Neurobiology of Ketamine Addiction

项目摘要 单次注射小剂量氯胺酮诱导自杀意念迅速消退。 由于氯胺酮的急性效应是短暂的，最近的临床研究正在测试， 氯胺酮的亚慢性治疗可以防止抑郁症复发。的结果予以 研究是有希望的，因为它们清楚地表明重复氯胺酮输注实现了上级 与急性治疗相比。因此，很明显，氯胺酮的可行性 因为抗抑郁治疗需要在一定的剂量下反复输注小剂量， 慢性疗法这种治疗的安全性仍然不是很清楚， 氯胺酮被认为是一种滥用药物此外，抑郁症与 滥用其他药物，特别是酒精，会使氯胺酮的有效性进一步复杂化 作为治疗抑郁症的药物最后，氯胺酮对两性的影响仍然是 替补演员用于治疗难治性抑郁症的氯胺酮剂量 [TRD]在人类工作的两性，到目前为止，还没有努力研究 低剂量氯胺酮对女性的抗抑郁作用。尽管有证据表明， 人类显示氯胺酮的使用会导致女性严重的认知障碍， 与男性相比，啮齿动物中的一些证据显示，雌性啮齿动物对 氯胺酮的镇痛和抗抑郁作用在啮齿类动物中，氯胺酮也会导致 与雄性动物相比，雌性动物的神经毒性更大。因此，至关重要的是， 临床和临床前研究检查了用低剂量的 在批准氯胺酮作为TRD的安全治疗方法之前，氯胺酮适用于男性和女性。通过这个 我们将回答关于长期治疗安全性的非常具体的问题， 氯胺酮：1-在两种性别中，低剂量氯胺酮重复给药是否诱导 成瘾行为2-女性荷尔蒙状态是否在对氯胺酮的反应中起作用 使人上瘾的特性？3-酒精滥用是否会增强氯胺酮的成瘾性， 男女都行4-大脑在重复的大脑活动中会发生什么样的生理适应 氯胺酮治疗我们真的相信，对这些问题的回答将告知临床医生 长期氯胺酮治疗TRD的安全性

PROJECT SUMMARY A single injection of small dose of ketamine induced a rapid resolution of suicidal ideation. Since acute ketamine effects are short lived, recent clinical studies are testing whether subchronic treatments with ketamine can prevent relapse to depression. The results of these studies are promising as they clearly show that repeated ketamine infusions achieved superior outcome when compared to acute treatment. It is clear therefore that the viability of ketamine as an antidepressant treatment will necessitate repeated infusions of small doses under a chronic regimen. The safety of such treatments is still not very clear when one acknowledges that ketamine is considered a drug of abuse. Furthermore, the comorbidity of depression with other drugs of abuse, especially alcohol adds further complications to the viability of ketamine as a treatment for depression. Finally, the effects of ketamine in both sexes are still understudied. The ketamine doses that are used to treat Treatment Resistant Depression [TRD] in humans work for both sexes and, so far, there were no efforts made to examine the antidepressant effects of lower doses of ketamine in women. This is despite some evidence in humans showing that ketamine use leads to severe cognitive impairments in women when compared to men and some evidence in rodents, showing higher sensitivity of female rodents to the analgesic and the antidepressant effects of ketamine. In rodents, ketamine also leads to greater neurotoxicity in females when compared to males. Accordingly, it is critical that further clinical and preclinical studies examine the safety of repeated treatments with low doses of ketamine, in both sexes, before approving ketamine as a safe treatment for TRD. Through this application we shall answer very specific questions about the safety of long term treatment with ketamine: 1- In both sexes, do repeated treatments with low doses of ketamine induce addictive-like behaviors? 2- Does female hormonal status play a role in response to ketamine's addictive properties?; 3- Does alcohol abuse enhance the addictive properties of ketamine in either sex? 4- What are the physiological adaptations that occur in the brain with repeated ketamine treatments? We truly believe that the response to these questions will inform clinicians about the safety or not of chronic ketamine treatment for TRD.