Nicotinic regulation of cortical ACh release and behavioral function

描述（由申请人提供）：尼古丁和尼古丁乙酰胆碱受体（nAChR）亚型选择性激动剂可改善ADHD、精神分裂症、老年性痴呆等疾病患者的行为和认知症状。然而，nAChR激动剂认知作用的神经药理学机制仍未确定。皮质nachr主要位于突触前末端，刺激几种神经递质的释放，包括乙酰胆碱（ACh）。本研究是在一般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皮质（PFC）中乙酰胆碱（ACh）的释放来介导的。初步研究利用酶选择性微电极在高时间分辨率下监测乙酰胆碱和谷氨酸释放。服用nAChR激动剂可使乙酰胆碱和谷氨酸释放短暂增加。α -4/ β -2选择性nAChR激动剂比尼古丁产生更有效和“更清晰”的胆碱能信号；这些信号特征被假设为这些化合物强大的促进认知特性的基础。胆碱能信号的振幅取决于嗜离子性谷氨酸受体的活性。相反，尼古丁诱发的胆碱能信号较慢的时间动态似乎不是通过谷氨酸能机制介导的。初步证据还表明，在执行任务的动物中，触发注意力过程的线索会引起PFC中胆碱能活动的短暂增加，而尼古丁增加了线索引起的胆碱能信号的幅度并减缓了其衰减。本研究将验证nAChR激动剂对PFC中胆碱能活性影响的神经药理学机制、nAChR激动剂诱导的表演动物注意提示引起的胆碱能活性的调节，以及nAChR激动剂在认知条件下的有益认知作用的最佳揭示。叙述/相关性

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.