Antidepressant Actions of Glutamatergic Agents

 描述(申请人提供)：越来越多的证据表明，与情绪调节有关的大脑区域，如前额叶皮质(PFC)中谷氨酸能传递的失调与抑郁障碍有关。此外，N-甲基-D-天冬氨酸受体(NMDAR)拮抗剂的应用，如氯胺酮，表现出快速有效和持久的抗抑郁特性。然而，尽管有这些令人振奋的发现，氯胺酮作为抗抑郁药物使用的局限性，特别是它的解离/拟精神分裂效应和滥用潜力，突出了替代谷氨酸能药物的必要性。我们的长期研究目标是寻找和表征具有快速抗抑郁作用的新型谷氨酸能药物。这项应用的目的是评估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促进谷氨酸传递和突触发生有关，可能是通过抑制局部GABA能中间神经元和突触后激活mTOR通路中的细胞内信号级联。D-丝氨酸作为一种内源性NMDAR共激动剂，也促进谷氨酸的传递和突触发生。我们的初步结果和以前的研究一起导致了我们的中心假设，即D-丝氨酸激活NMDAR共同激动剂位点会导致快速作用的抗抑郁作用。此外，D-丝氨酸可能与氯胺酮协同工作，以降低其治疗阈值，减少滥用的可能性。在目标1中，我们将评估D-丝氨酸作为一种快速有效的抗抑郁药物在临床前抑郁症模型中的治疗潜力。目的2旨在检查D-丝氨酸和氯胺酮在治疗剂量或低于阈值剂量下联合使用的有效性。最后，我们将描述D-丝氨酸和氯胺酮单独或联合抗抑郁作用的突触和神经回路机制。完成后，上述研究可能会产生关于D-丝氨酸的快速作用抗抑郁潜力的机制信息，以及通过降低氯胺酮的治疗阈值来减少其不良副作用的可行性。

 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.