Nicotinic regulation of cortical ACh release and behavioral function

描述（由申请方提供）：给予尼古丁和烟碱乙酰胆碱受体（nAChR）亚型选择性激动剂可改善ADHD、精神分裂症、老年痴呆和其他疾病患者的行为和认知症状。然而，nAChR激动剂的认知作用的神经药理学机制仍然没有解决。皮质nAChR主要位于突触前末梢上，并刺激几种神经递质的释放，包括乙酰胆碱（ACh）。本研究的指导下的一般假设，nAChR激动剂的有益的注意力的影响是通过刺激前额叶皮层（PFC）的乙酰胆碱（ACh）的释放介导的。初步研究利用酶选择性微电极监测乙酰胆碱和谷氨酸释放在一个高的时间分辨率。给予nAChR激动剂产生ACh和谷氨酸释放的短暂增加。α-4/β-2选择性nAChR激动剂产生比尼古丁更有效和“更尖锐”的胆碱能信号;假设这些信号特征是这些化合物的强大促认知特性的基础。胆碱能信号的幅度依赖于离子型谷氨酸受体的活性。与此相反，尼古丁诱发的胆碱能信号的较慢的时间动力学似乎没有介导通过amatergic机制。初步证据还表明，在执行任务的动物，线索，触发注意力的过程引起短暂增加胆碱能活动的PFC和尼古丁管理的幅度增加，减缓衰减的线索诱发的胆碱能信号。本研究将测试有关nAChR激动剂对PFC中胆碱能活性的影响的神经药理学机制、nAChR激动剂诱导的对表演动物中注意线索诱发的胆碱能活性的调节以及nAChR激动剂的有益认知效应最佳显示的认知条件的假设。 烟碱受体的调节和表达的改变以及胆碱能神经传递的异常调节已被认为有助于几种神经精神和神经退行性疾病的认知症状，包括精神分裂症、自闭症和痴呆。这项研究有望证明，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PFC中的注意表现诱发的胆碱能活动来介导的。烟碱受体配体的认知作用，从而有助于确定和预测这组化合物的临床潜力。

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.