Effect of prenatal cocaine exposure on brain reward

描述(由申请人提供)： 在今天的美国，产前暴露于可卡因和酒精等滥用药物是导致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畸胎原，一种能够改变胎儿大脑发育和随后功能的药物。孕期可卡因暴露的动物模型已经能够从人类受试者的临床环境中遇到的无数混淆的协变量中识别和分离可卡因和可卡因诱导的营养不良在损害胎儿大脑生长和发育中的作用。临床前数据的趋同表明，在子宫内暴露于可卡因的动物中，参与药物自我给药的大脑系统持续妥协，这与大脑奖励的变化有关。具体地说，观察到边缘前脑结构中多巴胺D1受体的多巴胺反应的变化。 采用脑刺激奖赏(BSR)技术对一种特征明确的小鼠模型进行了一系列实验，以确定孕期可卡因暴露所导致的奖赏途径的差异。将确定子宫内暴露于可卡因的小鼠和它们的配对喂养对照组的BSR的比率-频率函数。急性注射可卡因对奖励自我刺激的影响将在暴露于可卡因的后代和对照组之间进行比较。剂量-反应曲线右移表明，在子宫内暴露于可卡因的小鼠将对急性可卡因给药在加强自我刺激方面的效果反应较差。除了孕期接触可卡因的模型外，还描述了研究可卡因对缺乏多巴胺-1a(D1a)受体的小鼠大脑刺激奖赏的影响的实验。据推测，与接触可卡因的小鼠一样，这些动物与它们的基因对照相比，急性可卡因的效力将会降低。此外，建议进行体外电生理和药理学实验，以探讨这些变化背后的细胞机制。 在衡量对发育中的人脑产生影响的因素时，必须考虑确定妊娠期药物暴露在改变大脑发育中的作用，并对随后的药物寻求行为产生特定后果的数据，这些因素独立于其他医疗、社会和经济变量，并导致此类暴露儿童的不良后果。在动物模型中识别特定的药理变化及其细胞机制的研究将有助于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育中的作用。希望这项临床前工作最终可能导致进一步的转化性研究，确定潜在的相关、选择性的治疗靶点，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，以钝化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的持续发育受损。

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.