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伏隔核多巴胺释放的影响。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，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还没有得到充分的调查，所以为什么这一人群中药物滥用程度如此之高，目前还没有一个明确的解释。虽然女性精神分裂症患者的整体功能通常更高，但这种功能随着药物滥用而消失，而且女性更容易受到精神兴奋剂滥用的负面影响。本研究中使用的啮齿动物精神分裂症模型是基于新生儿给予多巴胺D2/D3激动剂喹匹罗对多巴胺D2受体的长期启动。过去的研究表明，新生儿服用喹匹罗会在动物的一生中产生多巴胺D2受体的启动。本研究的初步数据表明，与未注射d2的新生大鼠相比，对d2启动大鼠急性注射安非他明可使新纹状体中多巴胺微透析液增加4倍。安非他明引起的多巴胺释放增加可能是解释精神分裂症人群中滥用精神兴奋剂发生率增加的重要原因，并可能导致快感缺乏症（精神分裂症的一种阴性症状）减少。本研究旨在分析三个具体目标：1)比较安非他明致敏效应，并利用微透析分析安非他明对d2受体启动与非d2受体启动大鼠伏隔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启动大鼠伏隔核致敏和多巴胺释放中的作用；3)分析D2-与非D2-启动大鼠苯丙胺诱导行为致敏的性别差异及其与NAcc多巴胺微透析的关系。简单的语言描述：精神分裂症影响了大约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公众的2-5倍。本研究旨在研究长期服用安非他明（俗称：Speed）对大鼠行为和神经化学的影响，这些大鼠在发育过程中被给予模仿精神分裂症神经化学的药物操纵。