Noradrenergic Regulation in the BNST

BNST 中的去甲肾上腺素能调节

基本信息

批准号：
10313263
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/10313263
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 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/总结：复发是成瘾治疗的障碍，而压力是 α2 肾上腺素受体 (AR) 的诱发刺激。激动剂可以阻止动物模型中应激诱导的药物寻求恢复，特别是通过其然而，在大脑中称为终纹床核（BNST）的区域中的活动。在之前的资助期间，我们发现这些受体具有意想不到的促恢复作用，这可能会限制此外，促进恢复的α2a-AR的存在提供了临床有效性。我们还发现 BNST 中的 α2a-AR 是确定控制恢复的神经回路的潜在方法。尽管与“抑制性”Gi 异三聚体 G 蛋白偶联，但仍诱导出意想不到的神经元兴奋形式，并且这种兴奋可能参与诱导药物相关行为的恢复。研究发现 BNST 神经系统被 α2-AR 激动剂胍法辛激发以驱动恢复我们建议在本申请中进行实验以 1) 确定功能电路。通过此过程激活的 BNST 细胞，2) 检验以下假设：这种激发是通过减少环AMP信号改变超极化激活的环核苷酸门控通道的功能这些细胞，3) 直接检验这些细胞驱动药物相关的恢复的假设这些研究的成功完成将有助于合理选择治疗方法。可能会减少压力引起的寻求毒品的行为。