The Effect of Glutamatergic Modulation on Cocaine Self-Administration

描述（由申请人提供）：谷氨酸系统的破坏代表了可卡因依赖药物开发的创新目标。我们对氯胺酮的初步研究表明，氯胺酮是一种具有强效前额叶效应的谷氨酸能调节剂。除了安全使用外，没有精神病或氯胺酮滥用的发展，我们发现，与主动对照相比，亚麻醉氯胺酮导致停止可卡因使用动机的显著变化（n=8）。此外，氯胺酮对线索诱导的渴望有很好的效果。这个项目的目的是研究这些有希望的效果是否延伸到可卡因的自我给药。我们将评估单次亚麻醉剂量氯胺酮（0.11 mg/kg / 2分钟，随后0.60 mg/kg / 50分钟）对20名寻求非抑郁可卡因依赖个体可卡因自我给药的影响，这些个体完成了一项为期9周的实验室-住院和门诊联合双盲、交叉、随机对照研究。参与者将在每次主动输注后24小时提供五种可卡因选择。我们预测，与咪达唑仑相比，氯胺酮在选择过程中会显著减少可卡因的选择次数。次要目的是关于氯胺酮对可卡因相关缺陷的影响，这些缺陷涉及前额叶功能障碍，如压力敏感性、渴望、冲动、低动机、低自我效能和低专注力。因此,我们

DESCRIPTION (provided by applicant): Disruptions in the glutamatergic system represent an innovative target of medications development for cocaine dependence. Our preliminary investigations with ketamine, a glutamatergic modulator with potent prefrontal effects, suggest that it represents a promising Candidate. Alongside being safely administered, with no development of psychosis or ketamine misuse, we found that sub-anesthetic ketamine led to significant changes in measures of motivation to stop cocaine use, when compared to an active control (n=8). Further, ketamine had promising effects on cue-induced craving. This project aims to examine whether these promising effects extend to cocaine self- administration. We will evaluate the effect of a single sub-anesthetic dose of ketamine (0.11 mg/kg over 2 minutes, followed by 0.60 mg/kg over 50 minutes) on cocaine self- administration in 20 non-treatment seeking non-depressed cocaine-dependent individuals who complete a 9-week combined laboratory-inpatient and outpatient double- blind, cross-over, randomized, controlled study. Participants will be provided a choice session of five cocaine choices 24 hours following each active infusion. We predict that, compared to midazolam, ketamine will significantly reduce the number of cocaine choices during the choice session. Secondary aims pertain to the effect of ketamine on cocaine-related deficits that implicate prefrontal dysfunction, such as stress sensitivity, craving, impulsivity, low motivation, low self-efficacy, and low mindfulness. Thus, we aim to evaluate a highly innovative intervention in a manner that has the capacity to make important and unprecedented contributions to the field. An effect of ketamine on cocaine self-administration would suggest that brief potent glutamatergic modulation represents a possible treatment strategy for cocaine dependence that merits further investigation.