Compensatory Mechanism of Nicotine in Psychiatric Disord

尼古丁在精神疾病中的代偿机制

• 批准号: 7215546
• 负责人: MARTHA ISABEL DAVILA-GARCIA
• 金额: $ 9.14万
• 依托单位: HOWARD UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7215546
• 关键词: behavior test; behavioral /social science research tag; disease /disorder model; dopamine; dopamine transporter; electron microscopy; hippocampus; intermolecular interaction; laboratory rat; minority institution research support; neurobiology; neuropsychology; neuroregulation; neurotransmitter transport; nicotine; nicotinic receptors; pharmacokinetics; protein structure function; receptor expression; schizophrenia; substance abuse related behavior

People with neuropsychiatric disorders, particularly those with schizophrenia and depression, tend to be heavy smokers. It has been suggested that this behavior is directly related to the reinforcing properties of nicotine in the brain. For example, nicotine induces the release of the neurotransmitter glutamate, the brain's major excitatory neurotransmitter, from sites implicated in arousal and attentive behavior. It also facilitates dopamine release from areas that activate the brain reward system. Nicotine has also been shown to reduce the sedative and sometimes aversive effects of antipsychotic medications by increasing their metabolism and clearance. Smoking also reduces, in some patients, the parkinson's-like rigidity caused by neuroleptics. The conclusion drawn from these studies is that patients self-medicate with nicotine to improve their concentration, reduce boredom and anxiety, and ameliorate the negative symptoms of schizophrenia. Recently, a number of neurpathological changes in nAChR levels and expression have been described in brains from schizophrenics, adding to the interest in studying the interaction between nicotinic receptors and psychosis. It is the objective of this proposal to determine the identity and location of the nicotinic iacetylcholine receptor(s) involved in nicotine-induced dopamine release and to characterize the molecular mechanisms that regulate this nicotinic effect. Our hypothesis is that nicotine plays a direct role in some of these effects by regulating dopamine release in selected brain areas and that this release is accomplished by a specific nicotinic acetylcholine receptor (nAChR) subtype(s) located presynaptically on doparninergic neurons. Therefore, Our specific aims are 1) to determine the distribution and levels of expression of nAChRs and dopamine transporters in mesolimbic, nigrostriatal, and mesocortical target areas, 2) to determine the co-expression of nAChR subunits upon dopaminergic nerve terminals at the ultrastructural level, and 3) to determine the mechanism of nicotine-induced responses of the dopaminergic system to short- and long-term presence of nicotine. All of these studies will be performed in control (sham) animals and in an animal model of schizophrenia, the neonatal ventral hippocampal lesion (NVHL) model of schizophrenia.

患有神经精神疾病的人，特别是精神分裂症和抑郁症的人，往往是重度吸烟者。有人认为，这种行为与尼古丁在大脑中的强化特性直接相关。例如，尼古丁诱导神经递质谷氨酸的释放，这是大脑中主要的兴奋性神经递质，从与唤醒和注意力集中行为有关的部位释放。它还促进多巴胺从激活大脑奖励系统的区域释放。尼古丁也被证明可以通过增加抗精神病药物的代谢和清除来减少其镇静作用，有时甚至是厌恶作用。在某些病人中，吸烟还能减轻由神经抑制剂引起的帕金森氏症样僵硬。的 从这些研究中得出的结论是，患者自我戒烟与尼古丁，以改善他们的 注意力集中，减少无聊和焦虑，改善精神分裂症的阴性症状。最近，一些nAChR水平和表达的神经病理学变化已被描述在精神分裂症患者的大脑中，增加了研究烟碱受体和精神病之间的相互作用的兴趣。这是本提案的目的，以确定身份和位置的烟碱iacetylcholine受体（S）参与尼古丁诱导的多巴胺释放和表征的分子机制，调节这种烟碱效应。我们的假设是，尼古丁通过调节特定脑区的多巴胺释放，在其中一些效应中发挥直接作用，这种释放是通过 一种位于多巴胺能神经元突触前的特异性烟碱乙酰胆碱受体（nAChR）亚型。因此，我们的具体目标是：1）确定nAChR和多巴胺转运蛋白在中脑边缘、黑质纹状体和中皮层靶区的分布和表达水平; 2）在超微结构水平上确定nAChR亚单位在多巴胺能神经末梢上的共表达; 3）确定尼古丁诱导的多巴胺能系统对尼古丁的短期和长期存在的反应机制。所有这些研究将在对照（假手术）动物和精神分裂症动物模型（精神分裂症新生儿腹侧海马病变（NVHL）模型）中进行。