Neural mechanisms preventing postpartum relapse to cocaine seeking in new mothers

防止新妈妈产后复发寻找可卡因的神经机制

• 批准号: 10614372
• 负责人: Mariana Pereira Arboleya
• 金额: $ 19.46万
• 依托单位: UNIVERSITY OF MASSACHUSETTS AMHERST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10614372
• 关键词: Abstinence; Address; Affect; Animal Model; Behavior; Behavioral; Birth; Canine Adenoviruses; Child; Child Care; Child Development; Child Health; Child Rearing; Clinical Research; Cocaine; Cocaine Dependence; Coupled; Decision Making; Dopamine; Drug Combinations; Drug Modelings; Drug usage; Drug user; Enterobacteria phage P1 Cre recombinase; Exhibits; Extinction; Goals; Health; Health Benefit; Human; Incentives; Infant; Infant Development; Injections; Intervention; Knowledge; Maternal Behavior; Medial; Mediating; Methods; Modeling; Mothers; Motivation; Neurobiology; Neurons; Nucleus Accumbens; Pathway interactions; Perinatal; Pharmaceutical Preparations; Postpartum Period; Postpartum Women; Preoptic Areas; Process; Rattus; Relapse; Resistance; Rewards; Role; Site; Societies; Stimulus; Structure; Technology; Testing; Therapeutic Intervention; Time; Ventral Tegmental Area; Viral; Woman; Work; clinically significant; cocaine relapse; cocaine relapse prevention; cocaine seeking; cocaine use; conditioned place preference; designer receptors exclusively activated by designer drugs; drug relapse; effective intervention; effective therapy; executive function; experimental group; experimental study; genetic approach; genetic manipulation; ineffective therapies; maternal cocaine use; motivated behavior; neural; neuroadaptation; neurobiological mechanism; neuromechanism; novel; offspring; pharmacologic; pre-clinical; prevent; pup; relapse prevention; response; reward circuitry; tool; virus Cre recombinase

Project Summary Relapse to cocaine use in postpartum women is a serious health problem that impacts the mother’s ability to care for her child, with life-long consequences for both the mother and child. There is a window of opportunity for treatment in the early postpartum period, as cocaine use in new mothers is significantly reduced by the competing motivation related to child rearing. Unfortunately, few women maintain abstinence and relapse to cocaine use beyond the first 6 months following their child’s birth. To date, little is known regarding the neurobiological mechanisms by which maternal motivation can prevent relapse to cocaine seeking in new mothers. The current proposal builds logically on my work from the past several years. Our prior work in rats demonstrates that during the unique early postpartum period, new mothers also reduce cocaine seeking, and that pharmacological inactivation of the medial preoptic area (mPOA), a critical structure orchestrating maternal behavior, results in increased maternal choice of cocaine-conditioned incentives in a concurrent pup/cocaine choice conditioned place preference (CPP) task. The objective of this proposal is to delineate the neural processes underlying the transient resistance to cocaine relapse in new mothers. To accomplish this goal, we will use a novel adaptation of the extinction-reinstatement CPP animal model of drug relapse and a pathway- specific chemogenetic approach to determine the role of mPOA neurons projecting to the infralimbic cortex (IL) and the ventral tegmental area (VTA) in preventing reinstatement of cocaine seeking in abstinent new mother rats. Both structures receive direct input from the mPOA and are critical nodes of the circuitry that mediates reward and response allocation, with the IL contributing to stimulus recognition and executive functions, and the VTA modulating the behavioral strategy via dopamine projections to the nucleus accumbens. The experiments in AIM 1 will use combined injections of a Cre-dependent inhibitory (hM4Di) or excitatory (hM3Dq) designer receptors exclusively activated by designer drugs (DREADD) AAV into the mPOA, with a retrograde transducing CAV2-Cre virus into the IL to assess the functional necessity and sufficiency of the mPOA à IL pathway on reinstatement of cocaine seeking in new mothers. Experiments in AIM 2 will determine the role of monosynaptic mPOA projections to the VTA (mPOAàVTA) in preventing reinstatement of previously extinguished cocaine seeking behavior in new mothers. This AIM will also use Gi- or Gq-DREADDs combined with CAV2-Cre to selectively manipulate mPOAàVTA pathway during reinstatement of cocaine CPP. The impact of these mPOAàIL and mPOAàVTA chemogenetic manipulations on maternal behavior will be also studied. Considering the consequences of maternal cocaine use on both mother and child health, it is of major clinical significance to understand the neurobiology contributing to this relapse-resistant state. This proposal will generate critical new knowledge of the natural neural adaptations that promote abstinence and may reveal novel targets for potential therapeutic intervention to treat cocaine addiction.

项目摘要 在产后女性中可卡因的复发是一个严重的健康问题，会影响母亲的能力 照顾她的孩子，对母亲和孩子造成了终生的影响。有机会窗口 对于产后早期的治疗，由于可卡因在新妈妈中的使用大大降低了 与抚养子女有关的竞争动机。不幸的是，很少有妇女保持禁欲和继承 可卡因在孩子生日后的前6个月内使用。迄今为止，关于 物质动机可以阻止可卡因寻求新的神经生物学机制 母亲。当前的提案以我过去几年的工作为基础。我们先前在老鼠的工作 证明在产后独特的独特时期，新妈妈也减少了可卡因的寻求， 内侧前区域（MPOA）的药物灭活，这是一种精心策划母体的临界结构 行为，导致同时幼犬/可卡因中可卡因条件激励措施的母校选择增加 选择条件的位置偏好（CPP）任务。该提议的目的是描述神经 在新妈妈中对可卡因缓解的瞬时抵抗力的过程。为了实现这一目标，我们 将使用药物继电器的延伸 - 重新陈述CPP动物模型和途径的新颖适应 确定投射到输卵管皮层（IL）的MPOA神经元的作用的特定化学论方法 以及防止可卡因在戒酒中恢复可卡因时的腹侧对盖区域（VTA） 老鼠。这两种结构都从MPOA接收直接输入，并且是介导的电路的关键节​​点 奖励和响应分配，IL有助于刺激识别和执行功能，以及 VTA通过多巴胺向伏隔核调节行为策略。实验 在AIM 1中，将使用CRE依赖性抑制（HM4DI）或兴奋性（HM3DQ）设计师的联合注射 由设计师药物（Dreadd）AAV专门激活MPOA的接收器，并具有逆行转导 CAV2-CRE病毒进入IL，以评估MPOA-IL途径的必要功能和充分性 恢复可卡因在新妈妈中寻求。 AIM 2中的实验将确定单突触的作用 MPOA项目前往VTA（MPOAàVTA），以防止恢复先前熄灭的可卡因 寻求新妈妈的行为。此目标还将使用与cav2-cre结合使用的GQ或GQ-DREADDS 在恢复可卡因CPP期间，有选择地操纵mpoaàvta途径。这些的影响 Mpoaàil和MpoaàVTA化学发生操作对孕产妇行为也将进行研究。 考虑到母校可卡因对母亲和儿童健康的后果，它是主要的临床 了解有助于这种抗救济状态的神经生物学的意义。该提议将 产生对自然神经适应的批判性新知识，这些知识可以促进戒酒并可能揭示新颖 潜在治疗干预可卡因成瘾的靶标。