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Identifying the Distinct Intracellular Pathways That Mediate Dopamine-Driven Behaviors

确定介导多巴胺驱动行为的独特细胞内途径

基本信息

批准号：
10477942
负责人：
CAROLINE RAUFFENBART
金额：
$ 4.68万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10477942
关键词：
Address Adult Antipsychotic Agents Arrestins Automobile Driving Autopsy Behavior Behavioral Binding Biological Assay Brain Brain region Categories Cells Chronic Clustered Regularly Interspaced Short Palindromic Repeats Cocaine Collaborations Complex Corpus striatum structure DRD2 gene Data Development Disease Dopamine Dopamine Receptor Dopaminergic Agents Drug abuse Engineering Exhibits Food Future G-Protein-Coupled Receptors GTP-Binding Proteins Gene Expression Genes Human Investigation Knock-out Knockout Mice Learning Location Locomotion Mediating Mediator of activation protein Molecular Motivation Mus NR2B NMDA receptor Neurons Neurotransmitters Nuclear Nucleus Accumbens Pathology Pathway interactions Pharmaceutical Preparations Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Process Protein Phosphatase 2A Regulatory Subunit PR53 Proteins RNA Interference Receptor Activation Recording of previous events Research Rewards Role Signal Pathway Signal Transduction Signaling Protein Surface Tissues Treatment Efficacy Up-Regulation Work arrestin 2 beta-arrestin brain cell cell type cocaine exposure cocaine self-administration conditioned place preference design differential expression dimer experimental study glycogen synthase kinase 3 beta human subject insight network models novel preference prevent psychostimulant putamen receptor recruit reward processing scaffold side effect stimulant dependence stimulant exposure transcriptome transcriptome sequencing transcriptomics willingness

项目摘要

PROJECT SUMMARY/ABSTRACT Dopamine (DA), a neurotransmitter implicated in learning and motivation, is also a critical player in the mechanisms of psychostimulant action and the pathology of drug abuse. Dopamine binds five receptors (D1- D5R), of which D2R carries particular relevance, as it takes on various functional roles in different brain regions and cells types and is a target of all antipsychotic medications. Dopamine receptors are G protein-coupled receptors (GPCRs) that activate intracellular G proteins and their downstream signaling cascades. This signal is terminated upon arrestin binding to the intracellular domain of the receptor. More recently, arrestins have been found to initiate their own G protein-independent signaling cascades by scaffolding various proteins upon receptor activation. The functional roles of these distinct intracellular pathways are unclear. D2R is expressed on striato-pallidal medium spiny neurons (spMSNs) of the nucleus accumbens, where it functions to mediate many psychostimulant-induced behaviors. Previous research in mice has shown that in these cells the arrestin pathway is able to mediate locomotion but not motivation, thus indicating that certain behaviors may be driven by arrestin independently of G protein signaling. GSK-3β, a kinase, is activated downstream of arrestin and is essential for the expression of certain cocaine-induced behaviors. Additionally, upon activation, striatal D2Rs dimerize with the NMDA receptor NR2B subunit, a mechanism that may be GSK-3β-dependent and seems to mediate conditioned place preference (CPP) for cocaine but not food. In post-mortem striatal sections from psychostimulant dependent humans, the proportion of D2R/NMDAR heteromers was ~3-fold higher compared to controls despite a substantial decrease of D2R expression. It is not clear what mediates the formation of these heteromers downstream of D2R. I hypothesize that, in spMSNs, D2R-driven arrestin and downstream GSK-3β signaling mediate cocaine but not food reward processing by facilitating D2R-NR2B heteromerization and transcriptomic changes. I will address this hypothesis through the following Specific Aims: Aim 1 will determine the roles of D2R-driven arrestin and GSK-3β signaling in cocaine versus food reward processing. I will use CRISPR to knockout β- arrestin 2 or GSK-3β in spMSNs of adult mice and assay preference for locations associated with, and willingness to work for, a food reward and cocaine. Aim 2 will use the same knockout strategy to investigate the molecular and transcriptomic changes mediated by βarr2 and GSK-3β upon chronic psychostimulant exposure. I will analyze ex vivo NAc tissue for NR2B-D2R heteromerization, as well as GSK-3β and NR2B phosphorylation, and perform transcriptomic analysis on spMSNs after chronic cocaine exposure using nuclear RNAseq. Together, the proposed experiments will provide insight into the molecular basis for D2R-driven behaviors and identify novel avenues for developing drugs for dopamine-related diseases.

项目总结/文摘