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The role of central GLP-1 receptors in animal models of cocaine addiction

中枢 GLP-1 受体在可卡因成瘾动物模型中的作用

基本信息

批准号：
10624869
负责人：
HEATH D SCHMIDT
金额：
$ 38.63万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-03-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10624869
关键词：
Abstinence Adverse effects Agonist Amygdaloid structure Animal Model Area Astrocytes Attenuated Behavior Behavioral Brain Cell Nucleus Cells Clinical Research Cocaine Cocaine Dependence Corticosterone Cues Data Development Disease Dorsal Dose Epigenetic Process Extinction FDA approved Fiber Funding GLP-I receptor Gene Delivery Genes Genetic Genetic Transcription Glutamates Goals Grant Histones Homeostasis Human Lateral Ligands Maps Mediating Methods Molecular Neuroanatomy Neurons Neurosciences Neurosecretory Systems Nucleus Accumbens Pharmaceutical Preparations Pharmacological Treatment Pharmacotherapy Phenotype Photometry Pilot Projects Play Post-Translational Protein Processing Pre-Clinical Model Psychological reinforcement Public Health Rattus Receptor Signaling Regulation Relapse Research Rodent Role Signal Transduction System Ventral Tegmental Area Viral Work behavioral study cell type chromatin immunoprecipitation cocaine craving cocaine exposure cocaine relapse cocaine seeking cocaine self-administration efficacy evaluation experience experimental study glucagon-like peptide 1 hindbrain insight mRNA Expression neuromechanism novel pharmacologic preproglucagons prevent programs response selective expression transcription factor

项目摘要

Project Summary Cocaine addiction continues to be a significant public health problem for which there are currently no effective FDA-approved pharmacological treatments. Therefore, there is a clear need to identify novel neural mechanisms underlying cocaine craving and relapse in order to develop new pharmacotherapies to treat this disease. We have recently shown that central glucagon-like peptide-1 receptors (GLP-1Rs) play an important role in cocaine reinforcement and the reinstatement of cocaine seeking, an animal model of relapse. Specifically, we identified behaviorally relevant doses of a GLP-1R agonist that selectively reduced cocaine seeking and did not produce adverse effects commonly associated with these medications in humans and rodents. While these exciting findings clearly highlight a novel neuroendocrine mechanism that could be targeted to prevent cocaine craving-induced relapse, the neural mechanisms mediating the effects of GLP-1R agonists on cocaine seeking remain unclear. One goal of this proposal is to fill the gaps in our understanding of the central GLP-1 circuits regulating cocaine seeking. In Aim 1, we will extend this circuitry to include the lateral dorsal tegmental area (LDTg) and amygdala, two nuclei known to play critical roles in the reinstatement of cocaine seeking. We will also use a systems neuroscience approach to phenotype GLP-1R-expressing cells and identify their targets. Findings from these studies will provide the first comprehensive neuroanatomical map of GLP-1 circuits in the rat brain. Our pilot studies also reveal that GLP-1Rs are expressed on astrocytes and neurons in the rat brain. Using viral-mediated gene delivery and fiber photometry approaches in Aim 2, we will determine if reduced GLP-1R expression selectively on astrocytes and/or neurons prevents the suppressive effects of a GLP-1R agonist on cocaine seeking. In addition, we will investigate cell-type specific effects of GLP-1R activation on astrocyte activity and neuronal function during the reinstatement of cocaine seeking. We have also discovered that cocaine self-administration and subsequent abstinence dynamically regulate expression of endogenous preproglucagon (PPG), the gene that encodes GLP-1, in the hindbrain. These provocative findings suggest that reduced endogenous PPG expression during abstinence may facilitate cocaine seeking. However, the molecular and epigenetic mechanisms by which cocaine exposure regulates PPG expression are unknown. We will use chromatin immunoprecipitation (ChIP) methods in Aim 3 to identify the histone posttranslational modifications (PTMs) associated with reduced PPG transcription in the hindbrain. We will also identify transcription factors that regulate cocaine-induced changes in PPG mRNA expression. Together, these studies will provide new mechanistic insights into how cocaine exposure influences endogenous central GLP-1 signaling and highlight molecular substrates that could serve as targets for novel medications to treat cocaine addiction.

项目总结