Sex differences in neuroendocrine mechanisms of HPA axis dysfunction in alcohol use disorder

酒精使用障碍HPA轴功能障碍神经内分泌机制的性别差异

• 批准号: 10271265
• 负责人: Joseph Munier
• 金额: $ 3.79万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2022-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10271265
• 关键词: Abstinence; Acute; Address; Adrenal Glands; Adrenergic Receptor; Adult; Alcohol dependence; Alcoholic Intoxication; Alcoholism; Alcohols; American; Award; Behavior Therapy; Behavioral; Biochemical; Biological; CRF receptor type 1; Catecholamines; Cells; Chronic; Chronic stress; Clinical; Corticotropin-Releasing Hormone; Data; Dependence; Disease; Dose; Electrophysiology (science); Endocrine; Estrogens; Ethanol; Exhibits; Feedback; Female; Financial Hardship; Functional disorder; Gap Junctions; Genetic; Glutamates; Goals; Hormonal; Hormones; Hydrocortisone; Hypothalamic structure; Impairment; Individual; Intake; Intervention; Maintenance; Mediating; Mental disorders; Mentors; Modeling; Modernization; N-Methyl-D-Aspartate Receptors; Neuroendocrine Cell; Neurons; Neurosecretory Systems; Neurotransmitters; Norepinephrine; Patients; Pharmacologic Substance; Pharmacology; Phenotype; Physiological; Physiology; Pituitary Gland; Population; Prazosin; Protocols documentation; Rattus; Receptor Signaling; Regimen; Relapse; Resistance; Sex Bias; Sex Differences; Signal Transduction; Slice; Stress; Stressful Event; Synapses; Synaptic plasticity; Techniques; Testing; Training; Withdrawal; acute stress; alcohol exposure; alcohol seeking behavior; alcohol use disorder; behavioral response; biological adaptation to stress; career development; chronic alcohol ingestion; coping; drinking; experimental study; hypothalamic pituitary gonadal axis; hypothalamic-pituitary-adrenal axis; insight; locus ceruleus structure; male; negative emotional state; neurochemistry; neuromechanism; neurotransmission; noradrenergic; paraventricular nucleus; parvocellular; patch clamp; postsynaptic; problem drinker; psychologic; receptor function; release factor; response; sex; sexual dimorphism; short-term potentiation; stressor; synaptic inhibition; trafficking; transmission process

Project Summary Alcohol use disorder (AUD) is a chronic relapsing disorder with unmet pharmacological needs, characterized by compulsive alcohol seeking, excessive intake, and a negative emotional state. The hypothalamic-pituitary- adrenal (HPA) axis which normally coordinates adaptive responding to stressors, is often dysregulated in alcohol dependence. Consequently, alcoholics trying to abstain have difficulty coping with stressful events which contributes to the high rates of relapse observed in these individuals. The parvocellular neuroendocrine cells (PNCs) in the paraventricular nucleus (PVN) of the hypothalamus serve as an integrative nexus for HPA axis function, coordinating excitatory, inhibitory and endocrine signals to initiate HPA axis activation. Acute stress was shown to induce synaptic plasticity in the form of short-term potentiation (STP) at glutamatergic synapses onto the corticotropin releasing factor (CRF)-releasing PNCs. Our lab has demonstrated that rats withdrawn from chronic intermittent ethanol treatment exhibit a loss of stress-induced STP in PNCs, concomitant with blunted hormonal responses to repetitive stress. Stress hormones and neurotransmitters such as CRF and norepinephrine appear as likely candidates in gating stress-dependent HPA axis plasticity. Accordingly, I will further my training in whole-cell patch clamp electrophysiology in ex vivo microdissected PVN slices to assess the efficacy of pharmacological manipulation to normalize ethanol-induced maladaptive phenotypes. While both males and females are capable of stress-induced STP in hypothalamic CRF-releasing PNCs, potential sex-differences have not been adequately addressed. Therefore, in Specific Aim 1 I will evaluate whether chronic ethanol-induced deficits to synaptic plasticity in the PVN are sex-specific. Norepinephrine inputs are critical for the initiation and maintenance of HPA activation. Thus, in Specific Aim 2 I will evaluate the specific contributions of a1 and a2 adrenergic receptors through specific antagonists (prazosin and atipamezole, respectively) to stress and ethanol-induced changes in PNC plasticity. These aims together will test the hypothesis that sex differences in CRF and noradrenergic signaling underlies differences in ethanol induced maladaptive HPA reactivity, contributing to the gross population differences seen clinically in AUD. I have developed a rigorous and thorough training regimen to achieve these electrophysiological endpoints allowing me to develop a critical expertise in pharmacology and physiology, by which I can help bring pharmaceutical interventions to patients in need. The plan is supported by a highly capable team of mentors to facilitate my training and career development under the proposed award period.

项目概要 酒精使用障碍（AUD）是一种慢性复发性疾病，药物需求未得到满足， 其特点是强迫性饮酒、过量饮酒和消极情绪状态。 下丘脑-垂体-肾上腺 (HPA) 轴通常协调适应性反应 对于压力源，酒精依赖常常失调。因此，酗酒者试图 戒酒者难以应对压力事件，这会导致高复发率 在这些人中观察到。细小细胞神经内分泌细胞（PNC） 下丘脑的室旁核 (PVN) 作为 HPA 轴的整合纽带 功能，协调兴奋性、抑制性和内分泌信号以启动 HPA 轴激活。 研究表明，急性应激会以短期增强 (STP) 的形式诱导突触可塑性 在谷氨酸能突触上释放促肾上腺皮质激素释放因子（CRF）的 PNC。我们的实验室 已经证明，从慢性间歇性乙醇治疗中退出的大鼠表现出损失 PNC 中应激诱导的 STP 的发生，伴随着对重复性的激素反应减弱 压力。应激激素和神经递质如 CRF 和去甲肾上腺素表现为 可能是门控压力依赖性 HPA 轴可塑性的候选者。因此，我将进一步我的 在离体显微解剖 PVN 切片中进行全细胞膜片钳电生理学培训 评估药理学操作使乙醇引起的适应不良正常化的功效 表型。虽然男性和女性都能够在下丘脑中产生应激诱导的 STP CRF 释放的 PNC，潜在的性别差异尚未得到充分解决。 因此，在具体目标 1 中，我将评估慢性乙醇是否会引起突触缺陷 PVN 的可塑性具有性别特异性。去甲肾上腺素输入对于启动和 维持 HPA 激活。因此，在具体目标 2 中，我将评估具体贡献 通过特定拮抗剂（哌唑嗪和阿替美唑， 分别）到压力和乙醇引起的 PNC 可塑性变化。这些目标共同将 检验 CRF 和去甲肾上腺素能信号传导中性别差异的假设 乙醇引起的适应不良 HPA 反应性的差异，导致总的 AUD 临床上观察到的人群差异。我制定了严格而彻底的 达到这些电生理终点的训练方案使我能够开发一个 药理学和生理学方面的关键专业知识，我可以通过这些专业知识帮助制药公司 对有需要的患者进行干预。该计划得到了一支高素质导师团队的支持 促进我在拟议奖励期内的培训和职业发展。