Nicotinic Receptor Effects on Neurophysiology of Dorsolateral Prefrontal Cortex

描述（由申请人提供）：本研究旨在研究尼古丁受体对背外侧前额叶皮层（dlPFC）网络生理的影响，以开发治疗精神疾病和尼古丁成瘾的药物。如果能找到不涉及皮质下成瘾机制的增强PFC的药物，那么尼古丁激动剂作为认知增强剂具有很大的潜力。a4b2和a7烟碱受体亚型定位于PFC的突触前末端，a7受体也定位于脊髓的突触后末端。a7受体是特别有趣的，因为它们在一些精神分裂症家庭中基因改变，可能在VTA中没有强化作用。本研究将首次表征a4b2和a7烟碱受体对dlPFC网络生理的影响。dlPFC网络通过NMDA受体相互激发，在工作记忆任务的延迟期保持持续的放电。目的1将描述a4b2激动剂和拮抗剂对dlPFC神经元在控制和分散条件下执行空间工作记忆任务时的反应的影响，在记录过程中使用离子电泳应用药物。Aim 2将描述7种尼古丁激动剂和拮抗剂的作用，而Aim 3将研究尼古丁影响与NMDA受体作用的相互作用。初步数据表明，a7受体刺激可增强延迟细胞和固定细胞的任务相关放电，并可挽救因NMDA受体阻断而丧失的放电，从而促进了a7激动剂作为认知增强剂的发展。

DESCRIPTION (provided by applicant): The proposed research will examine nicotinic receptor influences on dorsolateral prefrontal cortex (dlPFC) network physiology, with the goal of developing therapeutic agents to treat mental illness and nicotine addiction. Nicotinic agonists have great potential as cognitive enhancers if agents can be found that strengthen PFC without engaging subcortical addictive mechanisms. a4b2 and a7 nicotinic receptor subtypes are localized on presynaptic terminals in PFC, and a7 receptors are also post-synaptic on spines. a7 receptors are of particular interest, as they're genetically altered in some families with schizophrenia, and may not have reinforcing actions in the VTA. The proposed research will characterize the influence of a4b2 and a7 nicotinic receptors on dlPFC network physiology for the very first time. dlPFC networks excite each other via NMDA receptors to maintain persistent firing over the delay period in a working memory task. Aim 1 will characterize the effects of a4b2 agonists and antagonists on the responses of dlPFC neurons during performance of a spatial working memory task under control and distracting conditions, using iontophoretic application of drug during recording. Aim 2 will characterize the effects of a7 nicotinic agonists and antagonists, while Aim 3 will examine the interaction of nicotinic influences with NMDA receptor actions. Preliminary data indicate that a7 receptor stimulation enhances the task-related firing of both Delay and Fixation cells, and can rescue loss of firing from NMDA receptor blockade, encouraging the development of a7 agonists as cognitive enhancers.