Neurobiology of Ketamine Addiction

氯胺酮成瘾的神经生物学

基本信息

批准号：
10471826
负责人：
MOHAMED KABBAJ
金额：
$ 37.1万
依托单位：
FLORIDA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10471826
关键词：
Acute Adult Alcohol abuse Alcohol consumption Alcohols Analgesics Antidepressive Agents Behavior Behavioral Bipolar Disorder Brain Cannabinoids Chronic Clinical Clinical Research Cocaine Dependence Data Diestrus Dose Drug Addiction Drug usage Estrogens Exposure to Feeling suicidal Female Gender Hormonal Housing Human Impaired cognition Infusion procedures Injections Intravenous Ketamine Label Literature Major Depressive Disorder Mediating Mental Depression Modeling Molecular Mus N-Methyl-D-Aspartate Receptors Neurobiology Neurons Nicotine Nucleus Accumbens Opioid Outcome Ovarian Pathology Pharmaceutical Preparations Phase Phencyclidine Physiological Adaptation Play Population Post-Traumatic Stress Disorders Proestrus Progesterone Property Psychological reinforcement Psychopathology Psychotropic Drugs Rattus Recording of previous events Regimen Relapse Reporting Resolution Rewards Rodent Role Safety Self Administration Sex Differences Social isolation Stress Synapses Testing Therapeutic Effect Transgenic Organisms Woman Work abuse liability addiction alcohol exposure antagonist antidepressant effect anxiety-like behavior behavioral plasticity behavioral sensitization comorbid depression comorbidity depressed patient drug of abuse gender difference male men neurotoxicity pre-clinical preclinical study prevent psychostimulant response sex social group treatment-resistant depression

项目摘要

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.

项目概要单次注射小剂量氯胺酮可导致自杀意念迅速消退。由于急性氯胺酮作用持续时间较短，最近的临床研究正在测试是否使用氯胺酮进行亚慢性治疗可以预防抑郁症复发。这些结果研究是有希望的，因为它们清楚地表明重复氯胺酮输注取得了优异的效果与急性治疗相比的结果。因此很明显，氯胺酮的生存能力作为抗抑郁治疗，需要在一定时间内重复输注小剂量长期养生法。当人们承认这种治疗的安全性仍然不是很清楚时氯胺酮被认为是一种滥用药物。此外，抑郁症与其他滥用药物，尤其是酒精，会进一步增加氯胺酮的并发症作为抑郁症的治疗方法。最后，氯胺酮对男女的影响仍然存在待研究。用于治疗难治性抑郁症的氯胺酮剂量 [TRD] 在人类中对两性都有效，到目前为止，还没有做出任何努力来检查低剂量氯胺酮对女性的抗抑郁作用。尽管有一些证据表明这一点人类研究表明，使用氯胺酮会导致女性严重认知障碍与男性相比，以及啮齿类动物的一些证据表明，雌性啮齿类动物对氯胺酮的镇痛和抗抑郁作用。在啮齿类动物中，氯胺酮还会导致与男性相比，女性的神经毒性更大。因此，至关重要的是，进一步临床和临床前研究检查了低剂量重复治疗的安全性在批准氯胺酮作为 TRD 的安全治疗方法之前，男性和女性都需要服用氯胺酮。通过这个应用程序，我们将回答有关长期治疗安全性的非常具体的问题氯胺酮：1- 无论男女，重复使用低剂量氯胺酮治疗都会诱发类似上瘾的行为？ 2- 女性荷尔蒙状态是否对氯胺酮的反应起作用令人上瘾的特性？ 3- 酗酒是否会增强氯胺酮的成瘾性要么是性别？ 4- 大脑中发生的生理适应是什么？氯胺酮治疗？我们坚信对这些问题的回答将为临床医生提供信息关于长期氯胺酮治疗 TRD 的安全性。