The Neurokinin-1 Receptor as a Mediator of Alcoholism and Depression Comorbidity

Neurokinin-1 受体作为酒精中毒和抑郁症共病的中介

• 批准号: 10399662
• 负责人: JESSE R SCHANK
• 金额: $ 33.75万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10399662
• 关键词: Aggressive behavior; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Anhedonia; Animals; Anxiety; Behavior; Behavioral; Brain region; Cell Wall; Chronic; Consumption; Data; Development; Disease; Exposure to; Female; Genetic; Gram-Negative Bacteria; Immune response; Immunization; Individual; Injections; Ligands; Lipopolysaccharides; Major Depressive Disorder; Measures; Mediating; Mediator of activation protein; Mental Depression; Methods; Modeling; Mus; National Institute on Alcohol Abuse and Alcoholism; Neuropeptides; Nucleus Accumbens; Odds Ratio; Pathway interactions; Peptides; Pharmaceutical Preparations; Pharmacology; Phenotype; Population; Protocols documentation; Resistance; Risk; Rodent; Rodent Model; Role; Sex Differences; Social Interaction; Source; Stimulus; Stress; Substance P; Substance P Receptor; System; Technology; Territoriality; Testing; Viral Vector; alcohol comorbidity; alcohol seeking behavior; behavioral phenotyping; behavioral study; comorbid depression; comorbidity; depression model; depressive symptoms; experience; experimental study; intervention effect; male; mouse model; nerve supply; neural circuit; neurobiological mechanism; non-alcoholic; novel; overexpression; pre-clinical; problem drinker; receptor; receptor function; response; sex; social; social defeat; social influence; social stress; stressor

Project Summary/Abstract There is a significant comorbidity of alcoholism with other psychiatric conditions. One of the most prominent of these comorbid disorders is major depression, where alcoholics are at approximately four-fold greater risk of experiencing major depression relative to non-alcoholics. In this proposal we will examine the mechanisms that mediate this comorbidity by inducing co- expressed depressive-like behavior and escalated alcohol consumption using preclinical rodent models. Specifically, we will use exposure to chronic social defeat stress to induce these behavioral phenotypes. We will examine the hypothesis that the neurokinin-1 receptor (NK1R) mediates the influence of social defeat stress exposure on subsequent alcohol intake and depressive-like behavior. We have previously shown that this receptor influences stress- induced alcohol seeking in rodents, and as such, this receptor is an ideal target to influence social stress-induced alcohol intake in this mouse model. In specific regard to defeat stress, we have found that the NK1R is upregulated in animals that are sensitive to this stressor. However, one drawback of the defeat stress model is that it can only be used in male mice due to sex differences in territorial aggression. This is a significant issue for the concepts studied here because clinical depression is far more common in females than in males. Thus, we will use a different stressor, immune stimulation by the bacterial cell wall component lipopolysaccharide (LPS), to study these behaviors in both sexes. LPS is known to increase alcohol intake and depressive-like behavior in both male and female mice, and our preliminary data indicates that some effects of LPS are dependent upon the NK1R. Together, these aspects make LPS injection a relevant model for examining alcoholism and depression comorbidity in both sexes. The role of the NK1R in LPS effects suggests that a similar neurocircuitry may regulates the response to both defeat stress and LPS-induced behavioral alterations. The results of these studies will significantly contribute to our understanding of the factors that influence comorbid alcoholism and depression, and will identify novel candidate targets for medications development.

项目摘要/摘要 酒精中毒与其他精神疾病有很大的共病。其中一个 这些共病障碍中最突出的是重度抑郁症，酗酒者在这种情况下 与非酗酒者相比，经历严重抑郁症的风险大约高出四倍。 在这项建议中，我们将研究通过诱导共同发病来调节这种共同疾病的机制。 临床前啮齿动物表现出抑郁样行为并增加饮酒 模特们。具体地说，我们将利用长期的社会失败压力来诱导这些 行为表型。我们将检验神经激肽-1受体(NK1R)的假设。 调节社会失败压力暴露对随后饮酒的影响 类似抑郁的行为。我们之前已经证明，这种受体会影响压力- 在啮齿动物中诱导酒精寻求，因此，该受体是一个理想的影响目标 在这个小鼠模型中，社会压力导致酒精摄入。关于克服压力的具体问题，我们 已经发现NK1R在对这种应激源敏感的动物中上调。然而， 失败应激模型的一个缺点是，由于性别原因，它只能用于雄性小鼠。 领土侵略方面的分歧。对于这里研究的概念来说，这是一个重要的问题。 因为临床抑郁症在女性中比在男性中更常见。因此，我们将使用 不同应激源、细菌细胞壁组分脂多糖对免疫的刺激作用 (LP)，以研究两性的这些行为。众所周知，脂多糖会增加酒精摄入量，并 在雄性和雌性小鼠中都有类似抑郁的行为，我们的初步数据表明 内毒素的某些作用依赖于NK1R。这些方面加在一起，就形成了内毒素 为研究酒精中毒和抑郁症在两性中的共病提供了一个相关的模型。 NK1R在内毒素效应中的作用表明，类似的神经回路可能调节 对失败压力和内毒素诱导的行为改变的反应。这些研究的结果 研究将大大有助于我们理解影响并存的因素 酒精中毒和抑郁症，并将确定新的候选药物靶点 发展。

项目成果

Intermittent Ethanol Access Increases Sensitivity to Social Defeat Stress.

间歇性获取乙醇会增加对社交失败压力的敏感性。

• DOI: 10.1111/acer.14278
• 发表时间: 2020
• 期刊: Alcoholism, clinical and experimental research
• 作者: Nennig,SadieE;Fulenwider,HannahD;Eskew,JacobE;Whiting,KimberlyE;Cotton,MalloryR;McGinty,GabrielleE;Solomon,MatthewG;Schank,JesseR
• 通讯作者: Schank,JesseR

The effects of lipopolysaccharide exposure on social interaction, cytokine expression, and alcohol consumption in male and female mice.

脂多糖暴露对雄性和雌性小鼠社交互动、细胞因子表达和饮酒的影响。

• DOI: 10.1016/j.physbeh.2023.114159
• 发表时间: 2023
• 期刊: Physiology & behavior
• 影响因子: 2.9
• 作者: DeckerRamirez,EB;Arnold,ME;McConnell,KT;Solomon,MG;Amico,KN;Schank,JR
• 通讯作者: Schank,JR