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(申请人提供)：这项建议旨在分析苯丙胺敏化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，精神分裂症人群中的药物滥用大约是普通公众的2-5倍。精神刺激剂类药物的滥用，如苯丙胺和尼古丁，是精神分裂症人群中最常被滥用的药物。由于精神分裂症中的药物滥用一直没有得到充分的调查，因此没有一个明确的解释来解释为什么这一人群中的药物滥用水平很高。尽管女性精神分裂症患者的总体功能通常较高，但随着药物滥用，这种情况就消失了，女性更容易受到精神刺激剂滥用的负面影响。这项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予多巴胺D2/D3激动剂奎比罗长期启动多巴胺D2受体。过去的研究表明，新生儿服用喹比罗会在动物的整个一生中产生多巴胺D2受体的启动。这项建议的初步数据表明，给D2刺激的大鼠急性注射苯丙胺，新纹状体中的多巴胺微透析液比未注射D2的新生大鼠用生理盐水处理的动物增加了4倍。苯丙胺引起的多巴胺释放增加可能是精神分裂症人群中精神刺激剂滥用增加的重要原因，并可能导致快感缺失的减少，快感缺失是精神分裂症的负面症状。该建议旨在分析三个具体目标：1)比较苯丙胺敏化的效果，并利用微透析技术分析苯丙胺对D2受体激活和非D2受体激活大鼠伏隔核核心多巴胺释放的影响；2)研究D2受体和D2受体在D2受体激活和非D2受体激活大鼠伏隔核核心敏化和多巴胺释放中的作用；3)分析苯丙胺诱导的行为敏化的性别差异及其与D2受体刺激和非D2受体刺激大鼠NACc多巴胺微透析的关系。简而言之：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。这项建议旨在调查长期服用苯丙胺(街名：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。