Nicotinic regulation of cortical ACh release and behavioral function

烟碱对皮质乙酰胆碱释放和行为功能的调节

• 批准号: 7365409
• 负责人: MARTIN F SARTER
• 金额: $ 29.39万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-27 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7365409
• 关键词: AMPA Receptors; Acetylcholine; Affect; Agonist; Amphetamines; Animals; Area; Attention; Attention deficit hyperactivity disorder; Attenuated; Autistic Disorder; Behavior; Behavioral; Bilateral; Characteristics; Cholinergic Agents; Clinical; Cognitive; Condition; Cues; Deafferentation procedure; Dementia; Detection; Dihydro-beta-Erythroidine; Disease; Dopamine; Dopamine Receptor; Enzymes; Excision; Glutamate Receptor; Glutamates; Impaired cognition; Infusion procedures; Ligands; Mecamylamine; Medial; Mediating; Mediation; Microelectrodes; Monitor; Motor Cortex; Neurobehavioral Manifestations; Neurodegenerative Disorders; Neurons; Neurotransmitters; Nicotine; Nicotinic Receptors; Norepinephrine; Patients; Performance; Prefrontal Cortex; Presynaptic Terminals; Procedures; Process; Property; Prosencephalon; Rate; Regulation; Research; Resolution; Retrieval; Rewards; SK& F 83566; Schizophrenia; Senile dementia; Serotonin; Signal Transduction; Specificity; Taxes; Testing; acetylcholine receptor agonist; attentional modulation; cholinergic; eticlopride; methyllycaconitine; neuropsychiatry; neurotransmission; neurotransmitter release; response; therapy development

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.

描述（由申请人提供）：尼古丁和烟碱乙酰胆碱受体（NACHR）亚型选择性激动剂的给药使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受益。然而，NACHR激动剂的认知作用背后的神经药理机制仍然没有解决。皮质NACHR主要位于突触前末端，并刺激包括乙酰胆碱（ACH）在内的几个神经递质的释放。这项研究的指导下是由一般假设指导，即NACHR激动剂的有益注意作用是通过在额叶皮层（PFC）中刺激乙酰胆碱（ACH）释放来介导的。初步研究利用酶选择性微电极以高时间分辨率监测ACH和谷氨酸释放。 NACHR激动剂的给药会产生ACH和谷氨酸释放的短暂增加。 alpha-4/beta-2选择性nACHR激动剂比尼古丁产生的胆碱能信号更有效，“更清晰”。假设这些信号特性是这些化合物的鲁棒性促值特性的基础。胆碱能信号的幅度取决于离子谷氨酸受体活性。相比之下，尼古丁诱发的胆碱能信号的时间动力学较慢，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，引发注意力过程的提示引起了PFC中胆碱能活性的瞬时增加，并且尼古丁给药增加了振幅并减慢了提示诱发的胆碱能信号的衰减。这项研究将检验有关介导NACHR激动剂对PFC中胆碱能活性的影响的神经药理学机制的假设，NACHR激动剂诱导了注意力提示诱发的胆碱能活性的调节，在表现动物中及其在nachr agonists anchr Agonists的效果下的认知条件下， 烟碱受体调节和表​​达的改变以及胆碱能神经传递的异常调节已建议有助于几种神经精神疾病和神经退行性疾病的认知症状，包括精神分裂症，自闭症，自闭症和痴呆症。拟议的研究预计将证明尼古丁和烟碱受体亚型 - 选择性激动剂的有益认知作用主要是通过调节PFC中注意力表现引起的胆碱能活性来介导的。这项研究将揭示关键的神经元和认知机制，这是烟碱受体配体的积极认知作用的基础，从而有助于定义和预测这组化合物的临床潜力。