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: 9011776
• 负责人: RUSSELL WAYNE BROWN
• 金额: $ 3.58万
• 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/9011776
• 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; Health; 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; 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（由适用提供）：该提案基于一种精神分裂症的啮齿动物模型，该模型是通过新生儿注入多巴胺D2/D3激动剂Quinpirole到产后（p）1-21的大鼠来完成的，从而导致多巴胺D2受体敏感性增加，这在整个动物的生命中持续存在。增加的多巴胺D2敏感性与精神分裂症中D2激活的增加一致。尼古丁是精神分裂症患者中最常见的药物。初步数据报告四个主要发现：1）新生儿奎因螺旋的治疗导致纹状体中7种烟碱受体（NACHR）显着增加，这是对药物奖励重要的大脑区域； 2）新生儿奎因螺旋的治疗导致通过微透析分析的青少年大鼠伏隔核的敏感多巴胺对尼古丁的敏感反应； 3）我们报道了行为敏化的增强，并将调节性适应奎尼螺旋菌治疗的大鼠中的尼古丁。 4）新生儿奎因螺菌增强了脑衍生的神经营养因子（BDNF）对尼古丁在几个大脑区域的反应，并导致伏尊糖磷酸化的CAMP反应元件结合蛋白（PCREB）大幅增加。关于这一最终发现，已假设伏pcreb的稳健增加是对Anhedonia的物理测量，这是精神分裂症的负面症状。有趣的是，尼古丁降低了PCREB，这表明尼古丁可能会在精神分裂症中自我治疗，这与敏感的多巴胺反应一致。我们假设新生儿奎因梭治疗产生的7NACHR上调对于增强的行为和多巴胺对尼古丁的反应至关重要，因为它在尼古丁在尼古丁在介导奖励的大脑区域的作用中具有关键作用。该提议的主要假设是，与神经可塑性相关的蛋白质的变化对于用奎诺螺旋旋菌治疗的大鼠对尼古丁的敏感行为和多巴胺能反应至关重要。 AIM 1将研究nachrs nachrs在尼古丁行为敏感性和位置调节中的作用。子AIM将分析NACHRS在BDNF和PCREB上的作用，以响应尼古丁行为敏感性。该目标将检验新生儿奎因螺螺菌治疗大鼠中尼古丁敏感性和位置调节的假设，由�7NACHR介导，而77 NACHR拮抗剂MLA会降低尼古丁诱导的尼古丁诱导的新生儿奎因硫螺旋体中BDNF和P-CREB蛋白的增加。 AIM 2将使用微透析技术研究�7和4.2 NACHRS在对尼古丁的抗抑制剂多巴胺反应中的作用。该目的将检验以下假设：响应尼古丁预处理的多巴胺溢出将取决于新生儿奎因螺菌大鼠中的7nachrs，但不能控制。 AIM 3将分析成年雄性大鼠新生儿治疗的奎因螺旋菌素的尼古丁自我给药。检验的关键假设是，与盐水治疗的动物相比，用奎因瓜治疗的成年大鼠自我辅助治疗的尼古丁更为尼古丁。

项目成果

The effects of nicotine in the neonatal quinpirole rodent model of psychosis: Neural plasticity mechanisms and nicotinic receptor changes.

尼古丁对新生儿喹吡罗啮齿动物精神病模型的影响：神经可塑性机制和烟碱受体变化。

• DOI: 10.1016/j.bbr.2017.02.029
• 发表时间: 2017
• 期刊: Behavioural brain research
• 影响因子: 2.7
• 作者: Peterson,DanielJ;Gill,WDrew;Dose,JohnM;Hoover,DonaldB;Pauly,JamesR;Cummins,ElizabethD;Burgess,KatherineC;Brown,RussellW
• 通讯作者: Brown,RussellW