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

基本信息

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
项目类别：
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

项目摘要

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）对于女性来说是一个特别脆弱的时期，在此期间罹患精神障碍或原有疾病恶化的风险增加，例如用于治疗精神病症状的首次发作的精神分裂症/精神病或双相情感障碍。并不总是有效，并且经常因不良副作用而停药。围绝经期妇女，抗精神病药物可能会加重这一时期的常见症状（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，并且可能会导致严重的后果。在本提案中，我们将对如何影响女性的生活质量提供机械性的理解。腹侧海马对中脑边缘多巴胺系统的异常调节会导致症状我们将利用体内电生理学、化学遗传学和方法来解决这个问题。具有三个特定目标的行为：1) 检查 VHipp 对 VTA 多巴胺神经元和多巴胺的调节围绝经期 VCD 啮齿动物模型中与精神病相关的依赖行为 2) 评估年龄对 VCD 的精神病样作用的影响 3) 确定 α5-GABAAR PAM 作为治疗的效用。恢复多巴胺系统功能和与多巴胺相关的行为的干预我们的总体假设是 VCD 模型中的围绝经期 vHipp 调节异常。围绝经期期间的中脑边缘多巴胺系统是与精神病相关的行为变化的基础。此外，我们假设 α5-GABAAR 调节剂可能在绝经期具有治疗作用过渡。