Frontal cortical opioid modulation of striato-hypothalamic networks: roles in food-reward and impulsivity

纹状体下丘脑网络的额叶皮质阿片类药物调节：在食物奖励和冲动中的作用

• 批准号: 9098786
• 负责人: BRIAN A BALDO
• 金额: $ 37.83万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-15 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9098786
• 关键词: AMPA Receptors; Adolescent; Affect; Agonist; Alcohol consumption; Amino Acids; Amygdaloid structure; Appetitive Behavior; Area; Arousal; Behavior; Behavioral; Binge Eating; Binge eating disorder; Biological Assay; Brain; Brain imaging; Brain region; Bulimia; Code; Decision Making; Development; Disease; Eating Disorders; Engineering; Estrogens; Exhibits; Failure; Fatty acid glycerol esters; Feeding behaviors; Female; Food; Food Processing; Funding; GABA Receptor; GTP-Binding Proteins; Gambling; Glutamates; Health; Hyperactive behavior; Hypothalamic structure; Impairment; Impulsivity; Individual; Investigation; Laboratories; Lateral; Ligands; Literature; Mediating; Mental disorders; Morphine; Motivation; Naltrexone; Narcotic Antagonists; Neuronal Plasticity; Neurons; Nucleus Accumbens; Opioid; Opioid Peptide; Opioid Receptor; Output; Pathology; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phenotype; Population; Prefrontal Cortex; Prevalence; Process; Proteins; Psychological reinforcement; RNA Interference; Rattus; Receptor Signaling; Rewards; Role; SB-334867; Sex Behavior; Sex Characteristics; Signal Transduction; Site; System; Testing; Time; Virus; Vulnerable Populations; Woman; Work; addiction; base; binge type behavior; designer receptors exclusively activated by designer drugs; disability; drug standard; effective therapy; executive function; feeding; frontal lobe; gamma-Aminobutyric Acid; gender difference; heuristics; hypocretin; improved; monoamine; motivated behavior; motivational processes; network dysfunction; network models; neural circuit; neuroadaptation; neuromechanism; novel; orexin 1 receptor; psychologic; receptor; research study; response; transmission process; treatment strategy; university student

 DESCRIPTION (provided by applicant): Loss of inhibitory control over appetitively motivated behavior, sometimes manifested as `bingeing', is a phenotype present in multiple psychiatric conditions. It is widely assumed that bingeing emerges from the dysregulated function of frontal-executive control mechanisms that govern subcortical motivation systems; nevertheless, specific neuropharmacological mechanisms and circuit connections are not clearly understood. One clue derives from the fact that opiate antagonist drugs are among the only pharmacotherapies with some efficacy in improving inhibitory control across a wide variety of psychiatric disorders with binge features. Hence, opioid actions within frontal circuits could be a crucial substrate underlying binge-type pathologies. To date, however, opioid effects in frontal cortex have been almost completely overlooked. In the previous funding period, we discovered that µ-opioid receptor (µOR) stimulation in rat ventromedial prefrontal cortex (PFC) - an area analogous to those showing abnormal responses in a variety of disorders with binge features - engenders robust non-homeostatic feeding and hyperactivity, increased food motivation in a progressive-ratio task, and robust `impulsivity-like' impairments in a PFC-sensitive task of inhibitory control. These effects were not reproduced by a wide array of monoamine receptor agonists or antagonists, demonstrating unique actions of µORs relative to other PFC modulatory systems. Furthermore, dual-site drug microinfusion studies revealed that PFC µOR signaling engages appetitive drive via feeding/arousal circuits in the lateral-perifornical hypothalamic region (LH-PeF), including the hypocretin/orexin system, while concurrently causing activation of an AMPA-coded PFC→nucleus accumbens shell (AcbSh) circuit that limits food motivation. Finally, we found that repeated episodes of sweetened-fat `gorging' sensitize AcbSh GABA systems, potentially blunting the effect the PFC→AcbSh `limiter circuit'. Based on these findings, we propose a novel network model stating that loss of control over appetitive behavior occurs when subcortical systems are driven by excessive PFC-µOR signaling, and/or when there is an imbalance in the PFC→LH-PeF (`appetitive-driver') and PFC→AcbSh (`appetitive limiter') pathways. Moreover, we propose that palatable food gorging causes neuroplastic changes in AcbSh amino-acid (glutamate, GABA) systems that blunt incoming PFC signals, curbing the influence of the `limiter circuit', thereby allowing appetitive behavior to go unchecked. In this way, the neuroadaptations caused by intense reward-driven feeding could engage a vicious cycle, leading to further binge-like behavior. We will test this working hypothesis with a combination of classic pharmacology experiments and studies using virally introduced Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). These engineered receptors permit the activation of G-proteins with a synthetic ligand; thus, neuronal activity can be modulated within specific populations of virally transduced neurons. Using a dual-virus approach, we will target DREADD expression to PFC neurons specifically projecting either to the AcbSh or to the hypothalamus, and selectively manipulate these tagged neurons in rats performing operant tasks of food motivation and inhibitory control. Furthermore, using classic pharmacology + DREADD experiments, we will test the hypothesis that palatable-food bingeing desensitizes vmPFC→AcbSh `limiter circuit' and perhaps amplifies the vmPFC→hypothalamus `appetitive-driver' circuit. Using receptor antagonists, we will examine the role of endogenous µ-opioid and hypocretin/orexin transmission in mediating PFC-driven food motivation and impulsivity. Finally, we will explore possible gender differences in PFC-µOR control of food motivation and food impulsivity.

 描述（由适用提供）：在多种精神病疾病中存在的表型，有时表现为“ binging”的抑制性控制丧失，有时表现为“ binging”。人们普遍认为，暴饮暴食是从控制皮层动机系统的额叶连续控制机制的失调功能中出现的。然而，特定的神经药理机制和电路连接尚不清楚。一个线索源于以下事实：扩展拮抗剂是唯一的药物治疗之一，在改善具有暴饮暴食特征的各种精神疾病的抑制性控制方面具有有效性。因此，额叶电路中的阿片类药物的作用可能是 基于暴饮暴食型病理的关键基材。然而，迄今为止，额叶皮质中的阿片类药物作用几乎被完全忽略了。在上一个资金期间，我们发现大鼠腹腔前额叶皮层（PFC）中的µ-阿片受体（µOR）刺激 - 一个与表现出异常反应的那些区域相似的区域 - 与狂暴的特征中的多种疾病中的异常反应 - 强大的非室内喂养和超级动机，在富有的食物中增加了富有动力，并在稳固的效果中添加了良好的努力，并在促进了良好的任务，并努力锻炼，并努力锻炼，并在某种程度上提高了任务，并构成了任务，并努PFC敏感的抑制控制任务。这些作用不是由多种单胺受体或拮抗剂复制的，这表明了相对于其他PFC调节系统的独特作用。 Furthermore, dual-site drug microinfusion studies revealed that PFC µOR signaling engages appetitive drive via feeding/arousal circuits in the lateral-perifornical hypothalamic region (LH-PeF), including the hypocretin/orexin system, while concurrently causing activation of an AMPA-coded PFC→nucleus acoustic shell (AcbSh) circuit that limits food motivation.最后，我们发现，甜脂肪“ gorging”的重复发作是ACBSH GABA系统，可能会使PFC→ACBSH“限制器电路”产生效果。基于这些发现，我们提出了一个新颖的网络模型，指出当皮质下系统由过量的PFC-µOR信号传导驱动时，对食用行为失去控制，而/或/或当PFC→LH-PEF（`Appetitive-Driver'）和PFC→acbsh（acbsh（acbsh）（```offc）→acbsh（```offc→acbsh）patherage''''''''''''AppeTive limiter。此外，我们提出，可口的食物会导致ACBSH氨基酸（谷氨酸，GABA）系统的神经塑性变化，该系统钝化了传入的PFC信号，从而遏制了“限制器电路”的影响，从而允许食欲不受检查。通过这种方式，由激烈的奖励驱动喂养引起的神经适应可能会带来一个奇妙的周期，从而导致进一步的狂暴行为。我们将通过经典的药理学实验和研究使用了由设计师药物（Dreadds）激活的虚拟设计器受体的研究来检验这一工作假设。这些工程的受体允许使用合成配体激活G蛋白。因此，可以在虚拟翻译神经元的特定种群中调节神经元活性。使用双病毒方法，我们将靶向Dreadd表达到专门投射到ACBSH或下丘脑的PFC神经元中，并在大鼠中有选择地操纵这些标记的神经元，从而执行食物动机和抑制性控制的操作任务。此外，使用经典的药理学 + Dreadd实验，我们将测试以下假设：可口的食物折线脱敏VMPFC→ACBSH“限制器电路”，可能的放大器可能是VMPFC→Hypothalamus`haspetitive-Drive-Driver-Driver-Driver'电路。使用接收器拮抗剂，我们将研究内源性µ-阿片类药物和低螺旋蛋白/Orexin传播在介导PFC驱动的食物动机和冲动性中的作用。最后，我们将探索PFC-µ的性别差异，控制食物动机和食物冲动。