Cocaine disruption of maternal motivation: preference for pups vs. cocaine

可卡因破坏母亲的动机：对幼崽的偏好与可卡因的偏好

• 批准号: 7921991
• 负责人: Mariana Pereira Arboleya
• 金额: $ 3.82万
• 依托单位: RUTGERS THE STATE UNIV OF NJ NEWARK
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7921991
• 关键词: Action Potentials; Affect; Amides; Area; Award; Behavior; Behavioral; Bilateral; Birth; Brain; Brain region; Bupivacaine; Cannulas; Caring; Child; Choice Behavior; Chronic; Cocaine; Cocaine Abuse; Complex; Cues; Data; Development; Dopamine; Drug usage; Environment; Exhibits; Female; Funding; Glutamate Agonist; Glutamates; Health; Human; Implant; Infant; Infant Development; Infusion procedures; Laboratories; Learning; Local Anesthetics; Maternal Behavior; Measures; Medial; Mediating; Mental Health; Methods; Mothers; Motivation; Neurobiology; Neurons; Nucleus Accumbens; Pharmaceutical Preparations; Postpartum Period; Pre-Clinical Model; Prefrontal Cortex; Pregnancy; Pregnant Women; Preoptic Areas; Prevention; Procedures; Proteins; Public Health; Rattus; Recurrent disease; Research Personnel; Research Project Grants; Role; Site; Societies; Sodium Channel; Specificity; Stimulus; Structure of terminal stria nuclei of preoptic region; Substance abuse problem; Surveys; Techniques; Testing; Woman; Women' s Group; Work; base; cocaine use; design; insight; member; neural circuit; neuronal patterning; neurotransmission; offspring; pre-clinical; preclinical study; preference; public health relevance; pup; relating to nervous system; research study; response; social; stimulant abuse; treatment strategy; voltage

DESCRIPTION (provided by applicant): Cocaine abuse in women during the postpartum period is associated with dysfunctional maternal care, which can have severe lifelong consequences for the child. The preclinical model used in the following experiments employs a dual-choice paradigm based on the conditioned place preference procedure to offer postpartum maternal rats a choice between environments associated with pups and cocaine. In some females, cocaine is reinforcing enough to compete with maternal motivation for pups, whereas in others maternal motivation is the stronger, more resilient force. We identified neurons within discrete brain regions, including the medial prefrontal cortex (mPFC), nucleus accumbens (NA) and medial preoptic area/ventral bed nucleus of the stria terminalis (mPOA/vBST) that are differentially activated when postpartum rats express a motivated preference for cocaine- or pup-associated environments. The proposed research project is part of an ongoing research project funded by a NARSAD Young Investigator Award, designed to test the hypothesis that preference for pups versus cocaine-associated environments is regulated by the concerted activity of regionally distributed networks of neurons in the regions mentioned above. We will determine the functional role of these sites in the expression of motivated choices by transiently inactivating (bupivacaine infusion) each of them and then testing stimulus-associated environment preference (Specific Aim I). Immunocytochemical analysis of the early immediate gene product cFos will reveal regional specificity of neuronal inactivation, and consequent changes in neuronal activity within the remaining key components of the motivational circuitry (Specific Aim II). Further, the causal contribution of dopamine (DA) and glutamate (GLU) neurotransmission within key regions to the choice behavior will be determined with site- specific infusion of selective DA and GLU agonists and/or antagonists (Specific Aim III). These experiments will uncover which regions are causally involved in the motivated choice responses of pup- and cocaine-seeking behaviors, and further reveal how these CNS sites interact to promote the choice for one stimulus over the other. PUBLIC HEALTH RELEVANCE: The 2007 National Survey on Drug Use and Health (NSDUH) estimated the rate of cocaine use among pregnant women at 5.2%. Cocaine abuse in women during pregnancy and the postpartum period severely disrupts mother-infant interactions, which can have negative lifelong consequences for both members of the dyad, often including severe mental health consequences. Substance abuse remains a pressing public health problem that affects millions of women and their babies, and imposes enormous financial and social burdens on society. This application is focused in the understanding of the neural substrate that mediates the motivational aspects of maternal behavior during the postpartum period, particularly within the context of the disruptive effects of drugs with high abuse potential such as cocaine. Through a combination of neurobiological and behavioral techniques, this project will uncover which brain regions are causally involved in the motivated choice responses of pup- and cocaine-seeking behaviors, and further reveal how they interact to promote the preference for one stimulus over the other. Stimulant abuse is an insidious and dangerous chronic recurring and relapsing disease. While the human condition is vastly more complex than our preclinical model, our data offer critical information of the fundamental neurobiological underpinning of the disruptive effect of cocaine on maternal motivation. This preclinical information might contribute to the development of strategies for treatments or methods of prevention of this tragic human condition, with particular emphasis in maintaining or restoring mother- infant bonding.

描述（由申请人提供）：妇女在产后期间滥用可卡因与母亲护理功能失调有关，这可能对孩子造成严重的终生后果。以下实验中使用的临床前模型采用基于条件位置偏好程序的双重选择范例，为产后母鼠提供与幼崽和可卡因相关的环境之间的选择。对于一些雌性来说，可卡因的强化作用足以与幼崽的母性动机相竞争，而对于另一些雌性来说，母性动机则是更强大、更有弹性的力量。我们确定了离散大脑区域内的神经元，包括内侧前额叶皮层（mPFC）、伏隔核（NA）和内侧视前区/终纹腹侧床核（mPOA/vBST），当产后大鼠表达动机偏好时，这些神经元被差异激活用于与可卡因或小狗相关的环境。拟议的研究项目是由 NARSAD 青年研究者奖资助的正在进行的研究项目的一部分，旨在检验这样的假设：对幼崽与可卡因相关环境的偏好是由上述区域的区域分布神经元网络的协调活动调节的。我们将通过暂时失活（布比卡因输注）每个位点，然后测试与刺激相关的环境偏好（具体目标 I），来确定这些位点在表达动机选择中的功能作用。对早期直接基因产物 cFos 的免疫细胞化学分析将揭示神经元失活的区域特异性，以及动机回路其余关键组件内神经元活动的后续变化（具体目标 II）。此外，关键区域内多巴胺（DA）和谷氨酸（GLU）神经传递对选择行为的因果贡献将通过选择性 DA 和 GLU 激动剂和/或拮抗剂的位点特异性输注来确定（具体目标 III）。这些实验将揭示哪些区域与幼犬和可卡因寻求行为的动机选择反应有因果关系，并进一步揭示这些中枢神经系统位点如何相互作用以促进对一种刺激的选择而不是对另一种刺激的选择。 公共卫生相关性：2007 年全国药物使用与健康调查 (NSDUH) 估计孕妇可卡因使用率为 5.2%。妇女在怀孕期间和产后滥用可卡因会严重扰乱母婴互动，这可能会给夫妻双方带来终生的负面影响，通常包括严重的心理健康后果。药物滥用仍然是一个紧迫的公共卫生问题，影响着数百万妇女及其婴儿，并给社会带来巨大的经济和社会负担。该应用的重点是了解介导产后母亲行为动机方面的神经基质，特别是在可卡因等具有高滥用潜力的药物的破坏性影响的背景下。通过神经生物学和行为技术的结合，该项目将揭示哪些大脑区域与幼犬和可卡因寻求行为的动机选择反应有因果关系，并进一步揭示它们如何相互作用以促进对一种刺激相对于另一种刺激的偏好。兴奋剂滥用是一种阴险且危险的慢性复发性疾病。虽然人类的状况比我们的临床前模型复杂得多，但我们的数据提供了可卡因对母亲动机破坏性影响的基本神经生物学基础的关键信息。这些临床前信息可能有助于制定治疗策略或预防这种悲惨人类状况的方法，特别强调维持或恢复母婴关系。