Neurobiology of Ketamine Addiction

氯胺酮成瘾的神经生物学

• 批准号: 10229544
• 负责人: MOHAMED KABBAJ
• 金额: $ 37.15万
• 依托单位: FLORIDA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10229544
• 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; addiction; alcohol exposure; 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

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.

项目总结 单次注射小剂量氯胺酮可迅速消除自杀意念。 由于急性氯胺酮效应是短暂的，最近的临床研究正在测试 亚慢性氯胺酮治疗可以防止抑郁症复发。这些研究的结果 研究是有希望的，因为他们清楚地表明重复注射氯胺酮取得了更好的效果。 与急性治疗相比，结果。因此很明显，氯胺酮的生存能力 作为一种抗抑郁治疗，需要反复输注小剂量的 慢性养生法。当人们承认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，抑郁症与抑郁症的共病 其他滥用药物，特别是酒精，进一步增加了氯胺酮的生存能力 作为一种治疗抑郁症的方法。最后，氯胺酮对两性的影响仍然是 未得到充分研究。用于治疗难治性抑郁症的氯胺酮剂量 [TRD]人类对两性都有作用，到目前为止，还没有努力研究 小剂量氯胺酮对女性的抗抑郁作用。尽管有一些证据表明 人类表明，当使用氯胺酮时，会导致女性严重的认知障碍 与雄性相比，在啮齿动物中有一些证据表明雌性啮齿动物对 氯胺酮的镇痛和抗抑郁作用。在啮齿动物中，氯胺酮也会导致 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阿司匹林重复治疗的安全性 氯胺酮，无论男女，在批准氯胺酮作为一种安全的治疗TRD之前。通过这件事 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-在男女中，重复使用小剂量的氯胺酮会导致 令人上瘾的行为？2-女性荷尔蒙状况对氯胺酮的反应是否起作用 成瘾特性？；3-酒精滥用是否增强了氯胺酮的成瘾特性 性别？4-在大脑中反复出现的生理适应是什么 氯胺酮治疗？我们坚信，对这些问题的回答将使临床医生 关于慢性氯胺酮治疗TRD的安全性。