Neurochemical Substrates of Sedative/Hypnotic Action:Proton MRS Studies

描述（由申请人提供）：本提案描述了旨在了解镇静/催眠作用的神经化学底物的实验。苯二氮卓类是通过GABAA受体起作用的镇静剂/催眠药，通常用于治疗焦虑（即阿普唑仑），并且被有滥用酒精、阿片类药物或镇静剂史的个体滥用。较新的苯二氮卓类化合物也以更具选择性的方式调节GABAA受体，通常用于治疗失眠（即唑吡坦），并且认为与选择性较低的苯二氮卓类化合物相比，其滥用可能性降低。然而，尽管它们与GABAA受体的相互作用不同，与传统的苯二氮卓类药物相比，它们的行为效应也不同，但它们确实有共同的滥用潜力。唑吡坦尤其被滥用于高剂量。这些实验将检验以下假设：阿普唑仑和唑吡坦治疗剂量的不同主观（抗焦虑、增强和/或镇静）作用与不同的神经化学特征相关，而唑吡坦的较高剂量失去其选择性，并且在主观作用方面类似阿普唑仑（即，它变得更加抗焦虑和/或增强）和神经化学。这些实验将采用4 T质子磁共振波谱（1H MRS）结合主观问卷调查，以研究药物经验志愿者急性口服阿普唑仑或唑吡坦引起的脑代谢物浓度变化。比较阿普唑仑或唑吡坦对GABA、谷氨酸、谷氨酰胺等脑水平的影响，如果它们确实支持与镇静/催眠药的强化作用相关的神经化学机制是影响滥用倾向的共同最终途径这一假设，则可能对仅关注受体选择性的药物开发策略产生严重影响。公共卫生相关性：大约10%的人口患有某种类型的焦虑症，而近30%的人口报告睡眠困难。目前的镇静/催眠治疗是有效的短期解决方案，但伴随着限制其临床用途的副作用，例如滥用潜力。本申请中提出的实验旨在了解这类药物强化作用的神经化学基础，以有助于将镇静/催眠药的临床有用作用与其滥用潜力分开的研究。

DESCRIPTION (provided by applicant): This proposal describes experiments aimed at understanding the neurochemical substrates of sedative/hypnotic action. Benzodiazepines are sedative/hypnotics that work through the GABAA receptor, they are often prescribed to treat anxiety (i.e. alprazolam), and they are abused by individuals with a history of abusing alcohol, opiates, or sedatives. Newer benzodiazepine-like compounds also modulate the GABAA receptor in a more selective manner, they are typically prescribed to treat insomnia (i.e. zolpidem), and they are believed to have reduced abuse potential compared to their less selective benzodiazepine counterparts. However, despite their differential interactions with the GABAA receptor and their different behavioral effects compared to conventional benzodiazepines, they do share in common the potential to be abused. Zolpidem in particular is abused at high doses. These experiments will test the hypothesis that the different subjective (anxiolytic, reinforcing, and/or sedative) effects of therapeutic doses of alprazolam and zolpidem are associated with distinct neurochemical profiles, while a higher dose of zolpidem loses its selectivity and resembles alprazolam with respect to subjective effects (i.e., it becomes more anxiolytic and/or reinforcing) and neurochemistry. These experiments will employ proton magnetic resonance spectroscopy (1H MRS) at 4 Tesla in conjunction with subjective questionnaires in order to investigate the changes in brain metabolite concentrations resulting from acute oral administration of alprazolam or zolpidem in drug-experienced volunteers. Comparing the effect of alprazolam or zolpidem on brain levels of GABA, glutamate, glutamine, etc., could have serious implications for drug development strategies focusing solely on receptor selectivity if they do indeed support the hypothesis that the neurochemical mechanisms associated with the reinforcing effects of sedative/hypnotics are the common final pathway to influence abuse liability. PUBLIC HEALTH RELEVANCE: Approximately 10% of the population suffers from some type of anxiety disorder, while close to 30% of the population reports difficulty sleeping. Current sedative/hypnotic treatments are effective short- term solutions, but are accompanied by side effects that limit their clinical utility, such as abuse potential. The experiments proposed in this application are aimed at understanding the neurochemistry that underlies the reinforcing effects of this class of drugs in order to contribute to the research focused on separating the clinically useful effects of sedative/hypnotics from their abuse potential.