Compensatory Mechanism of Nicotine in Psychiatric Disord

患有神经精神障碍的人，特别是精神分裂症和抑郁症的人，往往是重度吸烟者。有研究表明，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，谷氨酸是大脑中主要的兴奋性神经递质，与唤醒和注意力行为有关。它还有助于从激活大脑奖励系统的区域释放多巴胺。尼古丁还被证明可以通过增加抗精神病药物的新陈代谢和清除来减少镇静作用，有时还会减少抗精神病药物的不良影响。在一些患者中，吸烟还会降低由抗精神病药物引起的帕金森氏症样僵硬。这个 从这些研究得出的结论是，患者自我用尼古丁来改善他们的健康状况 集中精神，减少厌烦和焦虑，改善精神分裂症的阴性症状。最近，精神分裂症患者大脑中nAChR水平和表达的一些神经病理变化被描述，这增加了人们对尼古丁受体与精神病之间相互作用的研究兴趣。本研究的目的是确定参与尼古丁诱导的多巴胺释放的烟碱型异乙酰胆碱受体(S)的身份和位置，并研究调节这种烟碱效应的分子机制。我们的假设是，尼古丁通过调节选定大脑区域的多巴胺释放，在其中一些效应中发挥直接作用，这种释放是通过 烟碱型乙酰胆碱受体(NAChR)亚型(S)位于多巴胺能神经元突触前。因此，我们的具体目标是1)确定nAChRs和多巴胺转运体在中脑边缘、黑质纹状体和中皮质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短期和长期存在的反应的机制。所有这些研究都将在对照(假)动物和精神分裂症的动物模型中进行，即精神分裂症的新生腹侧海马区病变(NVHL)模型。

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.