Effects of Cocaine on the Developing Nucleus Accumbens

描述(申请人提供)：中脑边缘多巴胺(DA)的作用 通路(特别是伏隔核。NACC)一直在奖励 在成年动物身上有很好的记录。滥用毒品，如可卡因，会增加DA 成年大鼠NAcc的水平。同样，在许多研究中，药物“预期” 或者，预期已被证明会增加成年人的伏隔DA。作为一名 结果，多项研究表明，该通路是一种神经底物。 调解药物滥用。在人类中，药物滥用通常是在青春期形成的。 不是成年期：可卡因尤其如此，不幸的是，很少有研究 研究了青春期可卡因对NAcc的反应变化。 研究这一奖励系统的功能反应性以及 青春期的可卡因是至关重要的。数据显示，吸毒开始 大约在青春期，一直持续到成年。此外，该技术的发展 在此期间，大脑仍在运行，DA系统可能是至关重要的 因接触可卡因而改变。为此，我们对体内的 微透析程序使我们能够有效和可靠地恢复DA 来自幼鼠的NAcc。透析程序允许测量 可卡因引起的神经化学变化。目前的研究建议： 使用微透析检查急性的、重复的或“预期的”影响 可卡因对青春期前(出生后25天；PND 25)、青春期周围NAcc的影响 (PND 35，45)和成年(PND 60)动物。此外，行为研究将 使用条件性位置偏爱(CPP)评估对可卡因的反应 用于评估与年龄相关的易感性的范式和求新行为 可卡因的影响。最后，我们建议检查重复的影响 这些关键年龄的可卡因对成人多巴胺系统的功能有影响。这个 拟议研究的主要目标是：第一，确定 急性、重复或“预期”可卡因对PND 25、35、45和60中脑边缘DA的影响 大鼠；第二，建立跨年龄的CPP；第三，测量新颖性 高反应者与低反应者在年龄和DA活性上的差异，最后， 确定青春期关键期可卡因暴露对健康的影响 后来的地区检察官反应。我们的基本假设是青春期的动物 它们对可卡因的反应是独一无二的，而且在 这一次可能会下调这一发展中系统的基本功能 但提高了对后续给药的反应性，因此 驱使人们反复吸毒。拟议的研究将使我们能够研究 可卡因对青春期的影响的潜在机制 为了了解这些过程如何控制启动和维护 可卡因滥用。

DESCRIPTION (provided by applicant): The role of the mesolimbic dopamine (DA) pathway (specifically the nucleus accumbens septi. NAcc) in reward has been well-documented in adult animals. Drugs of abuse, such as cocaine increase DA levels in the NAcc of adult rats. Similarly, in many studies drug "expectancy" or anticipation has been shown to increase accumbal DA in the adult. As a result, several studies have implicated this pathway as a neural substrate mediating drug abuse. In humans, drug abuse is often established in adolescence not adulthood: this is especially true of cocaine, Unfortunately, few studies have examined changes in the NAcc in response to cocaine during adolescence. Studying the functional responsiveness of this reward system and the effects of cocaine during adolescence is critical. The data show that drug use begins around adolescence and continues into adulthood. Moreover, development of the brain is still ongoing during this period, and the DA system may be critically altered by cocaine exposure. To this end, we modified and adapted the in vivo microdialysis procedure to enable us to effectively and reliably recover DA from the NAcc of young rats. The dialysis procedure allows measurement of the neurochemical changes resulting from cocaine. The present studies propose to use microdialysis to examine the effects of acute, repeated or "expected" cocaine on the NAcc in preadolescent (postnatal day 25; PND 25), periadolescent (PND 35, 45) and adult (PND 60) animals. Additionally, behavioral studies will assess responsiveness to cocaine using a conditioned place preference (CPP) paradigm and novelty-seeking behavior to assess age-related vulnerability to cocaine's effects. Finally, we propose to examine the effects of repeated cocaine at these critical ages on functioning of the adult DA system. The principal goals of the proposed studies are to: first, determine the effects of acute, repeated or "expected" cocaine on mesolimbic DA in PND 25, 35, 45 and 60 rats; second, establish CPP across age; third, measure novelty-seeking differences across age and DA activity in high vs. low responders and finally, determine effects of cocaine exposure during critical periods of adolescence on later DA responsiveness. It is our basic hypothesis that periadolescent animals are unique in their response to cocaine and that repeated administration during this time might down-regulate the basal functioning of this developing system but increase responsiveness to subsequent drug administration and therefore drive repeated drug use. The proposed studies will allow us to examine the underlying mechanism of cocaine's effects in adolescence which is critical in order to understand how these processes control the initiation and maintenance of cocaine abuse.