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障碍，其特征是寻求乙醇和失去对酒精摄入的控制。已知酒精中毒与下丘脑垂体肾上腺（HPA）轴和皮质激素释放激素（CRH）信号的持续失调有关，从而导致对压力的不适当反应，从而增加了含水含量的酒精中毒的复发易感性。然而，尚未发现，尚未发现罪名HPA轴对压力的钝化轴响应的细胞和分子机制尚未发现。 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兴奋性输入的（HFS）。这代表了一种细胞机制，通过该机制应力诱导HPA轴的神经适应性反应。初步导致慢性间歇性乙醇（CIE）暴露引起的酒精依赖模型的大鼠模型表明，可以在CIE大鼠的PNC中诱导STP而不急性应激。相比之下，STP在急性压力CIE大鼠的PNC中受损。我们还证明了与CIE大鼠PNC中NMDAR的Glun2b亚基的表达增加有关的突触后NMDAR功能的长期增强。总的来说，初步结果强烈表明，CIE暴露会改变PNC中的基础和应力诱导的突触可塑性，这可能是HPA轴对酒精依赖大鼠的压力的特征性钝化激素反应的原因。因此，该提案的主要假设是CIE诱导的STP损伤是由PVN中NMDAR功能和CRH信号的长期变化介导的。我们还假设恢复这种应力诱导的可塑性将恢复HPA轴对应激源的响应。 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长期戒断。这些研究将有助于发现HPA轴对酒精依赖压力反应反应失调背后的细胞机制，这将在发现新的有效疗法以用于应激引起的强迫性酒精寻求方案。