Nicotine and the roles of nicotinic receptors in a rodent model of schizophrenia

尼古丁和烟碱受体在啮齿动物精神分裂症模型中的作用

• 批准号: 8574551
• 负责人: RUSSELL WAYNE BROWN
• 金额: $ 40.82万
• 依托单位: EAST TENNESSEE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8574551
• 关键词: Adolescence; Adolescent; Adult; Agonist; Anhedonia; Animal Model; Animals; Area; Behavioral; Brain; Brain region; Brain-Derived Neurotrophic Factor; Calcium Channel; Comorbidity; Corpus striatum structure; Cyclic AMP-Responsive DNA-Binding Protein; DRD2 gene; Data Reporting; Development; Disease; Dopamine; Dopamine D2 Receptor; Dorsal; Glutamates; Goals; Human; Hypersensitivity; Impaired cognition; Injection of therapeutic agent; Laboratories; Laboratory Study; Link; Measures; Mediating; Microdialysis; Modeling; Motor; Neonatal; Neurodevelopmental Disorder; Neuronal Plasticity; Neurons; Nicotine; Nicotine Dependence; Nicotinic Receptors; Nucleus Accumbens; Pharmaceutical Preparations; Physiological; Population; Proteins; Psychological reinforcement; Quinpirole; Rattus; Reporting; Rewards; Rodent Model; Role; Saline; Schizophrenia; Self Administration; Self Medication; Self-Administered; Smoking; Smoking Behavior; Substance abuse problem; Symptoms; System; Techniques; Testing; Time; Tobacco; Tobacco Dependence; Tobacco use; Up-Regulation; Wit; Work; atypical antipsychotic; base; behavioral sensitization; cigarette smoking; conditioning; design; dopaminergic neuron; drug reward; extracellular; insight; male; neonate; neurochemistry; neurophysiology; neurotrophic factor; olanzapine; postnatal; public health relevance; receptor sensitivity; response

DESCRIPTION (provided by applicant): This proposal is based around a rodent model of schizophrenia that is accomplished through neonatal injection of the dopamine D2/D3 agonist quinpirole to rats from postnatal days (P) 1-21, which results in increased dopamine D2 receptor sensitivity that persists throughout the animal's lifetime. Increased dopamine D2 sensitivity is consistent with increased D2 activation in schizophrenia. Nicotine is the most frequently abused drug in schizophrenics. Preliminary data report four major findings: 1) Neonatal quinpirole treatment results in a significant increase in ¿7 nicotinic receptors (nAChRs) in the striatum, a brain area important in drug reward; 2) neonatal quinpirole treatment results in a sensitized dopamine response to nicotine in the nucleus accumbens core of adolescent rats as analyzed by microdialysis; 3) we have reported enhanced behavioral sensitization and place conditioning to nicotine in rats neonatally treated with quinpirole; 4) neonatal quinpirole enhanced the response of brain-derived neurotrophic factor (BDNF) to nicotine in several brain areas, and resulted in a substantial increase in accumbal phosphorylated cAMP response element binding protein (pCREB). Regarding this final finding, robust increases in accumbal pCREB have been hypothesized to be a physiological measure of anhedonia, a negative symptom of schizophrenia. Interestingly, nicotine reduced pCREB, which suggests nicotine may self-medicate anhedonia in schizophrenia, consistent with a sensitized dopamine response. We hypothesize that ¿7nAChR upregulation produced by neonatal quinpirole treatment is critical to the enhanced behavioral and dopamine response to nicotine because of its pivotal role in nicotine's role in dopamine function in brain regions that mediate reward. The primary hypothesis of this proposal is that ¿7nAChRs and changes in proteins related to neural plasticity are central to the sensitized behavioral and dopaminergic response to nicotine in rats neonatally treated with quinpirole. Aim 1 will investigate the role of ¿7 and ¿4¿2 nAChRs in nicotine behavioral sensitization and place conditioning. A sub-aim will analyze the roles of nAChRs on BDNF and pCREB in response to nicotine behavioral sensitization. This aim will test the hypotheses that enhanced nicotine sensitization and place conditioning in neonatal quinpirole-treated rats is mediated by the ¿7 nAChR, and the ¿7 nAChR antagonist MLA will reduce nicotine-induced increased of BDNF and p-CREB protein in neonatal quinpirole rats. Aim 2 will investigate the role of ¿7 and ¿4¿2 nAChRs in the accumbal dopamine response to nicotine using the microdialysis technique. This aim will test the hypothesis that dopamine overflow in response to nicotine pretreatment will depend on ¿7nAChRs in neonatal quinpirole rats, but not controls. Aim 3 will analyze nicotine self-administration in adult male rats neonatally treated wit quinpirole. The critical hypothesis tested is that adult rats neonatally treated with quinpirole wil self-administer more nicotine than animals neonatally treated with saline.

描述（由申请人提供）：该提议是基于精神分裂症的啮齿动物模型，该模型是通过从出生后（P）1-21天向大鼠注射多巴胺D2/D3激动剂喹吡罗来完成的，这导致多巴胺D2受体敏感性增加，并持续整个动物的一生。多巴胺D2敏感性增加与精神分裂症中D2激活增加一致。尼古丁是精神分裂症患者最常滥用的药物。初步数据报告了四个主要发现：1）新生儿喹吡罗治疗导致纹状体中的烟碱受体（nAChR）显著增加，纹状体是药物奖励中重要的大脑区域; 2）新生儿喹吡罗治疗导致青春期大鼠中脑核核心中对尼古丁的致敏多巴胺反应，如通过微透析分析的;（3）我们报道了经喹吡罗处理的大鼠对尼古丁的行为敏感化和位置条件化增强; 4）新生儿喹吡罗可增强脑内多个脑区脑源性神经营养因子（BDNF）对尼古丁的反应，并导致磷酸化cAMP应答元件结合蛋白（pCREB）的显著增加。关于这一最后的发现，已经假设pCREB的显著增加是快感缺乏的生理指标，快感缺乏是精神分裂症的阴性症状。有趣的是，尼古丁降低了pCREB，这表明尼古丁可能在精神分裂症中自我兴奋，与致敏多巴胺反应一致。我们假设，由新生儿喹吡罗治疗产生的7 nAChR上调对于增强对尼古丁的行为和多巴胺反应是至关重要的，因为其在尼古丁在介导奖赏的大脑区域中的多巴胺功能中的作用中起关键作用。该建议的主要假设是，在用喹吡罗治疗的大鼠中，与神经可塑性相关的蛋白质的变化和7 nAChR是对尼古丁的致敏行为和多巴胺能反应的核心。目的1将研究<$7和<$4 <$2 nAChR在尼古丁行为敏化和位置条件反射中的作用。一个子目标将分析nAChR对BDNF和pCREB在尼古丁行为敏化反应中的作用。本研究旨在验证以下假说：喹吡罗对新生大鼠的尼古丁增敏和位置条件反射的增强是由<$7 nAChR介导的，<$7 nAChR拮抗剂MLA可减少尼古丁诱导的新生大鼠BDNF和p-CREB蛋白的增加。目的2将使用微透析技术研究<$7和<$4 <$2 nAChR在多巴胺对尼古丁的反应中的作用。这一目的将检验以下假设：响应于尼古丁预处理的多巴胺溢出将取决于新生喹吡罗大鼠中的<$7nAChR，而不是对照。目的3分析喹吡罗对成年雄性大鼠的尼古丁自我给药。检验的关键假设是，经喹吡罗腹腔给药的成年大鼠比经生理盐水腹腔给药的动物自我给予更多的尼古丁。