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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.

项目总结/文摘

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

The area postrema (AP) and the parabrachial nucleus (PBN) are important sites for salmon calcitonin (sCT) to decrease evoked phasic dopamine release in the nucleus accumbens (NAc).

面积Postrema（AP）和副核核（PBN）是鲑鱼降钙素（SCT）的重要部位，可降低伏隔核（NAC）中诱发的质量多巴胺释放。