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Effects of cocaine taking and seeking on histone deacetylase class IIa enzyme activity in the nucleus accumbens of rats

可卡因吸食和寻找对大鼠伏隔核组蛋白脱乙酰酶 IIa 类酶活性的影响

基本信息

批准号：
9926476
负责人：
Shane Alan Perrine
金额：
$ 0.89万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9926476
关键词：
Address Adult American Animal Model Animals Autopsy Autoradiography Behavior Behavior Control Behavioral Biological Assay Brain Brain imaging Brain region Cell Nucleus Cells Characteristics Chromatin Chronic Cleaved cell Cocaine Cocaine Abuse Cocaine Dependence Complement Country Cues Data Development Disease Enhancers Enzymes Epigenetic Process Extinction (Psychology)Family Family Relationship Female Friends Gene Expression Gene Expression Regulation Genetic HDAC3 gene HDAC4 gene Healthcare Systems Histone Deacetylase Histones Image Imaging Techniques Immunohistochemistry Individual K-18 conjugate Knowledge Ligands Maintenance Measures Mediating Mental Health Mental disorders Methods Modeling Molecular Neurobiology Neurons Neurosciences Nuclear Nucleus Accumbens Personal Satisfaction Pharmaceutical Preparations Phase Plague Play Positron-Emission Tomography Process Proteins Rattus Regulation Rewards Role SECTM1 gene Sampling Self Administration Signal Transduction Slice Societies Stimulus Structure System Techniques Testing Time Transcription Repressor/Corepressor Transferase United States Viral X-Ray Computed Tomography addiction base cocaine use cohort design drug of abuse enzyme activity in vivo insight longitudinal design longitudinal positron emission tomography male motivated behavior multimodality mutant neurobiological mechanism neuroimaging novel novel therapeutics overexpression preclinical study psychostimulant public health relevance radiotracer response vector control

项目摘要

Project Summary / Abstract Cocaine addiction is a debilitating mental health disorder that interferes with an individual’s well-being, disrupts relationships, and burdens society. Cocaine, like other drugs of abuse, hijacks the brain’s reward center, producing enduring changes in brain regions, such as the nucleus accumbens (NAc), that perpetuate the cycle of addiction. Preclinical studies show that cocaine and other psychostimulants act as general enhancers of gene expression and that histone deacetylases (HDACs) in the NAc play a key role in the development of cocaine addiction. However, neurobiological understanding of the role of specific HDACs in these processes is limited and there are few in vivo studies on these targets. In response to the need for such studies, this proposal integrates state-of-the-art small animal positron emission tomography (PET) techniques with a model of cocaine self-administration (coc-SA) to study the role of NAc HDAC Class IIa (HDAC5) enzymatic activity during cocaine taking and seeking behaviors. The combination of in vivo neuroimaging and behavioral neuroscience methods in a longitudinal (repeated-measures) design presents an opportunity to advance understanding of the role of epigenetic activity in the NAc during the 4 phases of coc-SA, including acquisition, maintenance, extinction, and reinstatement. Our overall hypothesis is that cocaine will decrease the enzymatic activity of HDAC Class IIa proteins in the NAc, which will statistically explain increases in cocaine taking and seeking behaviors. Three aims will test this hypothesis. (1) Determine HDAC Class IIa enzymatic activity in the NAc using PET imaging and a novel substrate-based PET ligand at baseline and during the phases of coc-SA. (2) Determine the changes in HDAC Class IIa enzymes and protein targets in the NAc at the different phases of coc-SA using immunohistochemistry. (3) Determine the effect of nuclear HDAC5 in the NAc on class IIa HDAC enzymatic activity during cocaine seeking behavior. The combination of non-invasive PET assays with behavioral neuroscience methods to study the role of HDAC Class IIa enzyme activity in the NAc during cocaine taking and seeking behaviors provides a unique strategy to study the neurobiological mechanisms that underlie the stages of addiction. The proposed studies of this application will deliver translational knowledge that addresses theoretical and neurobiological gaps in our understanding of the role of epigenetics in cocaine addiction. This knowledge will aid in the development of novel neurotherapeutics that target epigenetic regulators and treat this devastating mental health disorder.

项目摘要/摘要