Amphetamine sensitization in a model of schizophrenia

精神分裂症模型中的安非他明致敏

• 批准号: 7854121
• 负责人: RUSSELL WAYNE BROWN
• 金额: $ 0.92万
• 依托单位: EAST TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7854121
• 关键词: Acute; Adult; Affect; Affinity; Agonist; Amphetamines; Anhedonia; Animals; Antipsychotic Agents; Area; Behavior; Brain; Cell Nucleus; Chronic; Control Animal; Corpus striatum structure; Data; Development; Disease; Dopamine; Dopamine D2 Receptor; Drug abuse; General Population; Incidence; Individual; Injection of therapeutic agent; Investigation; Laboratories; Language; Lead; Microdialysis; Modeling; Names; Neonatal; Neostriatum; Nicotine; Nucleus Accumbens; Pathway interactions; Pharmaceutical Preparations; Play; Population; Positive Reinforcements; Principal Investigator; Psychological reinforcement; Quinpirole; Rattus; Research; Rodent Model; Role; Saline; Schizophrenia; Sex Characteristics; Speed; Substance abuse problem; Symptoms; System; Time; Woman; base; bean; behavioral sensitization; design; drug of abuse; drug reinforcement; neonate; neurochemistry; programs; psychostimulant; relating to nervous system; research study; stimulant abuse

DESCRIPTION (provided by applicant): This proposal is designed to analyze the effects of amphetamine sensitization on dopamine release in the nucleus accumbens in a rodent model of schizophrenia. Research has shown that substance abuse in the schizophrenic population is approximately 2-5 times higher than that of the general public. The abuse of drug in the psychostimulants class, such as amphetamine and nicotine, are the most frequently abused drugs in the schizophrenic population. There is not a definitive explanation as to why there is a high level of drug abuse in this population, as substance abuse in schizophrenia has not been a well-investigated issue. Although there is typically higher overall functioning in women schizophrenics, this disappears with substance abuse, and women are more vulnerable to the negative effects of psychostimulant abuse. The rodent model of schizophrenia utilized in this proposal is based on long-term priming of the dopamine D2 receptor through neonatal administration of quinpirole, a dopamine D2/D3 agonist. Past research has demonstrated that neonatal quinpirole administration produces priming of the dopamine D2 receptor throughout the animal's lifetime. Preliminary data of this proposal demonstrates that an acute injection of amphetamine to D2-primed rats produced a 4-fold increase in dopamine microdialysate in the neostriatum compared to animals non-D2-primed rats neonatally treated with saline. The increase in dopamine release induced by amphetamine may be important in explaining the increased incidence of psychostimulant abuse in the schizophrenic population, and may lead to reduction in anhedonia, a negative symptom of the disorder. The proposal is designed to analyze three specific aims: 1) Compare the effects of amphetamine sensitization and analyze amphetamine's effects on dopamine release in the nucleus accumbens core utilizing microdialysis in D2-receptor-primed versus non-D2-receptor primed rats; 2) Investigate the role of dopamine D1 and D2 receptors in sensitization and dopamine release in the nucleus accumbens core in D2- versus non-D2-primed rats; 3) Analyze sex differences in amphetamine-induced behavioral sensitization and its relationship to dopamine microdialysis in the NAcc in D2- versus non-D2-primed rats. Plain language description: Schizophrenia affects approximately 1% of the U.S. population, and this population is 2-5 times more likely to use or abuse stimulants than the general public. This proposal is designed to investigate the effects of chronic amphetamine (street name: Speed) administration on behavior and neurochemistry of rats that been given a drug manipulation during development that mimics the neurochemistry of schizophrenia.

描述（由申请人提供）：本提案旨在分析安非他明致敏对精神分裂症啮齿动物模型中伏核中多巴胺释放的影响。研究表明，精神分裂症患者的药物滥用率大约是普通大众的 2-5 倍。精神兴奋剂类药物的滥用，例如安非他明和尼古丁，是精神分裂症人群中最常滥用的药物。由于精神分裂症患者的药物滥用问题尚未得到充分研究，因此目前还没有明确的解释说明为什么这一人群的药物滥用率很高。尽管女性精神分裂症患者的整体功能通常较高，但这种情况会随着药物滥用而消失，并且女性更容易受到精神兴奋剂滥用的负面影响。本提案中使用的精神分裂症啮齿动物模型基于通过新生儿给予喹吡罗（一种多巴胺 D2/D3 激动剂）对多巴胺 D2 受体的长期启动。过去的研究表明，新生儿服用喹吡罗会在动物一生中引发多巴胺 D2 受体。该提案的初步数据表明，与用盐水治疗的非 D2 引发的新生大鼠相比，对 D2 引发的大鼠急性注射安非他明，新纹状体中的多巴胺微透析液增加了 4 倍。安非他明引起的多巴胺释放增加可能对于解释精神分裂症人群中精神兴奋剂滥用发生率的增加很重要，并且可能导致快感缺乏（该疾病的阴性症状）的减少。该提案旨在分析三个具体目标：1）比较安非他明致敏作用，并利用微透析在 D2 受体引发与非 D2 受体引发的大鼠中分析安非他明对伏核核心多巴胺释放的影响； 2) 研究多巴胺 D1 和 D2 受体在 D2 与非 D2 引发大鼠的伏核核心敏化和多巴胺释放中的作用； 3) 分析 D2 与非 D2 启动大鼠中安非他明诱导的行为敏化的性别差异及其与 NAcc 中多巴胺微透析的关系。通俗易懂的语言描述：精神分裂症影响着大约 1% 的美国人口，而该人群使用或滥用兴奋剂的可能性是普通大众的 2-5 倍。该提案旨在研究长期服用安非他明（街道名称：Speed）对大鼠行为和神经化学的影响，这些大鼠在发育过程中接受了模拟精神分裂症神经化学的药物操作。