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: 6611568
• 负责人: C J MALANGA
• 金额: $ 13.78万
• 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 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6611568
• 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妥协的最大可预防原因。临床和临床前数据表明，可卡因可以充当行为性致畸，是一种能够改变胎儿脑发育和随后功能的药物。妊娠可卡因暴露的动物模型能够识别和分离可卡因和可卡因诱导的营养不良在损害胎儿脑生长和发育中，从临床环境中遇到的无数混杂的共同变异中遇到的无数混杂的共同变异。临床前数据的融合表明，在药物自我给药中涉及的大脑系统中持续妥协，这与脑奖励的变化有关，暴露于子宫内可卡因的动物中。具体而言，已经观察到了边缘前脑结构中多巴胺D1受体的多巴胺反应的改变。 提出了一系列实验，以使用脑刺激奖励（BSR）技术来研究特征良好的小鼠模型，以确定妊娠可卡因暴露导致奖励途径的差异。对于在子宫内与可卡因及其配对对照的小鼠，将确定BSR的速率频率功能。将比较可卡因暴露的后代和对照之间的急性可卡因对奖励自我刺激的影响。假设在子宫内暴露于可卡因的小鼠对急性可卡因给药对加强剂量响应曲线的向右移动所证明的增强自我刺激的影响的反应较小。除了妊娠可卡因暴露模型外，还描述了研究可卡因对缺乏多巴胺1A（D1A）受体的小鼠脑刺激奖励的影响。假设与可卡因暴露的小鼠一样，这些动物将显示出急性可卡因的效力与遗传对照相比。提出了进一步的体外电生理和药理实验，以研究这些变化的细胞机制。 确定妊娠药物暴露在改变大脑发育中的作用的数据，对随后的药物寻求行为的特定后果与其他医学，社会和经济变量无关，而在权衡影响发展中人类大脑的因素时，则必须考虑其他医学，社会和经济变量，这会导致这种暴露的儿童的不利影响。在动物模型中识别特定药理变化及其细胞机制的研究将对虐待药物及其在行为发展中的作用的基本奖励系统的基本功能产生见解。希望这项临床前的工作最终可能导致进一步的转化研究，以识别潜在相关的选择性治疗靶标，可以在适当的临床前和临床研究模型中探索，以揭示特定途径的毒性或增强功能的毒性，这些途径证明了在Gestenation Cocaine敞口的儿童中表现出的，表现出的途径损害的特定途径。