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

关于大鼠精神分裂症和尼古丁滥用共病的新假设。

• 批准号: 8548099
• 负责人: Natashia Swalve
• 金额: $ 3.31万
• 依托单位: UNIVERSITY OF NEBRASKA LINCOLN
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8548099
• 关键词: Accounting; Acute; Adverse effects; Affect; Alcohols; Anhedonia; Animal Model; Animals; Antipsychotic Agents; Area; Behavioral; Behavioral Assay; Behavioral Mechanisms; Brain; Cessation of life; Chronic; Comorbidity; Data; Disease; Dose; Exhibits; Exposure to; General Population; Goals; Health; Injection of therapeutic agent; Lead; Life Expectancy; Ligands; Light; Literature; Maintenance; Measures; Methods; Modeling; NMDA receptor antagonist; Neurobehavioral Manifestations; Nicotine; Nicotine Dependence; Patients; Phencyclidine; Population; Property; Rattus; Regimen; Research; Rewards; Saline; Schizophrenia; Self Administration; Self-Administered; Series; Smoke; Smoker; Smoking; Stimulus; Symptoms; System; Testing; Therapeutic Intervention; Tobacco use; Ultrasonics; United States; Withdrawal; Work; experience; global health; innovation; interest; neurobiological mechanism; nicotine abuse; novel; novel therapeutics; pleasure; pre-clinical; research study; response; reward circuitry; sex; visual stimulus; vocalization

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.

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远高于一般人群（88-90%的精神分裂症患者对22%的一般人群）。造成这种差异的原因尚不清楚，人们提出了许多假设，但没有一个能令人满意地解释这种合并症。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，因为快感缺乏（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方式；然而，关于精神分裂症患者奖励敏感性的研究数量有限，到目前为止，结果好坏参半。本研究旨在为精神分裂症患者尼古丁使用的增加提供一个新的假设，该假设涉及奖励系统，即对尼古丁的奖励增强效应的敏感性。尼古丁的奖励增强效应被定义为尼古丁对非尼古丁刺激的增强作用，并且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励效应更强。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，并为治疗这种合并症提供了新的方法。使用临床前方法，这组目标将提供三个独立的范例来测试这一想法：50 kHz的奖励发声，对自然奖励刺激（如灯光）的操作性反应，以及尼古丁的自我给药。动物将用生理盐水或苯环利定（PCP）进行预处理，苯环利定是一种NMDA受体拮抗剂，已被证实是精神分裂症的动物模型，并产生许多阳性、阴性和认知症状，这些症状在精神分裂症患者中表现出来。在前两个目标中，暴露于尼古丁后，对视觉刺激的发声和对视觉刺激的杠杆按压将被测量。在第三个目标中，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检查按压杠杆注射尼古丁的情况。这组实验不仅将提供对尼古丁奖励增强效应的潜在敏感性的数据，还将允许对精神分裂症临床前动物模型中尼古丁的一般奖励效应进行分析。