Aberrant dopamine system function in a rodent model of perimenopause: relevance to psychosis

围绝经期啮齿动物模型中多巴胺系统功能异常：与精神病的相关性

• 批准号: 10585490
• 负责人: Daniel Lodge
• 金额: $ 31.72万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585490
• 关键词: 4-vinylcyclohexene diepoxide; Adult; Affect; Age; Age Months; Age Years; Aging; Amphetamines; Antipsychotic Agents; Anxiety; Behavior; Behavioral; Bipolar Disorder; Brain; Clinical; Data; Development; Dopamine; Electrophysiology (science); Female; Genetic; Hippocampus; Hormonal; Human; Hyperactivity; Hyperprolactinemia; Incidence; Life; Locomotion; Manic; Measures; Menopause; Mental Depression; Mental Health Associations; Mental disorders; Methods; Modeling; Motor Activity; Ovarian Follicle; Pathologic; Perimenopause; Physiological; Pre-Clinical Model; Process; Psychiatric therapeutic procedure; Psychoses; Psychotic Disorders; Quality of life; Rattus; Regulation; Risk; Rodent; Rodent Model; Schizophrenia; Sprague-Dawley Rats; Stimulant; Symptoms; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Time; Ventral Tegmental Area; Weight Gain; Woman; common symptom; depression model; design; disabling symptom; dopamine system; dopaminergic neuron; experimental study; extracellular; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; in vivo; insight; mesolimbic system; neural circuit; novel; novel therapeutic intervention; positive allosteric modulator; postnatal; prepulse inhibition; psychotic symptoms; receptor; side effect; symptom treatment; translational model

Project Summary/Abstract: The transition to menopause (or perimenopause) is a period of unique vulnerability for a woman, in which there is an increased risk of developing a psychotic disorder or the exacerbation of a pre-existing condition, such as first onset schizophrenia/psychosis or bipolar disorder. Antipsychotics used to treat symptoms of psychosis, are not always effective and are often discontinued due to adverse side effects. Further, when given to perimenopausal women, antipsychotics can worsen common symptoms of this period (i.e., weight gain and hyperprolactinemia). This is important to note because psychotic symptoms are debilitating and can severely affect a woman’s quality of life. In the present proposal we will provide a mechanistic understanding into how aberrant regulation of the mesolimbic dopamine system, by the ventral hippocampus, contributes to symptoms of psychosis during perimenopause. We will address this using in vivo electrophysiology, chemogenetics, and behavior with three specific aims: 1) Examine vHipp regulation of VTA dopamine neurons and dopamine- dependent behaviors associated with psychosis in the VCD rodent model of perimenopause. 2) Evaluate the impact of age on the psychosis-like effects of VCD. 3) Determine the utility of α5-GABAAR PAMs as a therapeutic intervention for restoring dopamine system function and dopamine-dependent behaviors associated with perimenopause in the VCD model. Our overarching hypothesis is that aberrant vHipp regulation of the mesolimbic dopamine system during perimenopause underlies behavioral changes associated with psychosis. Furthermore, we posit that α5-GABAAR modulators may have therapeutic utility during the menopausal transition.

项目概要/摘要： 过渡到更年期（或围绝经期）是一个独特的脆弱时期的妇女，其中有 是发展为精神障碍的风险增加或预先存在的病症恶化，例如 首发精神分裂症/精神病或双相情感障碍。用于治疗精神病症状的抗精神病药， 并不总是有效的，并且经常由于不良副作用而中断。此外，当给予 对于围绝经期妇女，抗精神病药物可使该时期的常见症状恶化（即，体重增加和 高催乳素血症）。这一点很重要，因为精神病症状会使人衰弱， 会影响女性的生活质量在本建议中，我们将提供一个机械的理解，如何 腹侧海马对中脑边缘多巴胺系统的异常调节导致了症状 精神病的症状我们将使用体内电生理学、化学遗传学和 行为有三个具体目标：1）检查VTA多巴胺神经元和多巴胺的vHipp调节- 在VCD啮齿动物围绝经期模型中与精神病相关的依赖行为。2)评价 年龄对VCD精神病样效应的影响。3)确定α 5-GABAAR PAM作为治疗药物的效用 用于恢复多巴胺系统功能和多巴胺依赖性行为的干预 围绝经期的VCD模型。我们的总体假设是，vHipp对血管内皮细胞的异常调节， 围绝经期中脑边缘多巴胺系统是精神病相关行为改变的基础。 此外，我们认为α 5-GABAAR调节剂可能在绝经期具有治疗作用， 过渡