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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

基本信息

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
项目类别：
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

项目摘要

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.