Stress, depression and effects of novel antidepressants on excitatory synapses

压力、抑郁和新型抗抑郁药对兴奋性突触的影响

• 批准号: 9270600
• 负责人: SCOTT M. THOMPSON
• 金额: $ 38.18万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-15 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9270600
• 关键词: Adverse effects; Affect; Agonist; Anesthetics; Animals; Antidepressive Agents; Anxiety; Appetitive Behavior; Behavior; Behavioral; Behavioral Assay; Benzodiazepine Receptor; Benzodiazepines; Binding; Binding Sites; Biochemical; Biological Assay; Brain; Cannulations; Cells; Chemosensitization; Chronic; Chronic stress; Data; Depressed mood; Disinhibition; Dose; Down Syndrome; Drug Industry; Electrophysiology (science); Etiology; Excitatory Synapse; Exhibits; Food; Functional disorder; Gene Expression; Grant; Hippocampus (Brain); Hour; Human; Impairment; Individual; Injection of therapeutic agent; Instinct; Interneurons; Ketamine; Long-Term Potentiation; Measures; Mediating; Mental Depression; Modeling; Molecular; Morbidity - disease rate; Mus; National Institute of Mental Health; Nature; Neurons; Nucleus Accumbens; Outcome; Pathologic; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Property; Prosencephalon; Pyramidal Cells; Rattus; Research Domain Criteria; Rewards; Rodent; Seizures; Selective Serotonin Reuptake Inhibitor; Signal Pathway; Signaling Protein; Site; Social Dominance; Social Interaction; Stress; Sucrose; Synapses; Synaptic Transmission; Synaptic plasticity; Testing; Therapeutic; Therapeutic Effect; Work; base; behavioral impairment; brain tissue; cognitive enhancement; depressed patient; improved; in vivo; innovation; mortality; neural circuit; neuronal circuitry; novel; novel drug class; optogenetics; preference; public health relevance; receptor; receptor function; response; restoration; sex

 DESCRIPTION (provided by applicant): Depression is a major cause of mortality and morbidity worldwide. Its etiology is unknown. Current therapeutic treatments are effective in only half of patients and, when effective, work slowly. There is increasing evidence that a weakening of excitatory synaptic transmission between cells in multiple cortico-mesolimbic reward circuits is induced in rodents by chronic stress, perhaps underlying the wide range of behaviors affected by stress. Innovation: We discovered in the previous grant cycle that selective serotonin reuptake inhibitors act slowly to restore this weakened synaptic excitation. Based on the rapid antidepressant actions of ketamine, we identified a novel class of compounds that we predict will act rapidly to strengthen pathologically weakened excitatory synapses and can thus be predicted to exert a fast acting antidepressant action with fewer side effects than ketamine. Specifically, we will test the hypotheses that Partial inverse agonists of the benzodiazepine binding site of GABAA receptors containing a5 subunits (PIAGRA) will produce a rapid and persistent restoration of a range of behaviors that are affected by chronic stress paradigms in rats and mice and that they will restore the strength of pathologically weakened excitatory synapses, as measured in electrophysiological and biochemical assays. Approach: Our preliminary data show that a unique PIAGRA compound (L-655,078) restores normal sucrose preference and social interaction within 24hrs in rats subjected to two chronic stress paradigms and restores the strength of AMPAR-mediated synaptic excitation and GluA1 expression in hippocampal synapses in rats subjected to chronic stress. We also observed that synapses formed by hippocampal projections to neurons in the nucleus accumbens display activity-dependent long-term potentiation. We propose to test the following specific aims. 1: Determine the persistence and generality of PIAGRA's antidepressant actions on a range of appetitive and innate behaviors (food, social interactions, sex). 2: Determine the mechanism of action of PIAGRA at the level of synaptic circuits. 3: Determine the effects of stress and PIAGRA on hippocampal-NAc excitatory synapses. We will use multiple chronic stress paradigms to produce changes in reward behavior, then test whether PIAGRA compounds produce rapid (<24 hrs) and persistent normalization of these behaviors and determine how long these beneficial actions persist. We will then use electrophysiological recording to test the strength of excitatory interactions, along with several biochemical and molecular correlates, in brain tissue taken from these animals 24 hrs after injection of the compounds. Outcome: Our study will provide a thorough proof-of-concept test of a novel class of AD compounds at several levels of analysis from behavior to molecules, as encouraged by the NIMH's Research Domain Criteria initiative. Evidence of a beneficial therapeutic action in rodents after chronic stress, and the identification of key circuits at which they act, will encourage a test of their therapeutic effect in depressed patients.

 描述(申请人提供)：抑郁症是世界范围内死亡和发病的主要原因。其病因尚不清楚。目前的治疗方法只对一半的患者有效，而且有效时见效缓慢。越来越多的证据表明，慢性应激可导致啮齿类动物多个皮质-中脑边缘奖赏环路细胞间兴奋性突触传递减弱，这可能是应激影响的广泛行为的基础。创新：我们在前一个拨款周期中发现，选择性5-羟色胺再摄取抑制剂恢复这种减弱的突触兴奋的作用很慢。基于氯胺酮的快速抗抑郁作用，我们发现了一类新的化合物，我们预测它们将迅速起作用，加强病理上减弱的兴奋性突触，因此可以预测发挥快速作用的抗抑郁作用，副作用比氯胺酮少。具体地说，我们将测试这样的假设，即含有a5亚基的GABAA受体的苯二氮卓类结合位点的部分反向激动剂(PIAGRA)将产生一系列受慢性应激范式影响的行为的快速和持久恢复，并且它们将恢复在电生理和生化分析中测量的病理性减弱的兴奋性突触的强度。方法：我们的初步数据显示，一种独特的PIAGRA化合物(L-655,078)在24小时内恢复了两种慢性应激模式下大鼠正常的蔗糖偏好和社会互动，并恢复了AMPAR介导的突触兴奋和GluA1在慢性应激大鼠海马神经元中的表达。我们还观察到，由海马向伏隔核神经元投射形成的突触显示出活动依赖的长时程增强。我们建议测试以下具体目标。1：确定PIAGRA在一系列食欲和先天行为(食物、社交、性)上的抗抑郁作用的持久性和普遍性。2：从突触回路水平确定PIAGRA的作用机制。3：观察应激和PIAGRA对大鼠海马-NAc兴奋性突触的影响。我们将使用多种慢性应激范式来改变奖励行为，然后测试PIAGRA化合物是否能迅速(24小时)和持久地使这些行为正常化，并确定这些有益行为持续多久。然后我们将使用电生理记录来测试 在注射化合物24小时后，从这些动物的脑组织中提取的兴奋性相互作用以及几个生化和分子相关因素。结果：我们的研究将在NIMH的研究领域标准倡议的鼓励下，在从行为到分子的多个层面上对一类新的AD化合物进行彻底的概念验证测试。有证据表明在慢性应激后对啮齿动物采取了有益的治疗行动，并确定了它们作用的关键回路，这将鼓励对抑郁症患者进行治疗效果的测试。