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

描述（由申请人提供）：烟草使用是美国的一个主要健康问题，精神分裂症患者的吸烟率比一般人群高得多（88-90%的精神分裂症患者对22%的一般人群）。这种差异的原因仍然是未知的，许多假设已经推出，但没有一个是令人满意的解释共患病。奖励回路已成为精神分裂症研究中最近的一个感兴趣的领域，因为快感缺失（无法体验快乐和/或奖励）被认为是精神分裂症的一种阴性症状，抗精神病药物已被证明可以改变刺激的奖励程度;然而，只有有限数量的精神分裂症患者的奖励敏感性研究，迄今为止的结果好坏参半。本研究旨在确定一种新的假设，即精神分裂症患者尼古丁使用增加涉及奖励系统，即对尼古丁的奖励增强效应的敏感性。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作用，已被证明是维持尼古丁使用的一个稳健因素，产生的效应甚至可能比尼古丁的一般奖赏效应更强。对尼古丁奖赏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，并导致治疗这种合并症的新方法。使用临床前方法，这组目标将提供三个单独的范例来测试这一想法：50 kHz奖励发声，对自然奖励刺激（例如灯光）的操作性反应，以及尼古丁自我给药。动物将用生理盐水或苯环己哌啶（PCP）进行预处理，苯环己哌啶是一种NMDA受体拮抗剂，已被验证为精神分裂症的动物模型，并产生许多在该疾病患者中显示的阳性、阴性和认知症状。在前两个目标中，将在暴露于尼古丁后测量对视觉刺激的发声和对视觉刺激的按压。在第三个目标中，将在单独接受尼古丁或尼古丁与同时的视觉刺激的组之间检查用于注射尼古丁的按压。这组实验不仅将提供关于尼古丁奖赏增强效应的潜在敏感性的数据，而且还允许分析尼古丁在精神分裂症临床前动物模型中的一般奖赏效应。

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.