The Effect of Glutamatergic Modulation on Cocaine Self-Administration

描述(由申请人提供)：谷氨酸能系统的中断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，它是一个有希望的候选药物，它是一种具有强大的前额叶效应的谷氨酸能调节剂。除了安全地给药，没有出现精神病或氯胺酮滥用，我们发现，与主动对照组(n=8)相比，亚麻醉剂氯胺酮导致停止使用可卡因的动机措施发生显著变化。此外，氯胺酮对线索诱导的渴望有很好的效果。该项目旨在研究这些有希望的影响是否延伸到可卡因自我管理。我们将评估一次亚麻醉剂量的氯胺酮(在2分钟内为0.11 mg/kg，随后在50分钟内为0.60 mg/kg)对20名没有寻求抑郁的可卡因依赖者的可卡因自我给药的影响，这些人完成了一项为期9周的实验室-住院和门诊双盲、交叉、随机、对照研究。参与者将在每次主动注射后24小时内获得五种可卡因选择。我们预测，与咪达唑仑相比，氯胺酮将显著减少选择过程中的可卡因选择数量。次要目标与氯胺酮对可卡因相关缺陷的影响有关，这些缺陷涉及前额叶功能障碍，如应激敏感、渴望、冲动、动力不足、自我效能低下和注意力不集中。因此，我们 旨在评估一种高度创新的干预措施，使其有能力为该领域作出重要和前所未有的贡献。氯胺酮对可卡因自身给药的影响表明，短暂有效的谷氨酸能调制是可卡因依赖的一种可能的治疗策略，值得进一步研究。

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.