Cellular mechanisms of HPA axis neuroadaptations in alcohol dependence

酒精依赖中 HPA 轴神经适应的细胞机制

• 批准号: 8773358
• 负责人: IGOR SPIGELMAN
• 金额: $ 21.32万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-05 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8773358
• 关键词: Acute; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Behavioral; Biochemical; Cells; Chemosensitization; Chronic; Chronic stress; Corticosterone; Corticotropin; Corticotropin-Releasing Hormone; Corticotropin-Releasing Hormone Receptors; Data; Dependence; Development; Disease; Ethanol; Frequencies; Future; Glutamates; Hormonal; Hypothalamic structure; Impairment; Intervention; Mediating; Mental Depression; Modeling; Molecular; N-Methyl-D-Aspartate Receptors; Neuropharmacology; Neurosecretory Systems; Norepinephrine; Normalcy; Outcome; Plasma; Play; Predisposition; Rattus; Receptor Signaling; Relapse; Research; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Series; Signal Transduction; Stress; Synapses; Synaptic Transmission; Synaptic plasticity; System; Techniques; Testing; Time; Withdrawal; acute stress; alcohol exposure; alcohol seeking behavior; alcohol use disorder; allostasis; base; biological adaptation to stress; cell growth regulation; coping; craving; design; effective therapy; hypothalamic-pituitary-adrenal axis; in vivo; mRNA Expression; negative emotional state; neuroadaptation; novel; paraventricular nucleus; parvocellular; postsynaptic; problem drinker; public health relevance; receptor function; research study; response; restraint; restraint stress; stressor; transmission process

DESCRIPTION (provided by applicant): Alcoholism is a chronic relapsing disorder characterized by compulsive ethanol-seeking and loss of control over alcohol intake. Alcoholism is known to be associated with a persistent dysregulation of the hypothalamic pituitary adrenal (HPA) axis and corticotropin-releasing hormone (CRH) signaling that leads to inappropriate responses to stress, thereby increasing relapse susceptibility in abstinent alcoholics. However, the cellular and molecular mechanisms responsible for the blunted HPA axis responses to stress in abstinent alcoholics have yet to be uncovered. In rats, acute restraint stress induces a CRH-dependent depression of N-methyl-D- aspartate receptor (NMDAR) function in parvocellular neurosecretory cells (PNCs) of the paraventricular nucleus of the hypothalamus (PVN) which allows for the unmasking of associative short-term synaptic potentiation (STP) following a burst of high-frequency stimulation (HFS) of excitatory inputs. This represents a cellular mechanism by which stress induces neuroadaptive responses of the HPA axis. Preliminary results in a rat model of alcohol dependence induced by chronic intermittent ethanol (CIE) exposure show that STP can be induced in PNCs of CIE rats without acute stress. By contrast, STP is impaired in PNCs from acutely stressed CIE rats. We also demonstrated long-lasting potentiation of postsynaptic NMDAR function associated with increased expression of the GluN2B subunit of NMDARs in PNCs of CIE rats. Altogether, preliminary results strongly suggest that CIE exposure modifies both basal and stress-induced synaptic plasticity in PNCs, which could be responsible for the characteristically blunted hormonal response of the HPA axis to stress in alcohol- dependent rats. Thus, the main hypothesis of this proposal is that CIE-induced impairment of STP is mediated by the long-lasting alterations in both NMDAR function and CRH signaling in the PVN. We also hypothesize that restoring this stress-induced plasticity will restore the HPA axis responsiveness to stressors. To test these hypotheses we will use a combination of behavioral, electrophysiological, biochemical and pharmacological techniques to determine: 1) the role of altered NMDAR signaling in stress-induced plasticity at glutamatergic synapses in PNCs after withdrawal from chronic EtOH exposure, and 2) the mechanisms by which chronic EtOH exposure alters CRH signaling in PNCs of the PVN during protracted withdrawal. These studies will help uncover the cellular mechanisms behind the dysregulation of the HPA axis response to stress in alcohol dependence, which will be useful in the discovery of new effective therapies for stress-induced compulsive alcohol seeking.

描述（由申请人提供）：酒精中毒是一种慢性复发性疾病，其特征是强迫性地寻求乙醇和失去对酒精摄入的控制。众所周知，酗酒与下丘脑垂体肾上腺（HPA）轴和促肾上腺皮质激素释放激素（CRH）信号的持续失调有关，导致对压力的不当反应，从而增加戒酒者复发的可能性。然而，导致戒酒者 HPA 轴对压力反应减弱的细胞和分子机制尚未被揭示。在大鼠中，急性束缚应激会导致下丘脑室旁核 (PVN) 的小细胞神经分泌细胞 (PNC) 中的 N-甲基-D-天冬氨酸受体 (NMDAR) 功能出现 CRH 依赖性抑制，从而暴露出联想性短期症状。兴奋性输入的高频刺激（HFS）爆发后的术语突触增强（STP）。这代表了压力诱导 HPA 轴神经适应性反应的细胞机制。慢性间歇性乙醇（CIE）暴露诱导的酒精依赖大鼠模型的初步结果表明，在没有急性应激的情况下，可以在CIE大鼠的PNC中诱导STP。相比之下，急性应激 CIE 大鼠的 PNC 中 STP 受损。我们还证明了 CIE 大鼠 PNC 中突触后 NMDAR 功能的持久增强与 NMDAR GluN2B 亚基表达增加相关。总而言之，初步结果强烈表明，CIE 暴露会改变 PNC 的基础突触可塑性和应激诱导的突触可塑性，这可能是酒精依赖大鼠的 HPA 轴对应激的典型激素反应减弱的原因。因此，该提议的主要假设是 CIE 引起的 STP 损伤是由 PVN 中 NMDAR 功能和 CRH 信号传导的长期改变介导的。我们还假设恢复这种压力引起的可塑性将恢复 HPA 轴对压力源的反应能力。为了测试这些假设，我们将结合使用行为、电生理学、生物化学和药理学技术来确定：1）在退出长期乙醇暴露后，NMDAR 信号改变在 PNC 谷氨酸突触应激诱导可塑性中的作用，以及 2）长期戒断期间慢性乙醇暴露改变 PVN PNC 中 CRH 信号传导的机制。这些研究将有助于揭示酒精依赖中 HPA 轴对压力反应失调背后的细胞机制，这将有助于发现针对压力引起的强迫性饮酒的新有效疗法。