Relapse and 5-HT2CR-PLD signaling in rat amygdala

大鼠杏仁核的复发和 5-HT2CR-PLD 信号传导

基本信息

批准号：
8445849
负责人：
BALAJI KRISHNAN
金额：
$ 11.59万
依托单位：
UNIVERSITY OF TEXAS MED BR GALVESTON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-30 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8445849
关键词：
Abstinence Acute Address Advanced Development Agonist Amygdaloid structure Animal Experiments Animals Area Association Learning Attenuated Auditory Behavior Behavior Disorders Behavioral Biochemical Biological Assay Brain Brain region Chronic Co-Immunoprecipitations Cocaine Cocaine Dependence Consumption Cues Data Drug Targeting Drug usage Environment Enzymes Event Exposure to Feeling G13 Protein GTP-Binding Proteins Hyperactive behavior Indium Individual Infusion procedures Intervention Investigation Knowledge Lead Learning Link Lipids Measures Mediating Memory Modeling Molecular Pharmaceutical Preparations Phospholipase D Phosphorylation Play Pre-Clinical Model Predisposition Property Proteins Psychological reinforcement Rattus Receptor Activation Relapse Rewards Risk Role Serotonin Signal Pathway Signal Transduction Tactile Testing Therapeutic Training Visual Western Blotting addiction base classical conditioning cocaine use conditioning drug craving experience inhibitor/antagonist innovation long term memory motivated behavior neuroadaptation novel preclinical study preference prevent protein expression psychostimulant public health relevance receptor receptor expression receptor function research study response

项目摘要

DESCRIPTION (provided by applicant): Relapse to cocaine can be initiated after long periods of abstinence in response to cues (visual, auditory, tactile) associated with drug-taking. Repeated use of cocaine induces long-term changes (neuroadaptations) in the key brain regions potentially by usurping the learning mechanisms normally used to reinforce natural rewards. The rewarding properties and interoceptive feelings linked to cocaine become associated with environmental cues. This association is clinically important since intense drug craving causing the addicts to remain highly susceptible to relapse can predominantly occur in response to such environmental cues. However, we still have a poor understanding of the molecular mechanisms underlying drug-dependent learned associations. In the present proposal, we will test the hypothesis that expression of a conditioned behavioral response to a previously cocaine-paired environment requires phospholipase D (PLD) signaling in the amygdala, a key brain area for the formation and expression of associative memories downstream to serotonin (5-hydroxytryptamine, 5-HT) 2C receptors (5-HT2CRs). We propose to investigate the requirement of PLD and 5-HT2CR function for the expression of cocaine induced conditioned hyperactivity behavior using pharmacological intervention and to determine the effect of modulating PLD activity specifically in the amygdala and study its effect on 5-HT2CR mediated suppression of conditioned hyperactivity. Such amygdala specific experimental investigation of cocaine-cue associated neuroadaptations in long-term memory mechanism act two-fold by advancing the basic understanding of the signaling mechanism associated with drug-environment conditioned associations and performing preliminary investigations of therapeutic potential in preclinical models directed towards reducing the risk of relapse.

描述（由申请人提供）：可卡因在长期戒断后可能会因与吸毒相关的提示（视觉、听觉、触觉）而开始复发。重复使用可卡因可能会篡夺通常用于强化自然奖励的学习机制，从而导致关键大脑区域发生长期变化（神经适应）。与可卡因相关的奖励特性和内感受与环境线索相关。这种关联在临床上很重要，因为强烈的药物渴望导致成瘾者仍然高度容易复发，这主要是在对这种环境线索的反应中发生的。然而，我们对药物依赖性习得性关联背后的分子机制仍然知之甚少。在本提案中，我们将测试这样的假设：对先前可卡因配对环境的条件行为反应的表达需要杏仁核中的磷脂酶 D (PLD) 信号传导，杏仁核是形成和表达血清素下游联想记忆的关键大脑区域（5-羟色胺，5-HT）2C 受体（5-HT2CR）。我们建议利用药物干预研究 PLD 和 5-HT2CR 功能对可卡因诱导的条件性多动行为表达的要求，并确定在杏仁核中特异性调节 PLD 活性的效果，并研究其对 5-HT2CR 介导的条件性多动抑制的影响。多动症。这种对长期记忆机制中可卡因提示相关神经适应的杏仁核特异性实验研究具有双重作用，一方面推进了对与药物环境条件关联相关的信号传导机制的基本理解，另一方面在临床前模型中对治疗潜力进行初步研究，旨在减少复发的风险。