Effects of Cocaine on the Developing Nucleus Accumbens

可卡因对伏核发育的影响

• 批准号: 6643568
• 负责人: CHERYL L KIRSTEIN
• 金额: $ 18.13万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6643568
• 关键词: age difference; behavioral /social science research tag; cocaine; developmental neurobiology; dopamine; dopamine transporter; drug abuse; juvenile animal; laboratory rat; mature animal; microdialysis; neurochemistry; neurogenesis; neurotransmitter metabolism; nucleus accumbens; postnatal growth disorder; preference; psychological reinforcement; reinforcer; substance abuse related behavior

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.

描述（由申请人提供）：中脑边缘多巴胺（DA）的作用 奖励途径（特别是伏隔核 NAcc） 在成年动物中已有充分记录。滥用药物，例如可卡因会增加 DA 成年大鼠 NAcc 中的水平。同样，在许多研究中药物“期望” 或预期已被证明会增加成人的累积 DA。作为一个 结果，多项研究表明该途径是神经底物 调解药物滥用。在人类中，药物滥用通常发生在青春期 不是成年期：可卡因尤其如此，不幸的是，很少有研究 研究人员检查了青春期期间 NAcc 对可卡因反应的变化。 研究该奖励系统的功能反应及其影响 青春期的可卡因至关重要。数据显示吸毒开始 大约在青春期并持续到成年。此外，开发 在此期间大脑仍在持续运转，DA系统可能处于危急状态 因接触可卡因而改变。为此，我们对 in vivo 进行了修改和改编 微透析程序使我们能够有效、可靠地回收 DA 来自幼鼠的 NACC。透析过程可以测量 可卡因引起的神经化学变化。目前的研究建议 使用微透析来检查急性、重复或“预期”的影响 青春期前（出生后第 25 天；PND 25）、青春期期间 NAcc 上的可卡因 (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 范式和寻求新奇的行为来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效果 可卡因在这些关键年龄对成人 DA 系统功能的影响。这 拟议研究的主要目标是：首先，确定 PND 25、35、45 和 60 中脑边缘 DA 出现急性、重复或“预期”可卡因 老鼠；第二，建立跨年龄的CPP；第三，衡量猎奇心理 高反应者与低反应者的年龄和 DA 活性差异，最后， 确定青春期关键时期接触可卡因的影响 后来的DA反应性。我们的基本假设是青春期动物 他们对可卡因的反应是独特的，并且在 这次可能会下调这个发育系统的基本功能 但会增加对后续给药的反应性，因此 驱使重复吸毒。拟议的研究将使我们能够检验 可卡因对青春期影响的潜在机制至关重要 为了了解这些过程如何控制启动和维护 可卡因滥用。