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.

项目摘要/摘要： 过渡到更年期（或围绝经期）是女人的独特脆弱时期，在那里 是患有精神病疾病的风险增加或曾经存在的疾病的加剧，例如 第一次发作精神分裂症/精神病或躁郁症。用于治疗精神病症状的抗精神病药是 并非总是有效的，并且由于不利的副作用而经常停止。此外，当给予 绝经妇女，抗精神病药可能会恶化这一时期的常见症状（即体重增加和 高品位激素血症）。这一点很重要，因为精神病症状令人衰弱，可能会严重 影响女人的生活质量。在本提案中，我们将提供有关如何 腹侧海马对中唇胶多巴胺系统的异常调节，有助于症状 围绕期间的精神病。我们将使用体内电生理学，化学遗传学和 具有三个特定目的的行为：1）检查VTA多巴胺神经元和多巴胺的VHIPP调节 与精神病相关的依赖行为在围膜的VCD啮齿动物模型中。 2）评估 年龄对VCD类似精神病的影响的影响。 3）确定α5-Gabaar PAMS作为治疗的效用 恢复多巴胺系统功能和多巴胺依赖性行为的干预措施 VCD模型中的围栏。我们的总体假设是，异常的VHIPP调节 围膜期间的中断多巴胺系统是与精神病相关的行为变化的基础。 此外，我们肯定α5-Gabaar调节器在更年期期间可能具有热用性 过渡。