Modulation of Nac-DA Signaling by Learning, Motivational State and Peptides

学习、动机状态和肽对 Nac-DA 信号传导的调节

基本信息

批准号：
10661688
负责人：
MITCHELL F ROITMAN
金额：
$ 37.98万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-15 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10661688
关键词：
Address Animals Attention Behavior Behavioral Biological Assay Body Fluids Caloric Restriction Cell Nucleus Cells Central Nervous System Communication Consummatory Behavior Consumption Cues Dehydration Development Disease Dopamine Drug Addiction Drug abuse Eating Elements Equilibrium Feeding behaviors Fiber Fluid Balance Food Glutamates Goals Homeostasis Hormones Hunger Hyperphagia Hypothalamic structure Ingestion Knowledge Lateral Hypothalamic Area Lateral Hypothalamic Nucleus Learning Light Liquid substance Measures Morphine Morphine Dependence Motivation Negative Reinforcements Neurons Nucleus Accumbens Nutrient Obesity Obesity Epidemic Opiate Addiction Opioid Output Peptides Peripheral Persons Pharmaceutical Preparations Phase Photometry Physiological Play Population Process Psychological reinforcement Public Health Rattus Relapse Research Rewards Risk Factors Role Satiation Self Administration Self Stimulation Services Shapes Signal Transduction Site Stimulus Structure of nucleus infundibularis hypothalami Subfornical Organ Thirst Translating Ventral Tegmental Area Water Water consumption Withdrawal addiction approach behavior blood-brain barrier permeabilization comorbidity cost dopaminergic neuron drug relapse drug reward drug withdrawal feeding food consumption hormonal signals hypocretin in vivo mesolimbic system motivated behavior negative affect neural circuit new therapeutic target opioid abuse opioid epidemic opioid withdrawal parent grant programs psychostimulant receptor recruit response therapeutic target

项目摘要

Project Summary/Abstract Combined, the preventable diseases of obesity and drug addiction impact an enormous number of people and cost billions to treat. Physiological need (e.g. thirst, hunger), its hormonal signals and related central circuits, modulate seeking for and consumption of both nutritive and drug stimuli and thus may serve as risk factors for overeating and drug relapse. Ventral tegmental area (VTA) dopamine neurons and dopamine release in the nucleus accumbens play critical roles in reinforcement. This mesolimbic system also integrates physiological state with primary reward and environmental cues to tune approach and consumption. Indeed, the parent grant of this competitive renewal determined that deviations from homeostasis potentiate phasic mesolimbic signaling evoked by cues predictive of restorative stimuli. It also determined that gut hormones signaling deviations from homeostasis act centrally to modulate phasic mesolimbic signaling in the context of both food and drug reward. Peripheral signals act on central “first order” hypothalamic sites (e.g. subfornical nucleus (SFO), arcuate nucleus (ARC)) that have a permeable blood-brain barrier. Modulation of discrete populations of the SFO or ARC is sufficient to induce negative affect and modulate consummatory behavior for restorative stimuli in a manner consistent with negative reinforcement. How first order hypothalamic neurons communicate with the mesolimbic system for reinforcement and to bias approach and consummatory behavior is unknown. We hypothesize that parallel circuits for thirst and hunger access the VTA via lateral hypothalamic area (LHA) orexin neurons. As LHA orexin neurons are recruited during morphine withdrawal and orexin receptor blockade reduces negative affect associated with morphine withdrawal, we also hypothesize that aberrant activity in first order thirst and hunger circuits during morphine withdrawal are excellent targets for the treatment of negative affect and to break the cycle of addiction. While hypothalamic signals clearly modulate aspects of psychostimulant seeking and taking, their role in modulating responses to other classes of drugs – chiefly opioids – has received little attention. In light of the obesity and opioid epidemics and their co- morbidity, these are critical gaps in knowledge which will be addressed here. We will measure VTA dopamine cell body activity or nucleus accumbens dopamine release using in vivo fiber photometry in behaving rats while selectively modulating first and second order hypothalamic neurons. The aims of the proposal are: 1) to determine the mechanism by which first order thirst neurons (SFO) modulate phasic mesolimbic signaling to cues that predict water and drive approach; 2) to determine the mechanism by which first order hunger/satiety neurons (ARC) modulate phasic mesolimbic signaling to cues that predict food and drive approach; and 3) to intervene at the level of first order thirst and hunger neurons to modulate the aberrant dopamine signaling that contributes to the negative affective state of morphine withdrawal. Results will identify novel therapeutic targets for treating disorders of motivation, including obesity and opioid dependence.

项目摘要/摘要结合在一起，可预防的肥胖症和吸毒疾病影响了许多人，花费数十亿件事。生理需求（例如口渴，饥饿），其马信号和相关的中央电路，调节营养和药物刺激的寻求和消费，因此可以作为风险因素暴饮暴食和释放药物。腹侧对盖区（VTA）多巴胺神经元和多巴胺释放伏隔核在加强中起关键作用。这种中唇系统还整合了生理陈述主要奖励和环境线索，以调整方法和消费。确实，父母授予这种竞争性更新确定脱离稳态潜在的阶段性中比通过可预测恢复性刺激的提示引起的信号传导。它还确定了肠荷尔蒙信号传导在两种食物的背景下，脱离体内稳态的行为，以调节阶段性中唇信号传导和毒品奖励。外围信号对中央“一阶”下丘脑位点作用（例如亚叶核（SFO），具有可渗透血脑屏障的弧形核（ARC）。离散人群的调节 SFO或ARC足以引起负面影响，并调节完整的行为以进行修复以与负强化一致的方式刺激。一阶下丘脑神经元如何与中左右系统进行沟通，以加强和偏向方法和完整的行为是未知的。我们假设3个平行电路3，并通过下丘脑的饥饿进入VTA 区域（LHA）OREXIN神经元。由于LHA Orexin神经元在吗啡戒断和Orexin期间被募集接收器封锁减少了与吗啡戒断相关的负面影响，我们还假设一阶3的异常活动3和吗啡提取期间的饥饿电路是极好的目标负面影响的治疗并打破成瘾的周期。下丘脑信号清楚调节心理刺激寻求和采取的各个方面，它们在调节对其他类别的反应中的作用药物（主要是阿片类药物）很少受到关注。鉴于肥胖和阿片类药物的发作及其共同发作发病率，这些是Knowle中的关键差距，将在这里解决。我们将测量VTA多巴胺细胞体活性或伏隔核多巴胺在行为大鼠中使用体内纤维光度法释放有选择地调节第一阶和二阶下丘脑神经元。该提案的目的是：1）确定一阶第三神经元（SFO）调节阶段中溶液信号的机制预测水和驱动方法的提示； 2）确定一阶饥饿/饱腹感的机制神经元（ARC）调节阶段性中唇信号传导，以预测食物和驱动方法的线索；和3）到在一阶3的水平和饥饿神经元的水平上进行干预，以调节异常多巴胺信号传导导致吗啡戒断的负面情感状态。结果将确定新的疗法治疗动机疾病的靶标，包括肥胖和阿片类药物依赖性。

项目成果

期刊论文数量（38）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Prolonged high fat diet reduces dopamine reuptake without altering DAT gene expression.

DOI：
10.1371/journal.pone.0058251
发表时间：
2013
期刊：
PloS one
影响因子：
3.7
作者：
Cone JJ;Chartoff EH;Potter DN;Ebner SR;Roitman MF
通讯作者：
Roitman MF

Electrode calibration with a microfluidic flow cell for fast-scan cyclic voltammetry.

使用微流体流动池进行电极校准，用于快速扫描循环伏安法。

DOI：
10.1039/c2lc40168a
发表时间：
2012
期刊：
Lab on a chip
影响因子：
6.1
作者：
Sinkala,Elly;McCutcheon,JamesE;Schuck,MatthewJ;Schmidt,Eric;Roitman,MitchellF;Eddington,DavidT
通讯作者：
Eddington,DavidT

Primary food reward and reward-predictive stimuli evoke different patterns of phasic dopamine signaling throughout the striatum.