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）：该提案基于精神分裂症啮齿类动物模型，该模型是通过在出生后第 1-21 天（P）向大鼠注射多巴胺 D2/D3 激动剂喹吡罗来完成，从而导致多巴胺 D2 受体增加动物一生中持续存在的多巴胺 D2 敏感性增加与精神分裂症中 D2 激活的增加是最常见的。初步数据报告了四项主要发现：1) 新生儿喹吡罗治疗导致 ¿纹状体中的 7 种烟碱受体 (nAChR) 是药物奖励中重要的大脑区域；2) 通过微透析分析，新生儿喹吡罗治疗导致青少年大鼠伏隔核核心对尼古丁产生敏感的多巴胺反应；3) 我们报道了增强的多巴胺反应。用喹吡罗治疗的新生大鼠对尼古丁的行为过敏和位置条件反射；4) 新生儿喹吡罗增强了脑源性神经营养因子（BDNF）在几个大脑区域对尼古丁的反应，并导致accumbal磷酸化cAMP反应元件结合蛋白（pCREB）大幅增加。关于这一最终发现，accumbal pCREB的强劲增加已被放弃。快感缺失的生理测量，精神分裂症的一种阴性症状，尼古丁减少了 pCREB，这表明尼古丁可以自我治疗快感缺失。精神分裂症，与敏感的多巴胺反应一致。新生儿喹吡罗治疗产生的 7nAChR 上调对于增强对尼古丁的行为和多巴胺反应至关重要，因为它在尼古丁介导奖励的大脑区域的多巴胺功能中发挥着关键作用。 7nAChR 和与神经可塑性相关的蛋白质的变化是用喹吡罗治疗的新生大鼠对尼古丁敏感的行为和多巴胺能反应的核心，目标 1 将研究 ¿ 7 和 ¿ 4¿2 nAChR 在尼古丁行为敏化和位置调节中的作用 将分析 nAChR 对 BDNF 和 pCREB ​​响应尼古丁行为敏化的作用。该目标将测试增强新生儿喹吡罗尼古丁敏化和位置调节的假设。老鼠的治疗方法是 ¿ 7 nAChR，和 ¿ 7 nAChR 拮抗剂 MLA 将减少尼古丁诱导的新生喹吡罗大鼠中 BDNF 和 p-CREB ​​蛋白的增加，目的 2 将研究 ¿ 7 和 ¿使用微透析技术的累积多巴胺对尼古丁的反应中的 4¿2 nAChR 该目标将检验这样的假设：响应于尼古丁预处理的多巴胺溢出将取决于使用微透析技术的累积多巴胺对尼古丁的反应中的 ¿2 nAChR。目标 3 将分析用喹吡罗治疗的新生成年雄性大鼠的 7nAChR，但不分析对照组的尼古丁自我施用情况。测试的关键假设是，用喹吡罗治疗的新生成年大鼠会比用喹吡罗治疗的新生大鼠自我施用更多的尼古丁。盐水。