The impact of HPA axis dysregulation on the interoceptive effects of alcohol

描述(申请人提供)：HPA轴功能受损，包括糖皮质激素反馈失调和对应激源反应迟钝，是酒精中毒的特征特征。HPA轴功能受损在有饮酒增加风险的人群中也很明显，例如有酗酒家族史的非酒精性个人，以及患有某种形式的抑郁症和其他情绪和焦虑症的个人。鉴于这些关键观察将HPA轴功能失调与饮酒增加的易感性联系在一起，该领域有必要了解这种相互作用的机制。我们提出一个可能的行为机制是改变酒精的内感效应。所有滥用药物都有一个共同的特征，那就是它们在人类身上产生相互感觉/主观影响。这些内感线索可以有力地影响吸食和寻找毒品的行为。新的证据表明，代谢性谷氨酸受体，特别是亚型5(MGluR5)调节酒精的内感效应。使用反复激活HPA轴(饮用水中的皮质酮(Cort))导致HPA轴失调的模型，我们显示出对酒精相互感觉效应的敏感性降低，伏隔核中mGluR5和磷酸化ERK1/2免疫反应性同时降低。这些发现提出了这一应用的主要假设：重复的HPA轴激活/失调导致伏隔核mGluR5的适应，从功能上调节酒精的内感效应。鉴于内感药物效应可以影响吸毒行为，以及HPA轴功能受损与饮酒增加的易感性之间的关系，我们还提出了推论：皮质醇诱导的对酒精内感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，实验将表征皮质醇暴露对酒精的内感效应的影响。从这些研究中获得的信息将建立HPA轴激活/失调与酒精的内感效应之间的关系。其次，实验将检查在皮质醇暴露后mGluR5系统内发生的适应，并将从药理学上操纵mGluR5，这将提供关于mGluR5表达变化与ERK1/2和CREB表达之间的关系的新信息，ERK1/2和CREB是下游靶标，以及酒精效应的相互感受。第三，利用脑部特定部位的微量注射，研究将通过评估mGluR5化合物恢复对酒精的相互感觉效应的敏感性的有效性，来评估mGluR5在反复激活HPA轴/失调后酒精的相互感觉效应表达中的功能参与。最后，实验将解决自我给予酒精和自我给予酒精之间的相互感觉效应之间的关系，并将确定伏隔核和杏仁核中mGluR5在这些行为中的功能作用。总之，这项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效应来推动该领域的发展，酒精是药物寻找的关键机制。

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.