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.

项目概要 产后妇女重新吸食可卡因是一个严重的健康问题，影响母亲的能力 照顾她的孩子，这对母亲和孩子都会产生终生的影响 有一个机会之窗。 用于产后早期的治疗，因为新妈妈使用可卡因的情况显着减少 不幸的是，很少有女性能够保持禁欲并旧病复发。 孩子出生后 6 个月后是否吸食可卡因 迄今为止，人们对此知之甚少。 母亲动机可以防止新的可卡因寻求复发的神经生物学机制 目前的建议逻辑上是建立在我过去几年在老鼠身上的工作的基础上的。 表明在独特的产后早期，新妈妈也会减少对可卡因的寻求，并且 内侧视前区（mPOA）的药理失活，这是一个重要的结构协调母亲 行为，导致同时幼犬/可卡因中母亲对可卡因条件激励的选择增加 选择条件位置偏好（CPP）任务的目的是描述神经网络。 为了实现这一目标，我们研究了新妈妈对可卡因复发的短暂抵抗的过程。 将使用一种新的适应药物复发的灭绝-恢复 CPP 动物模型和途径- 特定的化学遗传学方法来确定投射到边缘皮层 (IL) 的 mPOA 神经元的作用 和腹侧被盖区（VTA）在防止戒断新妈妈恢复可卡因寻求方面的作用 这两种结构都接收来自 mPOA 的直接输入，并且是介导电路的关键节​​点。 奖励和反应分配，IL 有助于刺激识别和执行功能，而 VTA 通过多巴胺投射到伏隔核来调节行为策略。 AIM 1 将使用 Cre 依赖性抑制性 (hM4Di) 或兴奋性 (hM3Dq) 设计器的联合注射 受体专门由设计药物 (DREADD) AAV 激活进入 mPOA，并具有逆行转导 CAV2-Cre 病毒进入 IL，以评估 mPOA à IL 途径的功能必要性和充分性 AIM 2 中的实验将确定单突触的作用。 mPOA 对 VTA (mPOAàVTA) 的预测，以防止恢复先前熄灭的可卡因 该 AIM 还将使用 Gi- 或 Gq-DREADD 与 CAV2-Cre 相结合来寻找新妈妈的行为。 在可卡因 CPP 恢复期间选择性地操纵 mPOAàVTA 途径这些影响。 还将研究 mPOAàIL 和 mPOAàVTA 化学遗传学操作对母亲行为的影响。 考虑到孕产妇使用可卡因对母亲和儿童健康的影响，它具有重大的临床意义。 该提案对于了解导致这种抗复发状态的神经生物学具有重要意义。 产生关于促进禁欲的自然神经适应的重要新知识，并可能揭示新颖的知识 治疗可卡因成瘾的潜在治疗干预目标。