT release during MWM testing, resulting in improved performance. We will test this in offspring pretreated with metyrapone; (3) MA induced increases in CORT during the SHRP are the cause of the subsequent L&M deficits observed later and preventing this increase will prevent the deficits. We will test this by adrenal removal following by alloengraftment, causing a 7-10 day interruption of adrenal function during the treatment interval and test the offspring for L&M as adults; (4) Exposure to MA during periods outside the SHRP will not result in the L&M deficits or NMDA receptor changes observed from exposures within the SHRP. We will test this with 4 exposure intervals, 2 within and 2 outside (1 before and 1 after) the SHRP and determine the effects on L&M and hippocampal NMDA receptors by 3H-MK-801 autoradiography and receptor complex-associated immunocytochemistry for PSD95, nNOS, CAPON, Dexras1, and Synapsin I-III. We will also determine the contribution of drug-induced undernutrition on multiple types of spatial learning, on hippocampus-dependent non-spatial learning, and on attention. The number of prenatally MA exposed children continues to grow. Our goal is to develop models of early MA exposure that permit an understanding of the long-term consequences on brain development and cognition.

描述（由申请人提供）：这是经修订的竞争续约。我们发现，D-甲基苯丙胺（MA）在P11-20而不是P1-10暴露后诱导Morris Water Maze（MWM）诱导空间学习和记忆（L＆M）缺陷，并增加了皮质酮（Cort）。在最近时期，我们发现MA会导致剂量依赖性的MWM空间和“策略”，但没有提示缺陷，参考，但没有工作记忆缺陷和备件序列学习。空间赤字概括为巴恩斯迷宫厌恶，但尚不清楚食欲增强。 MA导致纹状体DA，D2受体，PKA以及树突状棘和轴的降低约15％。 MWM缺陷出现在P40中，并一直持续到至少P360。分级P11-20揭示了P11-15之后的MWM缺陷，而不是P16-20。应力次应力期（SHRP）为P4-14。我们发现单剂量的MA相关SHRP的P7-13 SHRP，但为期5天的MA在24小时时Cort上升了5天。新假设：（1）P11-15中对MA的发育暴露导致对压力源和L＆M的反应改变。我们将在应激源暴露或海马介导的L＆M之后测量Cort的后代测试。 （2）在MA暴露大鼠中抑制CORT合成将减少MWM测试期间的Cort释放，从而改善性能。我们将在用metyrapone预处理的后代中进行测试； （3）MA在SHRP期间诱导的Cort诱导的增加是随后观察到的L＆M缺陷的原因，并防止这种增加将阻止缺陷。我们将通过同异菌植物后通过肾上腺去除来测试这一点，在治疗间隔期间导致7-10天的肾上腺功能中断，并测试成年L＆M的后代； （4）在SHRP以外的时期暴露于MA不会导致L＆M缺陷或SHRP内暴露中观察到的NMDA受体变化。我们将通过3H-MK-801自放射摄影和受体复杂相关的免疫细胞化学化学，在PSD95，NNOS，Capon，capon，dexras1，decras1，synapsin Iii Iii Iii Iii Inii测试，并在外部和2个外部的4个接触时间间隔内（1和1后）（1和1之后）进行测试，并确定对L＆M和海马NMDA受体的影响。我们还将确定药物诱导的营养不良对多种类型的空间学习，海马依赖性非空间学习以及注意力的贡献。产前MA暴露的儿童的数量继续增加。我们的目标是开发早期MA暴露模型，以了解对大脑发育和认知的长期后果。