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，其特征是强迫性乙醇寻求和酒精摄入失控。已知酒精中毒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，导致对压力的不适当反应，从而增加戒酒者复发的易感性。然而，在戒酒的酗酒者中，HPA轴对压力反应迟钝的细胞和分子机制尚未被发现。在大鼠中，急性束缚应激诱导下丘脑室旁核（PVN）的小细胞神经分泌细胞（PNC）中N-甲基-D-天冬氨酸受体（NMDAR）功能的CRH依赖性抑制，这允许在兴奋性输入的高频刺激（HFS）的突发之后揭示关联性短时程突触增强（STP）。这代表了应激诱导HPA轴神经适应性反应的细胞机制。在慢性间歇性乙醇（CIE）暴露诱导的酒精依赖大鼠模型中的初步结果表明，STP可以在没有急性应激的CIE大鼠的PNC中诱导。相比之下，STP在急性应激CIE大鼠的PNC中受损。我们还证明了突触后NMDAR功能的持久增强与CIE大鼠PNC中NMDAR的GluN 2B亚基的表达增加相关。总之，初步结果强烈表明，CIE暴露改变了PNC中的基础和应激诱导的突触可塑性，这可能是导致酒精依赖大鼠中HPA轴对应激的特征性钝化激素反应的原因。因此，该建议的主要假设是CIE诱导的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，恢复这种压力诱导的可塑性将恢复HPA轴对压力的反应。为了验证这些假设，我们将使用行为，电生理，生物化学和药理学技术的组合，以确定：1）改变NMDAR信号在压力诱导的可塑性的作用，在从慢性EtOH暴露退出后，在PNC中的神经元能突触，和2）慢性EtOH暴露改变CRH信号在PVN的PNC在长期退出的机制。这些研究将有助于揭示HPA轴对酒精依赖的应激反应失调背后的细胞机制，这将有助于发现新的有效治疗应激诱导的强迫性酒精寻求。