Nicotinic regulation of cortical ACh release and behavioral function

描述(申请人提供)：尼古丁和烟碱型乙酰胆碱受体(NAChR)亚型选择性激动剂的应用有利于ADHD、精神分裂症、老年痴呆症和其他疾病患者的行为和认知症状。然而，nAChR激动剂认知效应背后的神经药理学机制仍未确定。皮质nAChRs主要位于突触前终末，刺激包括乙酰胆碱(ACh)在内的几种神经递质的释放。这项研究是在一个普遍假设的指导下进行的，即nAChR激动剂的有益注意效应是通过刺激前额叶皮质(PFC)释放乙酰胆碱(ACh)来实现的。初步研究利用酶选择性微电极以高时间分辨率监测ACh和谷氨酸的释放。给予nAChR激动剂后，ACh和谷氨酸的释放一过性增加。α-4/β-2选择性nAChR激动剂产生的胆碱能信号比尼古丁更强、更“尖锐”；这些信号特征被认为是这些化合物强大的前认知特性的基础。胆碱能信号的幅度依赖于离子型谷氨酸受体的活性。相比之下，尼古丁诱发的胆碱能信号的较慢时间动力学似乎并不是通过谷氨酸能机制来调节的。初步证据还表明，在执行任务的动物中，触发注意过程的提示会引起PFC胆碱能活动的一过性增加，尼古丁的使用会增加提示诱发的胆碱能信号的幅度，并减缓其衰减。这项研究将检验关于nAChR激动剂对前额叶胆碱能活动的神经药理学机制、nAChR激动剂对表演动物注意线索诱发的胆碱能活动的调节以及最佳揭示nAChR激动剂有益认知效应的认知条件的假说。 尼古丁受体调节和表达的改变以及胆碱能神经传递的异常调节被认为是导致一些神经精神和神经退行性疾病的认知症状的原因，包括精神分裂症、自闭症和痴呆症。这项拟议的研究有望证明尼古丁和尼古丁受体亚型选择性激动剂的有益认知效应主要是通过调节注意操作-PFC中的胆碱能活动来实现的。这项研究将揭示尼古丁受体配体促进认知的关键神经和认知机制，从而帮助定义和预测这类化合物的临床潜力。

DESCRIPTION (provided by applicant): Administration of nicotine and nicotinic acetylcholine receptor (nAChR) subtype-selective agonists benefit the behavioral and cognitive symptoms of patients with ADHD, schizophrenia, senile dementia and other disorders. However, the neuropharmacological mechanisms underlying the cognitive effects of nAChR agonists have remained unsettled. Cortical nAChRs are situated predominantly on presynaptic terminals and stimulate the release of several neurotransmitters, including acetylcholine (ACh). This research is guided by the general hypothesis that the beneficial attentional effects of nAChR agonists are mediated via stimulation of acetylcholine (ACh) release in the prefrontal cortex (PFC). Preliminary studies utilized enzyme-selective microelectrodes to monitor ACh and glutamate release at a high temporal resolution. Administration of nAChR agonists produced transient increases in ACh and glutamate release. Alpha-4/beta-2 selective nAChR agonists yielded more potent and "sharper" cholinergic signals than nicotine; these signal characteristics are hypothesized to underlie the robust pro-cognitive properties of these compounds. The amplitudes of cholinergic signals depended on ionotropic glutamate receptor activity. In contrast, the slower temporal dynamics of nicotine-evoked cholinergic signals did not seem to be mediated via glutamatergic mechanisms. Preliminary evidence also indicates that in task-performing animals, cues that trigger attentional processes evoke transient increases in cholinergic activity in the PFC and that nicotine administration augmented the amplitude and slowed the decay of cue-evoked cholinergic signals. This research will test hypotheses concerning the neuropharmacological mechanisms mediating the effects of nAChR agonists on cholinergic activity in the PFC, nAChR agonist-induced modulation of attentional cue-evoked cholinergic activity in performing animals, and the cognitive conditions under which beneficial cognitive effects of nAChR agonists are optimally revealed.Narrative/Relevance Alterations in the regulation and expression of nicotinic receptors and abnormal regulation of cholinergic neurotransmission have been suggested to contribute to the cognitive symptoms of several neuropsychiatric and neurodegenerative disorders, including schizophrenia, autism and dementia. The proposed research is expected to demonstrate that the beneficial cognitive effects of nicotine and nicotinic receptor subtype- selective agonists are mediated primarily by modulation of attentional performance-evoked cholinergic activity in the PFC. This research will reveal critical neuronal and cognitive mechanisms underlying the pro-cognitive effects of nicotinic receptor ligands and thereby assist in defining and predicting the clinical potential of this group of compounds.