Noradrenergic Regulation in the BNST

BNST 中的去甲肾上腺素能调节

基本信息

批准号：
10472646
负责人：
DANNY G WINDER
金额：
$ 40.71万
依托单位：
VANDERBILT UNIVERSITY
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：
2016-09-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10472646
关键词：
Adrenergic Agonists Adrenergic Receptor Affective Alleles Anatomy Animal Model Behavior Behavior Control Behavioral Brain Brain region Cells Clinical effectiveness Cocaine Coupled Coupling Cyclic AMP Cyclic AMP-Dependent Protein Kinases Cyclic Nucleotides Data Development Fiber Financial Hardship Fire - disasters Fluorescence Fluorescent in Situ Hybridization Funding Genetic Recombination Goals Guanfacine Health Heterotrimeric GTP-Binding Proteins Human Immunohistochemistry Light Maps Measures Microscopy Monitor Mus Nature Neurons Neurosciences Pharmaceutical Preparations Pharmacology Phenocopy Photometry Population Population Characteristics Population Heterogeneity Process Regulation Relapse Reporter Role Signal Transduction Societies Stimulus Stress Structure of terminal stria nuclei of preoptic region System Testing Therapeutic Therapeutic Studies Time Viral Work addiction addiction liability base behavioral outcome behavioral response brain circuitry conditioned place preference cyclic-nucleotide gated ion channels designer receptors exclusively activated by designer drugs disorder later incidence prevention drug action drug of abuse drug seeking behavior experimental study fluorescence lifetime imaging genetic approach in vivo insight neurochemistry neuronal circuitry new therapeutic target noradrenergic optogenetics preference receptor recruit small hairpin RNA stressor therapeutic development therapy outcome

项目摘要

Abstract/Summary: Relapse is a barrier in addiction treatment, and stress is a precipitating stimulus. α2-adrenergic receptor (AR) agonists can block stress-induced reinstatement of drug-seeking in animal models, particularly through their actions in a region of the brain known as the bed nucleus of the stria terminalis (BNST). However, in the previous funding period we found unexpected pro-reinstatement actions of these receptors which may limit the clinical effectiveness of α2-AR agonists. Moreover, the finding that pro-reinstatement α2a-ARs exist provides a potential way to determine neuronal circuits controlling reinstatement. We also found that α2a-ARs in the BNST induce an unexpected form of neuronal excitation despite coupling to “inhibitory” Gi heterotrimeric G-proteins, and that this excitation may participate in inducing reinstatement of drug-associated behaviors. Thus, we hypothesize that a BNST neuronal ensemble is excited by the α2-AR agonist guanfacine to drive reinstatement of drug-associated behavior. We propose experiments in this application to 1) determine the functional circuitry of BNST cells activated through this process, 2) test the hypothesis that this excitation occurs by decreased cyclic AMP signaling to alter the function of hyperpolarization-activated cyclic nucleotide gated channels in these cells, and 3) directly test the hypothesis that these cells drive reinstatement of drug-associated behaviors. The successful completion of these studies will facilitate rational choices regarding therapeutics likely to reduce stress-induced drug seeking behavior.

摘要/摘要：复发是成瘾治疗中的障碍，压力是一种沉淀的刺激。 α2-肾上腺素受体（AR）激动剂可以阻止在动物模型中阻止压力引起的毒品寻求药物，尤其是通过其在大脑区域中的作用，称为质子末端的床核（BNST）。但是，在以前的资金期，我们发现这些受体的意外促进动作可能会限制 α2-ar激动剂的临床有效性。此外，存在pro-Reinstatementα2a-ars的发现提供了一个确定控制恢复原状的神经元电路的潜在方法。我们还发现BNST中的α2A-ARS 诱导神经元兴奋的目的地耦合到“抑制性” GI异三聚体G蛋白的意外形式，并且这种兴奋可能参与诱导恢复与药物相关行为的恢复。那，我们假设BNST神经元合奏会被α2-AR激动剂鸟丝激发以驱动恢复原状与药物相关的行为。我们建议在此应用中进行实验1）确定功能电路通过此过程激活的BNST细胞的元素，2）检验以下假设：这种兴奋是通过改善而发生的循环AMP信号传导改变超极化激活的环状核苷酸门控通道的功能这些细胞，以及3）直接检验了这些细胞驱动恢复药物相关的假设行为。这些研究的成功完成将促进有关治疗的合理选择可能减少压力引起的毒品寻求行为。