Drug Abuse, Schizophrenia, NMDA Receptor

药物滥用、精神分裂症、NMDA 受体

• 批准号: 8491057
• 负责人: JOSEPH T. COYLE
• 金额: $ 19.75万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-15 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8491057
• 关键词: Accounting; Affect; Agonist; Alleles; 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; Risk; 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 sharing; serine racemase; stimulant abuse

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）：多达 20% 的人口在一生中的某个阶段受到药物滥用 (SA) 的影响，并且遗传率在 40% 到 60% 之间。 SA 可能是由于复杂的遗传学造成的，即具有适度影响的多个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，并具有显着的遗传性（约 80%），是一种 SA 患病率非常高的疾病。近 90% 的精神分裂症患者大量吸烟，约 50% 的人有乙醇依赖，并且滥用兴奋剂的比例很高。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学有关。 NMDAR 还与动物模型中 SA 的获得和消失有关。我们假设精神分裂症中 SA 的高患病率是由于破坏 NMDAR 功能的共同风险基因所致。具体来说，精神分裂症的 3 个风险基因会影响 D-丝氨酸的可用性，D-丝氨酸是大脑皮质边缘区域 NMDAR 的共同激动剂。 我们培育了小鼠，其丝氨酸消旋酶（合成 D-丝氨酸的酶）已被基因灭活（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。他们还表现出对安非他明条件性过度活跃的获得和消失的异常，这与对SA的脆弱性增加一致。我们将使用 SR-/- 小鼠和作为阳性对照的 GlyT1+/- 小鼠（它们具有增强的 NMDAR 功能）来评估 NMDAR 功能在两种 SA 动物模型中的作用：可卡因自我给药范式，测量可卡因的增强作用和颅内自我刺激，本质上测量小鼠自我管理奖励性脑刺激的倾向。 主体的享乐状态。 SR-/-和GlyT1+/-小鼠自我施用可卡因后表现的改变将与通过与SA相关的脑区域中的cFos和DFosB表达监测的神经元活动相关。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。