Drug Abuse, Schizophrenia, NMDA Receptor

描述(由申请人提供)：药物滥用(SA)在他们生命中的某个时候影响到多达20%的人口，遗传率在40%到60%之间。SA可能是由于复杂的遗传学，即多个效应不大的危险等位基因与环境因素相互作用而产生的成瘾表型。精神分裂症是一种SA患病率很高的疾病，它影响着大约1%的人口，并表现出相当大的遗传性(~80%)。近90%的精神分裂症患者吸烟严重，约50%的人有酒精依赖和高兴奋剂滥用率。药理学、尸检和最近的遗传学研究表明，NMDAR与精神分裂症的病理生理学有关。在动物模型中，NMDAR也与SA的获得和消亡有关。我们假设，精神分裂症中SA的高患病率是由于共同的风险基因扰乱了NMDAR功能。具体地说，精神分裂症的3个风险基因影响D-丝氨酸的可获得性，D-丝氨酸是大脑皮质边缘区域NMDAR的一种共同激动剂。 我们开发了一种小鼠，在这种小鼠中，合成D-丝氨酸的丝氨酸外消旋酶已经遗传失活(SR-/-)。SR-/-小鼠在结构、神经化学和行为上与精神分裂症相似。它们还表现出对苯丙胺的条件性过度活动的获得和消退的异常，这与SA的易感性增加一致。我们将使用SR-/-小鼠和GlyT1+/-小鼠作为阳性对照，这些小鼠增加了NMDAR功能，以评估NMDAR功能在SA的两个动物模型中的作用：可卡因自我给药范式，它测量可卡因和颅内自我刺激的强化效果，它测量小鼠自我管理奖励大脑刺激的倾向，本质上是受试者的享乐状态。根据与SA相关的脑区CFos和DFosB表达的监测，SR-/-和GlyT1+/-小鼠对可卡因自我给药的表现的改变将与神经元活动相关。最后，我们将确定SR-/-小鼠的行为异常是否可以通过替代缺陷的D-丝氨酸的治疗而逆转。

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.