Novel Interventions in Alcohol Induced Depression

酒精引起的抑郁症的新干预措施

• 批准号: 8700043
• 负责人: YOUSEF TIZABI
• 金额: $ 7.54万
• 依托单位: HOWARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8700043
• 关键词: Acute; Affect; Alcohol consumption; Alcohol dependence; Alcohol withdrawal syndrome; Alcoholism; Alcohols; Anesthetics; Anhedonia; Animals; Antidepressive Agents; Behavior; Behavioral; Biogenic Amines; Brain region; Brain-Derived Neurotrophic Factor; CREB1 gene; Chronic; Clinical Research; Cyclic AMP-Responsive DNA-Binding Protein; Data; Development; Dose; Drug effect disorder; Effectiveness; Epidemiologic Studies; Exposure to; Foundations; Glutamates; Goals; Health; Heavy Drinking; Hippocampus (Brain); Human; Intervention; Ketamine; Knowledge; Lead; Major Depressive Disorder; Mediation; Mental Depression; Mission; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurotransmitters; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Propionic Acids; Public Health; Rattus; Relapse; Request for Proposals; Research; Resistance; Selective Serotonin Reuptake Inhibitor; Sucrose; Swimming; Testing; Treatment Protocols; Veterinarians; Wistar Rats; Withdrawal; Withholding Treatment; Work; addiction; base; depressive symptoms; drug efficacy; frontal lobe; improved; innovation; insight; mTOR protein; mood regulation; neurobiological mechanism; novel; postsynaptic; preference; prevent; problem drinker; public health relevance; receptor; success; synaptogenesis; tool

ABSTRACT Novel Interventions in Alcohol-Induced Depression There is a strong positive association between heavy drinking (i.e., alcoholism) and depression, and epidemiological studies suggest that this depression can negatively influence successful cessation of alcohol use. Therefore, there is a fundamental need to develop new antidepressants that effectively treat depression, and can be used in conjunction with alcohol and/or are quick acting. Ketamine, a glutamatergic NMDA receptor antagonist shows promise as quick acting antidepressant. Preliminary studies also indicate a possible similar effect with AMPA (2-amino-3-(5-methyl-3-oxo-1,2- oxazol-4-yl) propanoic acid). However, the efficacy of these drugs with alcohol-induced depression is unknown. Our central hypothesis is that ketamine and AMPA will both be effective in blocking and alleviating depression caused by long-term alcohol use through mediation of neurotrophic and synaptogenic pathways. Our rationale for these studies is that identification of the central mechanisms by which ketamine and AMPA act to induce behavioral changes will help establish a strong scientific framework for new cessation treatment protocols in human patients with alcoholism or other addiction-depression co-morbid conditions. Guided by our preliminary data, and knowledge of the field, this hypothesis will be tested by pursuing two specific aims: 1) Examine the antidepressant effects of ketamine and AMPA during alcohol use and in acute withdrawal. 2) Examine the underlying neurobiological mechanisms of ketamine and AMPA in alcohol-induced depression. Under the first aim, we will compare rats treated with various doses of ketamine or AMPA during or after chronic exposure to high doses of alcohol to assess the drugs' potential to block the formation, or alleviate alcohol-induced depression, respectively. Under the second aim, we will elucidate how effective doses of ketamine or AMPA may alter central neurotrophic and synaptogenic markers. This approach is innovative, in our opinion, because it departs from the status quo of using biogenic amine based antidepressants (e.g. serotonin reuptake inhibitors: SSRIs), which can negatively interact with alcohol and have a lag in effectiveness. The proposed research is significant, because it is the first step in a continuum of research that will set a foundation for understanding how ketamine and AMPA can be effectively used to aid in alcohol use cessation, and possibly other addiction-depression co-morbid conditions. Moreover, findings will lead to further studies using ketamine and AMPA in combination treatment, and provide direction in understanding the differential acute and long-term mechanistic actions of these drugs in depression associated with alcoholism.

抽象的 酒精引起的抑郁症的新干预措施 大量饮酒（即酗酒）与抑郁症之间存在很强的正相关性，并且 流行病学研究表明，这种抑郁会对成功戒酒产生负面影响 使用。因此，迫切需要开发有效治疗抑郁症的新型抗抑郁药， 可以与酒精一起使用和/或起效迅速。氯胺酮，一种谷氨酸能 NMDA 受体 拮抗剂有望成为速效抗抑郁药。初步研究也表明可能存在类似的情况 与 AMPA（2-氨基-3-（5-甲基-3-氧代-1,2-恶唑-4-基）丙酸）作用。然而，这些药物的功效 药物与酒精引起的抑郁症的关系尚不清楚。我们的中心假设是氯胺酮和 AMPA 都会 通过调解，有效阻断和缓解长期饮酒引起的抑郁症 神经营养和突触发生途径。我们进行这些研究的理由是确定中央 氯胺酮和 AMPA 诱导行为改变的机制将有助于建立强大的 酗酒或其他疾病人类患者新戒烟治疗方案的科学框架 成瘾-抑郁共病。在我们的初步数据和该领域知识的指导下， 将通过追求两个具体目标来检验假设：1）检查氯胺酮的抗抑郁作用和 AMPA 在饮酒期间和急性戒断时。 2）检查潜在的神经生物学机制 氯胺酮和 AMPA 治疗酒精引起的抑郁症。在第一个目标下，我们将比较用 在长期接触高剂量酒精期间或之后使用不同剂量的氯胺酮或 AMPA 来评估 药物分别具有阻止形成或缓解酒精引起的抑郁症的潜力。第二下 为了实现这一目标，我们将阐明有效剂量的氯胺酮或 AMPA 如何改变中枢神经营养和 突触发生标记。我们认为这种方法是创新的，因为它脱离了现状 使用基于生物胺的抗抑郁药（例如血清素再摄取抑制剂：SSRIs），这可能会产生负面影响 与酒精相互作用并且效果存在滞后。拟议的研究意义重大，因为它是第一个 连续研究中的一步，将为了解氯胺酮和 AMPA 如何发挥作用奠定基础 有效地用于帮助戒酒，以及可能的其他成瘾抑郁症共病。 此外，研究结果将导致使用氯胺酮和 AMPA 联合治疗的进一步研究，并提供 理解这些药物在抑郁症中不同的急性和长期机制作用的方向 与酗酒有关。