权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Neuropeptide receptors, behavioral states and acute ethanol effects

神经肽受体、行为状态和急性乙醇效应

基本信息

批准号：
10615671
负责人：
JILL C BETTINGER
金额：
$ 34.93万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10615671
关键词：
Acute Affect Affective Alcohol consumption Alcohols Behavior Behavior Control Behavioral Biological CRISPR/Cas technology Caenorhabditis elegans Cells Chronic Classification Complex Coupled Data Development Drug usage Emotional Enkephalins Ethanol Exploratory Behavior GTP-Binding Proteins Genes Genetic Genetic Techniques Genetic Variation Genetic study Goals Human Human Genetics Individual Investigation Life Locomotion Maps Measures Mediating Modeling Molecular Mutation Nematoda Neprilysin Nervous System Nervous System Physiology Neurons Neuropeptide Receptor Neuropeptides Neurotransmitters Organism Orthologous Gene Outcome Output Pattern Peptide Signal Sequences Peptides Pharmaceutical Preparations Predisposition Proteins RNA Interference Receptor Gene Regulation Research Resistance Resources Role Serotonin Signal Transduction Site Speed Substance P System Tachykinin Testing Time Variant Work alcohol effect alcohol response alcohol sensitivity alcohol use disorder behavioral outcome behavioral phenotyping drug of abuse experimental study gene conservation gene discovery gene network in vivo insight interest loss of function mutation mutant negative affect neuronal circuitry receptor resistance mutation response

项目摘要

PROJECT SUMMARY There are two, partially overlapping goals of this research: (1) comprehensively define the array of G protein- coupled neuropeptide receptors that act to modulate and mediate acute actions of ethanol in vivo. (2) investigate the impact of specific behavioral states on acute sensitivity to ethanol. We will characterize the roles of all neuropeptide receptors in C. elegans in basal locomotion behaviors and ethanol-induced behavioral effects. This comprehensive assessment will identify receptors that positively and negatively regulate the neuronal circuit that controls locomotion and those receptors that act to promote or negatively regulate ethanol actions. We will assess both the level of initial sensitivity to ethanol and the time-dependent development of acute functional tolerance to the drug. In addition, for those receptors that act to modify responses to ethanol, we will classify any interactions with the neuropeptidase nep-2, which is orthologous to the mammalian neprilysin protein. The mammalian neprilysin protein is involved in the regulation of levels of multiple important signaling peptides, including enkephalins, tachykinin, substance P and others. A mutation in the nep-2 gene produces an ethanol-resistant behavioral phenotype. We hypothesize that a peptide target of NEP-2, which is likely to be elevated in a nep-2 mutant background, acts to counteract acute effects of ethanol via increased signaling through a neuropeptide receptor. The proposed experiments will identify that receptor and test the hypothesis that the receptor acts in a defined neuronal circuit that controls behavioral state decisions. Our preliminary data has identified several mutants that affect both ethanol responses and a behavioral state decision that affects exploratory behavior. The circuit that regulates that decision is well defined, and includes the sites of action of neuropeptides and serotonin. We will define networks of genes that act to regulate that behavioral decision and ethanol responses, and test specific neurons in the controlling circuit for their role in regulating ethanol responses. The relationship between an emotional (or affective) state in humans and the problematic use of drugs of abuse is of significant interest. The successful outcome of this proposed research will provide a better understanding of how specific behavioral states, controlled by a known regulatory circuit, can impact the acute responses to an abused drug. There is a significant correlation between the level of an individual’s initial response to alcohol and their likelihood to develop an alcohol use disorder (AUD). Genetic variation in any of the human orthologs of the C. elegans genes identified in this study has the potential to alter an individual’s level of response to ethanol, and therefore could impact that individual’s predisposition to develop an AUD later in life.

项目总结