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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：
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
项目类别：
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

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）：药物滥用（SA）在其生命的某个阶段影响多达20%的人口，并表现出40%至60%的遗传率。SA可能是由于复杂的遗传，即多种影响适度的风险等位基因与环境因素相互作用产生成瘾表型。精神分裂症是一种SA患病率非常高的疾病，约占人口的1%，具有很高的遗传性（约80%）。近90%的精神分裂症患者重度吸烟，约50%的人酒精依赖，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有关。在动物模型中，NMDARs也与SA的获得和灭绝有关。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。具体来说，精神分裂症的3个风险基因影响d -丝氨酸的可用性，d -丝氨酸是大脑皮质边缘区域NMDAR的一种共激动剂。