Novel hypothesis for the comorbidity of schizophrenia and nicotine abuse in rats.

描述(申请人提供)：在美国，吸烟是一个主要的健康问题，精神分裂症患者的吸烟率远远高于普通人群(88-90%的精神分裂症患者与22%的普通人群)。这种差异的原因尚不清楚，已经提出了许多假说，但没有一种假说能令人满意地解释共病。奖赏回路最近已成为精神分裂症研究中的一个感兴趣的领域，因为快感缺失(无法体验快乐和/或奖赏)被认为是精神分裂症的一种负面症状，抗精神病药物已被证明可以改变刺激的奖赏程度；然而，关于精神分裂症患者奖赏敏感性的研究有限，到目前为止，结果喜忧参半。这项研究旨在为精神分裂症患者增加尼古丁使用提出一个新的假说，该假说涉及奖赏系统，即对尼古丁的奖赏增强效应的敏感性。尼古丁的奖赏增强效应被定义为尼古丁对非尼古丁刺激的增强，已被证明是维持尼古丁使用的一个强有力的因素，产生的效果甚至可能比尼古丁的一般奖赏效应更强。对尼古丁奖励增强效应的敏感性可以解释精神分裂症患者吸烟率高的原因，并导致治疗这种共病的新方法。使用临床前方法，这组AIMS将提供三个单独的范例来测试这一想法：50 kHz奖赏发声，对自然奖赏刺激(例如光)的操作者反应，以及尼古丁自我给药。动物将接受生理盐水或苯环利定(PCP)的预处理，PCP是一种NMDA受体拮抗剂，已被验证为精神分裂症的动物模型，它会产生许多阳性、阴性和认知症状，与精神分裂症患者的症状相同。在前两个目标中，对视觉刺激的发声和对视觉刺激的杠杆按压将在接触尼古丁后进行测量。在第三个目标中，注射尼古丁的杠杆按压将在单独接受尼古丁或同时接受尼古丁视觉刺激的两组之间进行检查。这组实验不仅将提供尼古丁对奖赏增强效应的潜在敏感性的数据，还将允许在临床前精神分裂症动物模型中分析尼古丁的一般奖赏效应。

DESCRIPTION (provided by applicant): Tobacco use is a major health problem in the United States and schizophrenics smoke at a much higher rate that the general population (88-90% of schizophrenics versus 22% of the general population). The reason for this discrepancy is still unknown and many hypotheses have been introduced but none have been satisfactory in explaining the comorbidity. The reward circuitry has become a recent area of interest within schizophrenia research as anhedonia (inability to experience pleasure and/or reward) is considered a negative symptom of schizophrenia and antipsychotics have been shown to change how rewarding a stimulus is; however, there are only a limited number of studies on reward sensitivity in patients with schizophrenia and results so far have been mixed. This study purports to identify a novel hypothesis for the increase in nicotine use in schizophrenics that involves the reward system, i.e. a sensitivity to the reward- enhancement effects of nicotine. The reward-enhancement effect of nicotine is defined as enhancement by nicotine of non-nicotine stimuli and has proven to be a robust factor in the maintenance of nicotine use, producing an effect that may even be stronger than the general rewarding effect of nicotine. Sensitivity to the reward-enhancement effect of nicotine could provide an explanation for the high rate of smoking seen in patients with schizophrenia and lead to novel methods of treatment of this comorbidity. Using preclinical methods, this set of aims will provide three separate paradigms in which to test this idea: 50 kHz reward vocalizations, operant responding for a naturally rewarding stimulus (e.g. lights), and nicotine self- administration. Animals will be pretreated with either saline or phencyclidine (PCP), an NMDA receptor antagonist that has been validated as an animal model of schizophrenia and that produces many of the positive, negative, and cognitive symptoms that are shown in patients with the disorder. In the first two aims, vocalizations to a visual stimulus and lever-pressing for a visual stimulus will be measured after exposure to nicotine. In the third aim, lever-pressing for an injection of nicotine will be examined between groups that either receive nicotine alone or nicotine with a concurrent visual stimulus. This set of experiments will provide data not only on the potential sensitivity to the reward-enhancement effect of nicotine but also allow for analyses on the general rewarding effect of nicotine in a preclinical animal model of schizophrenia.