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

描述（由申请人提供）：该提案基于啮齿动物精神分裂症模型，该模型通过从出生后(P) 1-21天(P)新生大鼠注射多巴胺D2/D3激动剂喹匹罗来完成，这导致多巴胺D2受体敏感性增加，并持续整个动物的一生。在精神分裂症中，多巴胺D2敏感性的增加与D2激活的增加是一致的。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)新生儿喹匹罗治疗导致纹状体中- 7烟碱受体（nAChRs）显著增加，这是一个在药物奖励中重要的大脑区域；2)微透析分析新生儿喹匹罗治疗导致青春期大鼠伏隔核对尼古丁致敏的多巴胺反应；3)我们已经报道了给予喹匹罗的新生大鼠对尼古丁的行为敏感性和场所条件反射增强；4)新生儿喹匹罗增强了脑源性神经营养因子（BDNF）在多个脑区对尼古丁的反应，导致伏隔区磷酸化cAMP反应元件结合蛋白（pCREB）显著升高。关于这一最终发现，伏隔区pCREB的强劲增长被假设为快感缺乏症的生理测量，精神分裂症的阴性症状。有趣的是，尼古丁降低了pCREB，这表明尼古丁可能会自我治疗精神分裂症的快感缺乏，这与多巴胺的增敏反应一致。我们假设新生儿喹匹罗治疗产生的- 7nAChR上调对尼古丁增强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多巴胺功能中起关键作用。这一提议的主要假设是- 7nachr和与神经可塑性相关的蛋白质的变化是新生儿接受喹匹罗治疗的大鼠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在尼古丁行为致敏和场所条件反射中的作用。一个子目标将分析nAChRs对BDNF和pCREB在尼古丁行为致敏反应中的作用。本研究旨在验证喹匹罗处理后新生大鼠尼古丁致敏和场所条件反射的增强是由- 7 nAChR介导的，而- 7 nAChR拮抗剂MLA可以降低尼古丁诱导的新生大鼠BDNF和p-CREB蛋白的升高。目的2将使用微透析技术研究- 7和- 4 - 2 nachr在伏隔多巴胺对尼古丁的反应中的作用。这一目的将验证一种假设，即新生儿喹匹罗大鼠对尼古丁预处理反应中的多巴胺溢出将取决于- 7nachr，而不是对照。目的3分析喹匹罗给药后成年雄性大鼠的尼古丁自我给药情况。关键的假设是，与用生理盐水治疗的新生动物相比，用喹匹罗治疗的成年大鼠会自我注射更多的尼古丁。

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.