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Kappa Receptor Antagonists as Rapid Acting Antidepressants

Kappa 受体拮抗剂作为速效抗抑郁药

基本信息

批准号：
9030490
负责人：
IRWIN LUCKI
金额：
$ 38.5万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-05 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9030490
关键词：
AMPA Receptors Acute Amygdaloid structure Anhedonia Animal Behavior Animal Model Anti-Anxiety Agents Antidepressive Agents Anxiety Anxiety Disorders Behavior Behavioral Brain Brain region Brain-Derived Neurotrophic Factor C57BL/6 Mouse Chronic Chronic stress Clinical Clinical Treatment Dependence Depression screen Development Disease Dose Drug usage Dynorphins Exposure to Fluoxetine Foundations Genetic Goals Injection of therapeutic agent Ketamine Ligands Major Depressive Disorder Medial Mediating Medical Mental Depression Mental disorders Modeling Moods Morbidity - disease rate Motivation Mus Neuronal Plasticity Nucleus Accumbens Opioid Receptor Patients Pharmaceutical Preparations Predisposition Prefrontal Cortex Process Production Public Health Receptor Signaling Refractory Research Rewards Role Site Stress Sucrose Swimming Testing Therapeutic Therapeutic Effect Time Validation Wild Type Mouse anxiety-like behavior anxiety-related behavior behavior test comorbid depression depression model depressive symptoms dysphoria economic impact kappa opioid receptors neural circuit neuromechanism novel novel therapeutics pre-clinical preference prevent programs public health relevance receptor research study response treatment-resistant depression

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this research program is to determine whether kappa opioid receptor antagonists have the potential to be developed as rapidly acting antidepressants. There is a clear medical need for new drugs that would expand the options for treating comorbid depression and anxiety, especially for the substantial number of patients refractory to current medications. Kappa opioid receptors and their endogenous ligand dynorphin are thought to be involved in the production of dysphoria and depression accompanying exposure to stress. Kappa opioid receptor antagonists can produce antidepressant and anxiolytic effects in animal models, but the pharmacological profile of existing compounds make them unsuitable for clinical development. The proposed studies would evaluate the effects of two novel kappa opioid receptors, LY2456302 and LY2444295, as potential antidepressant and anxiolytic drugs using animal behavior tests. Studies will determine whether the kappa opioid receptor antagonists produce their effects more rapidly than established antidepressants and similar to ketamine on tests such as the forced swim test, novelty-induced hypophagia and on acutely reversing the effects of chronic mild stress on anhedonia and anxiety. The mechanism of action of kappa opioid receptor antagonists will be confirmed using mice with constitutive deletion of kappa opioid receptors. Additional studies will identify the neural circuitry involved in producing these behavioral effects. Taken together, these experiments will strengthen a basic foundation for considering the development of a novel kappa opioid receptor antagonists as rapid acting antidepressants for eventual therapy in treatment-resistant depression.