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: 7127485
• 负责人: RUSSELL WAYNE BROWN
• 金额: $ 21.58万
• 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/7127485
• 关键词: amphetamines; central nervous system stimulants; dopamine; model; receptor; schizophrenia

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脑核多巴胺释放的影响。研究表明，精神分裂症患者滥用药物的比例大约是普通大众的2-5倍。精神兴奋剂类药物的滥用，如安非他明和尼古丁，是精神分裂症患者最常滥用的药物。对于这一人群中药物滥用率高的原因，目前还没有明确的解释，因为精神分裂症中的药物滥用问题尚未得到充分研究。虽然女性精神分裂症患者的总体功能通常较高，但这在药物滥用中消失，女性更容易受到精神兴奋剂滥用的负面影响。本建议中使用的精神分裂症啮齿动物模型是基于通过新生儿给药喹吡罗（一种多巴胺D2/D3激动剂）对多巴胺D2受体的长期激发。过去的研究已经证明，新生儿喹吡罗给药在动物的一生中产生多巴胺D2受体的启动。该提案的初步数据表明，急性注射安非他明的D2致敏大鼠产生4倍增加多巴胺微透析液在新纹状体的动物相比，非D2致敏大鼠用生理盐水治疗。安非他明引起的多巴胺释放的增加可能是重要的，在解释精神分裂症人群中精神兴奋剂滥用的发病率增加，并可能导致减少快感缺乏，一种阴性症状的障碍。1）比较苯丙胺致敏的效果，并利用微透析技术分析苯丙胺对D2受体致敏大鼠和非D2受体致敏大鼠中脑延髓核核心区多巴胺释放的影响;（2）研究多巴胺D_1和D_2受体在D_2-和非D_2-致敏大鼠延髓核团致敏和多巴胺释放中的作用; 3）分析D2-和非D2-致敏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。简单的语言描述：精神分裂症影响大约1%的美国人口，这一人群使用或滥用兴奋剂的可能性是普通大众的2-5倍。该提案旨在研究慢性安非他明（街道名称：速度）管理对大鼠的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。