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

描述(申请人提供)：这项建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1-21天给大鼠注射多巴胺D2/D3激动剂奎比罗来实现的，这导致增加了多巴胺D2受体的敏感性，并在动物的一生中持续存在。精神分裂症患者对多巴胺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。初步数据报告了四项主要发现：1)新生儿期喹哌酮治疗导致纹状体内尼古丁受体(NAChRs)显著增加，纹状体是药物奖赏的重要大脑区域；2)根据微透析分析，新生儿喹哌酮治疗导致青春期大鼠伏隔核对尼古丁的敏化多巴胺反应；3)我们报道了奎比罗增强新生大鼠对尼古丁的行为敏感化和位置调节；4)新生儿奎匹罗增强了脑源性神经营养因子(BDNF)对尼古丁的反应，并导致伏核磷酸化cAMP反应元件结合蛋白(PCREB)大幅增加。关于这一最终发现，伏隔pCREB的强劲增加被假设为快感缺失的一种生理指标，快感缺失是精神分裂症的一种负面症状。有趣的是，尼古丁减少了pCREB，这表明尼古丁可能会自我治疗精神分裂症的快感缺失，这与敏化的多巴胺反应一致。我们假设，由新生儿奎比罗治疗产生的7nAChR上调对于增强行为和多巴胺对尼古丁的反应至关重要，因为它在尼古丁在大脑中介导奖赏的区域的多巴胺功能中发挥关键作用。这一建议的基本假设是，7nAChRs和与神经可塑性相关的蛋白质的变化是使用喹比罗治疗的新生大鼠对尼古丁的敏化行为和多巴胺能反应的中心。目的1研究7和4 nAChRs在尼古丁行为敏感化和位置条件作用中的作用。一个子目标将分析nAChRs在尼古丁行为敏化反应中对BDNF和pCREB的作用。这一目的将验证这样的假设，即7nAChR介导了新生鼠对尼古丁的敏化和位置条件反射的增强，而7nAChR拮抗剂MLA将降低尼古丁诱导的新生大鼠BDNF和p-CREB蛋白的增加。目的2利用微透析技术研究7和4 nAChRs在伏隔区多巴胺对尼古丁反应中的作用。这一目标将检验这样一种假设，即尼古丁预处理对新生大鼠的多巴胺溢出反应将依赖于7nAChRs，而不是对照组。目的3将分析成年雄性新生大鼠服用喹比罗后尼古丁的自我给药情况。测试的关键假设是，用喹比罗治疗的成年大鼠比用生理盐水治疗的成年大鼠自身摄入更多的尼古丁。

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.