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Drug Abuse, Schizophrenia, NMDA Receptor

药物滥用、精神分裂症、NMDA 受体

基本信息

批准号：
8658065
负责人：
JOSEPH T. COYLE
金额：
$ 23.7万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-05-15 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8658065
关键词：
Accounting Affect Agonist Am 80 Amphetamines Anhedonia Animal Model Animals Behavior Behavior Disorders Behavioral Behavioral Model Brain Brain region Cocaine Comorbidity Complex Cues Cycloserine Dendritic Spines Development Disease Dose Drug Addiction Drug abuse Environmental Risk Factor Enzymes Ethanol dependence Exhibits Extinction (Psychology)Failure Fragile X Syndrome Functional disorder Gene Silencing Genes Genetic Genetic Research Heritability High Prevalence Hyperactive behavior Individual Intervention Measures Mediating Meta-Analysis Modeling Monitor Morbidity - disease rate Mus N-Methyl-D-Aspartate Receptors Neurons Nucleus Accumbens Patients Performance Pharmaceutical Preparations Phenotype Population Proteins Research Resistance Rewards Role Schizophrenia Self Administration Self Stimulation Self-Administered Serine Stimulus Substance abuse problem Testing Time Update Variant Wild Type Mouse addiction autism spectrum disorder base cigarette smoking density endophenotype hedonic inhibitor/antagonist insight mortality neurochemistry neurotransmission null mutation prevent public health relevance receptor function research study response risk variant serine racemase stimulant abuse

项目摘要

DESCRIPTION (provided by applicant): Substance abuse (SA) affects up to 20% of the population at some point in their lives and exhibits a heritability rate between 40 and 60%. SA is likely due to complex genetics, i.e., multiple risk alleles of modest effect interacting with environmental factors to produce the addiction phenotype. Schizophrenia, which affects ~1% of the population and exhibits substantial heritability (~80%), is a disorder with a very high prevalence of SA. Nearly 90% of individuals with schizophrenia smoke cigarettes heavily, ~50% have ethanol dependence and high rates of stimulant abuse. Pharmacologic, post-mortem and recent genetic research have implicated NMDA receptors (NMDAR) in the pathophysiology of schizophrenia. NMDARs have also been implicated in the acquisition and extinction of SA in animal models. We hypothesize that the high prevalence of SA in schizophrenia is due to shared risk genes that disrupt NMDAR function. Specifically, 3 risk genes for schizophrenia affect the availability D-serine, a co-agonist at the NMDAR in cortico-limbic regions of the brain. We have developed mice, in which serine racemase, the enzyme that synthesizes D-serine has been genetically inactivated (SR-/- ). The SR-/- mice exhibit structural, neurochemical and behavioral homologies to schizophrenia. They also present abnormalities in the acquisition and extinction of conditioned hyperactivity to amphetamine, consistent with an increased vulnerability to SA. We will use SR-/- mice and, as positive controls, GlyT1+/- mice, which have increased NMDAR function, to assess the role of NMDAR function in two animal models of SA: the cocaine self-administration paradigm, which measures the reinforcing effects of cocaine and intracranial self-stimulation, which measures the propensity of the mouse to self-administer a rewarding brain stimulus, in essence the hedonic status of the subject. Alterations in the performance of SR-/- and GlyT1+/- mice on cocaine self- administration will be correlated with neuronal activity as monitored by cFos and DFosB expression in brain regions relevant to SA. Finally, we will determine whether behavioral abnormalities in the SR-/- mice can be reversed by treatments that replace the deficient D-serine.

描述（由申请人提供）：物质滥用（SA）影响高达20%的人口在他们的生活中的某个时候，并表现出40和60%之间的遗传率。SA可能是由于复杂的遗传学，即，多个适度影响的风险等位基因与环境因素相互作用产生成瘾表型。精神分裂症，影响约1%的人口，并表现出相当大的遗传性（约80%），是一种非常高的患病率SA的疾病。近90%的精神分裂症患者大量吸烟，约50%的人有酒精依赖和高比例的兴奋剂滥用。药理学、尸检和最近的遗传学研究表明，NMDA受体（NMDAR）与精神分裂症的病理生理有关。NMDAR也与动物模型中SA的获得和消退有关。我们假设SA在精神分裂症中的高患病率是由于共同的风险基因破坏了NMDAR功能。具体而言，精神分裂症的3个风险基因影响可用性D-丝氨酸，一种在大脑皮质边缘区的NMDAR的共激动剂。我们已经开发了小鼠，其中丝氨酸消旋酶，合成D-丝氨酸的酶已被遗传失活（SR-/-）。SR-/-小鼠表现出与精神分裂症的结构、神经化学和行为同源性。他们还提出异常的收购和灭绝条件多动症安非他明，符合SA的脆弱性增加。我们将使用SR-/-小鼠和作为阳性对照的GlyT 1 +/-小鼠（其NMDAR功能增强）来评估NMDAR功能在两种SA动物模型中的作用：可卡因自我给药范例，其测量可卡因和颅内自我刺激的强化作用，其测量小鼠自我给予奖励性脑刺激的倾向，本质上是主体的享乐状态。SR-/-和GlyT 1 +/-小鼠对可卡因自我给药的表现的改变将与神经元活性相关，如通过与SA相关的脑区域中的cFos和DFosB表达所监测的。最后，我们将确定SR-/-小鼠的行为异常是否可以通过替代缺乏的D-丝氨酸的治疗来逆转。