NITRIC OXIDE MEDIATION OF HIPPOCAMPAL NICOTINE EFFECTS

一氧化氮介导海马尼古丁效应

• 批准号: 2756694
• 负责人: CATHERINE E ADAMS
• 金额: $ 7.4万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-15 至 2000-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2756694
• 关键词: auditory discrimination; bungarotoxins; enzyme inhibitors; evoked potentials; experimental brain lesion; hippocampus; laboratory rat; neural information processing; neuropharmacology; nicotine; nicotinic receptors; nitric oxide; nitric oxide synthase; stimulant /agonist

DESCRIPTION (Adapted From The Applicant's Abstract): Central processing of sensory information requires discrimination between relevant and irrelevant stimuli, that is, facilitation of response to some stimuli and inhibition of others. Nicotine appears to enhance this discrimination process in rat hippocampus by inhibiting the response of hippocampal cell populations to repetitive stimulation. The inhibitory influence of nicotine in rat hippocampus is mediated via the alpha7 subtype of nicotinic receptor. A critical question is why a single dose of nicotine can improve sensory discrimination for up to 30 minutes when nicotinic receptors desensitize much more rapidly. A possible explanation is that activation of nicotinic receptors leads to the release of a neurotransmitter or neuromodulator that itself has a protracted effect, either directly or via second messenger systems or regulation of transcription and/or translation processes. The alpha7 receptor is associated primarily with subpopulations of inhibitory neurons in rat hippocampus, including neurons immunoreactive for nitric oxide synthase (NOS), the synthetic enzyme for the production of the gaseous neurotransmitter nitric oxide (NO). This observation led to the hypothesis that alpha7-stimulated release of NO mediates the effects of nicotine in rat hippocampus. The hypothesis will be tested in Experiment 1 by examining the effect of intracerebroventricular (icv) infusions of the NOS inhibitor N-nitro- L-arginine methyl ester (L-NAME) on hippocampal auditory evoked potentials in anesthetized rats. Experiment 2 will examine the ability of icv infusions of L-NAME to prevent the restoration of hippocampal auditory-mediated inhibitory gating by the selective alpha7 receptor agonist GTS-21 in anesthetized fimbria/fornix-lesioned rats. Experiment 3 will examine the ability of icv infusions of a saturated NO solution to overcome the disruption of auditory-associated inhibitory gating induced by icv infusions of the alpha7-selective antagonist alpha- bungarotoxin in anesthetized rats. Knowledge gained from the proposed experiments may help elucidate the mechanisms by which nicotine exerts its persistent effects in the central nervous system.

描述（改编自申请人的摘要）： 感觉信息的中央处理需要辨别力 相关刺激和不相关刺激之间的关系，即促进 对某些刺激的反应和对另一些刺激的抑制。尼古丁似乎 通过抑制 海马细胞群对重复刺激的反应。这 尼古丁对大鼠海马的抑制作用是通过 烟碱受体的α7亚型。一个关键问题是为什么 单剂量尼古丁可改善感官辨别力达 30 烟碱受体更快地脱敏的几分钟。一个 可能的解释是烟碱受体的激活导致 神经递质或神经调节剂的释放，其本身具有 直接或通过第二信使系统或 转录和/或翻译过程的调节。阿尔法7 受体主要与抑制亚群有关 大鼠海马神经元，包括对硝酸免疫反应的神经元 氧化合酶（NOS），用于生产 气态神经递质一氧化氮（NO）。这一观察结果导致 假设 α7 刺激的 NO 释放介导 大鼠海马体中的尼古丁。 该假设将在实验 1 中通过检查效果来检验 NOS 抑制剂 N-硝基的脑室内 (icv) 输注 L-精氨酸甲酯（L-NAME）对海马听觉诱发的影响 麻醉大鼠的电位。实验2考察能力 静脉注射 L-NAME 以防止海马体恢复 选择性α7受体听觉介导的抑制性门控 麻醉的海马伞/穹窿损伤大鼠中的激动剂 GTS-21。实验 3将检查ICV输注饱和NO溶液的能力 克服听觉相关抑制门控的干扰 由α7-选择性拮抗剂α-的ICV输注诱导 麻醉大鼠体内的银环蛇毒素。从建议中获得的知识 实验可能有助于阐明尼古丁发挥作用的机制 它对中枢神经系统的持续影响。