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基础的实验。苯二氮卓类药物是通过GABAA受体起作用的镇静/催眠药，通常用于治疗焦虑（如阿普唑仑），有滥用酒精、阿片类药物或镇静剂历史的人滥用它们。新的类苯二氮卓类化合物也以一种更有选择性的方式调节GABAA受体，它们通常被用于治疗失眠（如唑吡坦），与选择性较低的苯二氮卓类药物相比，它们被认为具有更低的滥用潜力。然而，尽管与传统的苯二氮卓类药物相比，它们与GABAA受体的相互作用不同，对行为的影响也不同，但它们确实有可能被滥用。特别是唑吡坦在高剂量时被滥用。这些实验将检验这样一个假设，即治疗剂量的阿普唑仑和唑吡坦的不同主观（抗焦虑、强化和/或镇静）作用与不同的神经化学特征有关，而高剂量的唑吡坦失去了选择性，在主观作用（即，它变得更抗焦虑和/或强化）和神经化学方面与阿普唑仑相似。这些实验将采用4特斯拉的质子磁共振波谱（1H MRS）结合主观问卷调查，以调查有药物经验的志愿者急性口服阿普唑仑或唑吡坦后脑代谢物浓度的变化。比较阿普唑仑或唑吡坦对GABA、谷氨酸、谷氨酰胺等大脑水平的影响，如果它们确实支持与镇静/催眠药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的假设，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，而接近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，但伴随着副作用，限制了其临床应用，如滥用的可能性。本应用程序中提出的实验旨在了解这类药物强化效应的神经化学基础，以便有助于将镇静/催眠药物的临床有用效果与其滥用潜力区分开来的研究。

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.