The Impact of HPA axis dysregulation on the interoceptive effects of alcohol- Adm

HPA 轴失调对酒精内感受作用的影响-Adm

• 批准号: 8738220
• 负责人: JOYCE BESHEER
• 金额: $ 13.65万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8738220
• 关键词: Address; Alcohol consumption; Alcoholism; Alcohols; Amygdaloid structure; Anxiety Disorders; Behavior; Behavioral; Behavioral Mechanisms; Brain; Brain region; CREB1 gene; Characteristics; Chronic; Corticosterone; Cues; Data; Family history of; Feedback; Glucocorticoids; Goals; Human; Individual; Link; MAPK3 gene; Mental Depression; Metabotropic Glutamate Receptors; Microinjections; Modeling; Mood Disorders; Nucleus Accumbens; Pharmaceutical Preparations; Phosphorylation; Population; Populations at Risk; Predisposition; Process; Psychological reinforcement; Rewards; Risk; Role; Self Administration; Self-Administered; Signal Pathway; Signal Transduction; Site; System; Testing; Time; alcohol effect; brain tissue; drinking; drinking water; drug mechanism; drug of abuse; drug seeking behavior; hypothalamic-pituitary-adrenal axis; immunoreactivity; insight; non-alcoholic; novel; relating to nervous system; research study; response; stressor

DESCRIPTION (provided by applicant): Compromised HPA axis function, including dysregulation of glucocorticoid feedback and blunted response to stressors, is a characteristic feature of alcoholism. Impaired HPA axis function is also evident in populations that are at risk for increased alcohol drinking such as nonalcoholic individuals with a family history of alcoholism, and individuals suffering from some forms of depression and other mood and anxiety disorders. Given these key observations that link dysregulated HPA axis function and susceptibility to increased drinking, there is a necessity in the field to understand the mechanisms underlying the interaction. We propose that a possible behavioral mechanism is alteration of the interoceptive effects of alcohol. All drugs of abuse share the common attribute that they produce interoceptive/subjective effects in humans. These interoceptive cues can potently influence drug taking and seeking behaviors. Emerging evidence shows that metabotropic glutamate receptors, specifically subtype 5 (mGluR5) regulate the interoceptive effects of alcohol. Using a model of repeated HPA axis activation (corticosterone (CORT) in the drinking water) that results in HPA axis dysregulation, we show reduced sensitivity to the interoceptive effects of alcohol, and a parallel decrease in both mGluR5 and phosphorylated ERK1/2 immunoreactivity in the nucleus accumbens. These findings suggest the primary hypothesis of this application: repeated HPA axis activation/dysregulation leads to adaptations in mGluR5 in the n. accumbens that functionally regulate the interoceptive effects of alcohol. Given that interoceptive drug effects can influence drug taking behavior, and the associations between compromised HPA axis function and susceptibility to increased alcohol drinking, we also propose the corollary hypothesis that: the CORT-induced reduction in sensitivity to the interoceptive effects of alcohol is associated with increased drinking. The studies in this application have four separate by integrated Specific Aims. First, experiments will characterize the effects of CORT exposure on the interoceptive effects of alcohol. The information gained from these studies will establish a relation between HPA axis activation/dysregulation and the interoceptive effects of alcohol. Second, experiments will examine adaptations within the mGluR5 system that occur after CORT exposure, and will pharmacologically manipulate mGluR5, which will provide novel information as to the relationship between changes in mGluR5 expression, and the expression of ERK1/2 and CREB, which are downstream targets, and the interoceptive of effects of alcohol. Third, using brain site-specific microinjections, studies will assess the functional involvement of mGluR5 in the expression of alcohol's interoceptive effects after repeated HPA axis activation/dysregulation, by evaluating the efficacy of mGluR5 compounds to restore sensitivity to the interoceptive effects of alcohol. Lastly, experiments will address the relation between the interoceptive effects of self-administered alcohol and alcohol self-administration and will determine a functional role for mGluR5 in the nucleus accumbens and amygdala in these behaviors. Together, the studies in this proposal have the potential to move the field forward by providing insight into how HPA axis activation/dysregulation can influence the interoceptive effects of alcohol, a critical mechanism of drug seeking.

描述（由申请人提供）：下丘脑-垂体-肾上腺轴功能受损，包括糖皮质激素反馈失调和对应激源的反应迟钝，是酒精中毒的典型特征。受损的HPA轴功能在处于增加饮酒风险的人群中也是明显的，例如具有酗酒家族史的非酒精个体，以及患有某些形式的抑郁症和其他情绪和焦虑症的个体。鉴于这些关键的观察结果，连接失调HPA轴功能和易感性增加饮酒，有必要在该领域了解相互作用的机制。我们认为，一个可能的行为机制是改变酒精的内感受性效应。所有滥用药物都有一个共同的属性，即它们对人体产生内感受/主观影响。这些内感受性线索可以有力地影响药物服用和寻求行为。新出现的证据表明，代谢型谷氨酸受体，特别是亚型5（mGluR 5）调节酒精的内感受性作用。使用一个模型的重复HPA轴激活（皮质酮（CORT）在饮用水），导致HPA轴失调，我们表现出降低敏感性的内感受性的影响，酒精，和平行减少mGluR 5和磷酸化ERK 1/2的免疫反应性的核神经元。这些发现表明了本申请的主要假设：重复的HPA轴激活/失调导致n中mGluR 5的适应。功能性调节酒精内感受性作用的激素。考虑到内感受性药物效应可以影响药物服用行为，以及HPA轴功能受损与饮酒增加的易感性之间的关联，我们还提出了推论假设：皮质醇诱导的对酒精内感受性效应的敏感性降低与饮酒增加有关。本申请中的研究有四个独立的综合具体目标。首先，实验将描述CORT暴露对酒精内感受性效应的影响。从这些研究中获得的信息将建立HPA轴激活/失调和酒精的内感受性效应之间的关系。第二，实验将检查CORT暴露后mGluR 5系统内发生的适应，并将间接操纵mGluR 5，这将提供关于mGluR 5表达变化与下游靶点ERK 1/2和CREB表达之间关系的新信息，以及酒精作用的内感受性。第三，使用脑部位特异性显微注射，研究将通过评估mGluR 5化合物恢复对酒精内感受效应的敏感性的功效，评估mGluR 5在重复HPA轴激活/失调后酒精内感受效应表达中的功能参与。最后，实验将解决自我管理的酒精和酒精自我管理的内感受性效应之间的关系，并将确定mGluR 5在这些行为的丘脑核和杏仁核中的功能作用。总之，该提案中的研究有可能通过深入了解HPA轴激活/失调如何影响酒精的内感受性效应（药物寻求的关键机制）来推动该领域的发展。