Effects of Cocaine on the Developing Nucleus Accumbens

描述（由申请人提供）：中脑边缘多巴胺（DA）的作用 （3）核（nucleus），即核的中心。在奖励中， 在成年动物中得到了很好的证明。药物滥用，如可卡因增加DA 成年大鼠的NAcc中的水平。类似地，在许多研究中， 或预期已被证明增加成年人的多巴胺。作为 结果，一些研究暗示这条通路是神经基质， 调解药物滥用在人类中，药物滥用通常在青春期建立 而不是成年期：可卡因尤其如此，不幸的是，很少有研究 研究了青少年时期可卡因对NAcc的影响。 研究这种奖励系统的功能反应以及 可卡因在青春期是至关重要的。数据显示， 并持续到成年期。此外， 在此期间，大脑仍在进行，DA系统可能是至关重要的 被可卡因改变了为此，我们修改并调整了体内 微透析程序，使我们能够有效和可靠地回收DA 从年轻大鼠的NAcc中提取。透析过程允许测量 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，重复或“预期”的影响 可卡因对青春期前（出生后第25天; PND 25）、青春期前后 (PND 35，45）和成年（PND 60）动物。此外，行为研究将 使用条件性位置偏好（CPP）评估对可卡因的反应性 范式和新奇寻求行为，以评估与年龄相关的脆弱性， 可卡因的影响。最后，我们建议检查重复的影响， 可卡因对成年人DA系统功能的影响的 拟议研究的主要目标是：首先，确定 PND 25、35、45和60中急性、重复或“预期”可卡因对中脑边缘DA的影响 第二，建立不同年龄的CPP;第三，测量新奇寻求 高应答者与低应答者的年龄和DA活性差异，最后， 确定在青春期的关键时期接触可卡因对 后来的DA反应。我们的基本假设是青春期前的动物 对可卡因的反应是独特的， 这段时间可能会下调这个发育系统的基本功能 但增加了对随后给药的反应性 导致反复吸毒。拟议的研究将使我们能够审查 可卡因对青春期影响的潜在机制， 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.