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

描述（由申请人提供）：下丘脑轴功能受损，包括糖皮质激素反馈失调和对压力源反应迟钝，是酒精中毒的特征。下丘脑轴功能受损在有饮酒增加风险的人群中也很明显，比如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障碍的个体。鉴于这些将下丘脑轴功能失调与饮酒增加的易感性联系起来的关键观察结果，有必要在该领域了解这种相互作用的机制。我们提出一种可能的行为机制是酒精的内感受效应的改变。所有滥用药物都有一个共同的属性，即它们对人类产生内感受性/主观效应。这些内感受性线索可以潜在地影响药物服用和寻求行为。新出现的证据表明，代谢性谷氨酸受体，特别是亚型5 （mGluR5）调节酒精的内感受作用。通过重复HPA轴激活（饮用水中的皮质酮（CORT））导致HPA轴失调的模型，我们发现伏隔核对酒精的内感受性影响敏感性降低，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：重复的下丘脑轴激活/失调导致伏隔n.n .脑中mGluR5的适应，从而在功能上调节酒精的内感受效应。鉴于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：cort诱导的酒精内感受性敏感性降低与饮酒增加有关。本应用程序中的研究有四个独立的综合具体目标。首先，实验将描述CORT暴露对酒精的内感受效应的影响。从这些研究中获得的信息将建立下丘脑轴激活/失调与酒精的内感受效应之间的关系。其次，实验将检查在CORT暴露后mGluR5系统内发生的适应性，并将从药理学上操纵mGluR5，这将为mGluR5表达变化、下游靶点ERK1/2和CREB的表达以及酒精作用的内感受性之间的关系提供新的信息。第三，使用脑部位特异性显微注射，研究将通过评估mGluR5化合物恢复对酒精内感受效应敏感性的功效，评估mGluR5在HPA轴反复激活/失调后对酒精内感受效应表达的功能参与。最后，实验将解决自我给酒和自我给酒的内感受效应之间的关系，并将确定mGluR5在伏隔核和杏仁核中在这些行为中的功能作用。总之，本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效应（药物寻找的关键机制）而推动该领域向前发展。

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.