Antidepressant Actions of Glutamatergic Agents

谷氨酸能药物的抗抑郁作用

基本信息

批准号：
8957702
负责人：
LiLian Yuan
金额：
$ 43.36万
依托单位：
DES MOINES UNIV OSTEOPATHIC MEDICAL CTR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-12 至 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8957702
关键词：
Adverse effects Affect Agonist Anhedonia Antidepressive Agents Anxiety Behavior Behavioral Assay Biomedical Research Brain region Career Choice Chronic Collaborations Depressive disorder Dose Drug Targeting Effectiveness Ensure Environment Exhibits Frequencies Glutamatergic Agents Glutamates Goals Human Incidence Institution Interneurons Ketamine Knowledge Lead Link Medial Medical Mental Depression Mental Health Mission Modeling Molecular Molecular Profiling Mood Disorders N-Methyl-D-Aspartate Receptors Pathway interactions Pharmaceutical Preparations Physiological Population Pre-Clinical Model Prefrontal Cortex Property Public Health Relapse Research Research Personnel Resistance Rodent Serine Signal Pathway Signal Transduction Site Stress Swimming Synapses Testing Therapeutic Time Training Universities Work base behavioral response depressive symptoms design disability graduate student human FRAP1 protein insight interdisciplinary approach mood regulation neural circuit neuromechanism new therapeutic target novel postsynaptic public health relevance response synaptic function synaptogenesis transmission process

项目摘要

DESCRIPTION (provided by applicant): Accumulating evidence suggests that dysregulation of glutamatergic transmission in brain regions involved in mood regulation, such as prefrontal cortex (PFC), is linked with depressive disorders. In addition, applications of N-methyl-D-aspartate receptor (NMDAR) antagonists, such as ketamine, exhibit fast-acting and long-lasting antidepressants properties. However, despite these promising findings, limitations of ketamine use as an antidepressant treatment, particularly its dissociative/psychotomimetic effects and abuse potential, highlight the need for alternative glutamatergic agents. Our long-term research goal is to search for and characterize novel glutamatergic agents that exhibit fast-acting antidepressant effects. The objective for this application is to evaluate the antidepressant potential of D- serine, an endogenous NMDAR co-agonist that acts on glutamatergic synapses. The proposed ketamine treatment mechanisms pertain to rapidly enhanced glutamate transmission and synaptogenesis, possibly through inhibition of local GABAergic interneurons and postsynaptic activation of intracellular signaling cascades in the mTOR pathway. D-serine, as an endogenous NMDAR co-agonist, also boosts glutamate transmission and synaptogenesis. Our preliminary results along with previous studies lead to our central hypothesis that activation of NMDAR co-agonist site by D-serine results in fast-acting antidepressant effects. Moreover, D-serine may work cooperatively with ketamine to lower its therapeutic threshold, diminishing the likelihood of abuse. In aim 1, we will evaluate the therapeutic potential of D-serine as a fast-acting antidepressant in preclinical models of depression. Aim 2 is designed to examine the effectiveness of combining D-serine and ketamine at their therapeutic or sub-threshold doses. Finally, we will delineate the synaptic and neural circuitry mechanisms of D-serine and ketamine antidepressant actions, alone or in combination in aim 3. Upon completion, the studies proposed above are likely to generate mechanistic information on D-serine's fast-acting antidepressant potential as well as its feasibility of reducing adverse side effects of ketamine by lowering its therapeutic threshold.

描述（由申请人提供）：越来越多的证据表明，涉及情绪调节的大脑区域（例如前额皮质（PFC））的谷氨酸传输失调与抑郁症有关。此外，N-甲基-D-天冬氨酸受体的应用。 (NMDAR) 拮抗剂，例如氯胺酮，具有快速作用和持久的抗抑郁特性。然而，尽管有这些有希望的发现，氯胺酮作为抗抑郁药的使用仍存在局限性。治疗，特别是其解离/拟精神病作用和滥用潜力，凸显了对替代谷氨酸能药物的需求。我们的长期研究目标是寻找和表征具有快速作用的抗抑郁作用的新型谷氨酸能药物。评估 D-丝氨酸的抗抑郁潜力，D-丝氨酸是一种作用于谷氨酸能突触的内源性 NMDAR 共激动剂。所提出的氯胺酮治疗机制与快速增强有关。谷氨酸传输和突触发生，可能通过抑制局部 GABA 能中间神经元和 mTOR 通路中细胞内信号级联的激活，作为内源性 NMDAR 共激动剂，也促进谷氨酸传输和突触发生。导致我们的中心假设是 D-丝氨酸激活 NMDAR 共激动剂位点会产生快速作用的抗抑郁作用。 D-丝氨酸可以与氯胺酮协同作用，降低其治疗阈值，减少滥用的可能性。在目标 1 中，我们将评估 D-丝氨酸作为快速作用抗抑郁药在抑郁症临床前模型中的治疗潜力。检查 D-丝氨酸和氯胺酮在治疗剂量或亚阈值剂量下组合的有效性。最后，我们将描述 D-丝氨酸和氯胺酮的突触和神经回路机制。单独或联合实现目标 3 的抗抑郁作用。完成后，上述研究可能会产生有关 D-丝氨酸快速起效抗抑郁潜力的机制信息，以及通过降低氯胺酮治疗阈值来减少氯胺酮不良副作用的可行性。