Effect of prenatal cocaine exposure on brain reward

产前接触可卡因对大脑奖赏的影响

• 批准号: 6791339
• 负责人: C J MALANGA
• 金额: $ 14.12万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-10 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6791339
• 关键词: behavioral /social science research tag; cocaine; craving; developmental neurobiology; dopamine receptor; electrodes; electrophysiology; embryo /fetus toxicology; laboratory mouse; neuropharmacology; receptor coupling; receptor expression; receptor sensitivity; reinforcer; statistics /biometry; stimulus /response; substance abuse related behavior; teratogens; voltage /patch clamp

DESCRIPTION (provided by applicant): Prenatal exposure to drugs of abuse such as cocaine and alcohol is the single largest preventable cause of developmental compromise of infants in America today. Clinical and preclinical data suggest that cocaine may act as a behavioral teratogen, a drug capable of altering fetal brain development and subsequent function. Animal models of gestational cocaine exposure have been able to identify and separate the role of cocaine and cocaine-induced malnutrition in impairing fetal brain growth and development from the myriad of confounding co-variables encountered in human subjects from the clinical setting. There is a convergence of preclinical data suggesting persistent compromise in brain systems involved in drug self-administration, which have been linked to alterations in brain reward, in animals exposed to cocaine in utero. Specifically, alterations in dopamine responses at the dopamine D1 receptor in limbic forebrain structures have been observed. A series of experiments is proposed to investigate a well-characterized mouse model using brain-stimulation reward (BSR) techniques to ascertain differences in reward pathways resulting from gestational cocaine exposure. Rate-frequency functions for BSR will be determined for mice exposed to cocaine in utero and for their pair-fed controls. The effects of acute cocaine administration on rewarding self-stimulation will be compared between cocaine-exposed offspring and controls. It is hypothesized that mice exposed to cocaine in utero will be less responsive to the effects of acute cocaine administration on reinforcing self-stimulation demonstrated by a rightward shift of the dose-response curve. In addition to models of gestational cocaine exposure, experiments are described to investigate the effect of cocaine on brain-stimulation reward in mice lacking the dopamine-1A (D1a) receptor. It is hypothesized that as in cocaine-exposed mice, these animals will show decreased potency of acute cocaine compared to their genetic controls. Further in vitro electrophysiological and pharmacological experiments are proposed to investigate the cellular mechanisms underlying these changes. Data identifying the role of gestational drug exposure in altering brain development with specific consequences on subsequent drug seeking behaviors independent of other medical, social and economic variables must be considered when weighing the factors that impact on the developing human brain, and which contribute to adverse outcomes in such exposed children. Research identifying specific pharmacological changes and their cellular mechanisms in animal models will yield insights into both the basic functions of brain reward systems underlying actions of drugs of abuse and their role in behavioral development. It is hoped that this preclinical work may ultimately lead to further translational research identifying potentially relevant, selective therapeutic targets, which can be explored in appropriate preclinical and clinical research models, to blunt the toxicity of or to augment function in specific pathways that demonstrate persistent developmental compromise in children following gestational cocaine exposure.

描述（由申请人提供）： 产前接触可卡因和酒精等滥用药物是当今美国婴儿发育受损的最大可预防原因。临床和临床前数据表明，可卡因可能是一种行为致畸剂，是一种能够改变胎儿大脑发育和后续功能的药物。妊娠期可卡因暴露的动物模型已经能够识别可卡因和可卡因引起的营养不良在损害胎儿大脑生长和发育中的作用，并将其与临床环境中人类受试者遇到的无数混杂的协变量区分开来。大量临床前数据表明，在子宫内接触可卡因的动物中，参与药物自我给药的大脑系统持续受损，这与大脑奖赏的改变有关。具体来说，已经观察到边缘前脑结构中多巴胺 D1 受体的多巴胺反应发生变化。 提出了一系列实验来研究使用大脑刺激奖励（BSR）技术的良好表征的小鼠模型，以确定妊娠期可卡因暴露导致的奖励途径的差异。将确定子宫内接触可卡因的小鼠及其配对喂养对照小鼠的 BSR 速率-频率函数。将在暴露于可卡因的后代和对照组之间比较急性可卡因给药对奖励性自我刺激的影响。据推测，在子宫内接触可卡因的小鼠对急性可卡因给药对增强自我刺激的影响反应较弱，这通过剂量反应曲线的右移来证明。除了妊娠期可卡因暴露模型外，还进行了一些实验来研究可卡因对缺乏多巴胺 1A (D1a) 受体的小鼠大脑刺激奖赏的影响。据推测，就像在接触可卡因的小鼠中一样，与它们的基因对照相比，这些动物的急性可卡因效力会降低。建议进一步进行体外电生理学和药理学实验来研究这些变化背后的细胞机制。 在权衡影响人类大脑发育的因素以及导致此类暴露儿童产生不良后果的因素时，必须考虑确定妊娠期药物暴露在改变大脑发育中的作用以及对随后独立于其他医学、社会和经济变量的寻求药物行为的具体影响的数据。在动物模型中识别特定药理学变化及其细胞机制的研究将深入了解滥用药物行为背后的大脑奖励系统的基本功能及其在行为发展中的作用。希望这项临床前工作最终可能导致进一步的转化研究，确定潜在相关的选择性治疗靶点，这些靶点可以在适当的临床前和临床研究模型中进行探索，以减轻特定途径的毒性或增强特定途径的功能，这些途径表明妊娠期可卡因暴露后儿童会出现持续的发育损害。