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EFFECTS OF ALCOHOL ON MESOACCUMBAL DOPAMINE LEVELS

酒精对中脑多巴胺水平的影响

基本信息

批准号：
6371477
负责人：
CHERYL L KIRSTEIN
金额：
$ 10.08万
依托单位：
UNIVERSITY OF SOUTH FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-04-01 至 2002-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6371477
关键词：
age difference alcoholism /alcohol abuse behavioral /social science research tag developmental neurobiology dopamine ethanol laboratory rat microdialysis neuropharmacology nucleus accumbens reinforcer

项目摘要

The role of the mesolimbic dopaminergic pathway (specifically the nucleus accumbens septi, NAcc) in reward has been well-documented in ,adult animals. Dnigs of abuse, such as alcohol increase dopamine (DA) levels in the NAcc of adult rats. Similarly, in many studies drug ,expectancy has been shown to increase DA in the adult NAcc. As a result, several studies have implicated this pathway as a potential neural substrate for drug abuse. In humans, drug abuse patterns are often established in adolescence, not adulthood; this is especially true of alcohol. A limited number of studies have examined changes in the NAcc in response to alcohol during development. The establishment of an animal model to study this reward system during early development and 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 this may be critical in elucidating the development of addiction. To this end, we modified and adapted the in vivo micro dialysis procedure to enable us to effectively and reliably recover DA from the NAcc of young rat pups. The dialysis procedure allows measurement of the neurochemical changes resulting from drug administration. The present studies propose to use in vivo micro dialysis to examine: 1. the effects of ethanol on the NAcc in preadolescent rats (postnatal day 25; PND 25) and 2. the function of the mesolimbic pathway in periadolescent (PND 35, 45) and adult animals (PND 60) after repeated ethanol exposure (n=bidaily injections for 4 days at each age) during these different periods of development. The principal goals of these proposed studies are: first, to isolate the dose-response effects of ethanol exposure on the mesolimbic DA pathway in male and female preadolescent rats to determine appropriate low and high doses for use in the repeated administration experiments; second, to examine the acute vs. repeated effects of ethanol on the mesolimbic DA pathway in preadolescent, periadolescent and adult animals; third to see how these processes are altered in periadolescent and adult animals following repeated administration of ethanol during adolescence and adulthood; and fourth to determine the effects of ethanol expectancy on the function of the mesolimbic DA system in preadolescent, pefiadolescent and adult animals. We will examine how this system responds to ethanol administration, how these responses differ between preadolescent, periadolescent and adult animals, and whether drug expectancy following repeated administration is sufficient to elicit the same neurochemical responses (ie., whether there are "expectancy-induced" increases in accumbal DA in response to saline alone after repeated ethanol). These studies will provide insight as to alterations in mesolimbic DA function following repeated exposure during a time when the brain reward system is developing. We have previously reported ethanol-induced increases in DA efflux in the NAcc of preadolescent rats. The proposed studies will allow us to examine the underlying mechanism of ethanol's effects in young animals which is critical in order to understand how these processes control the initiation of drug use. Moreover, we will be able to compare these responses across ages which is critical to understand the mechanisms which may underlie the continued maintenance of ethanol abuse.

中脑边缘多巴胺能通路（特别是核）的作用在成年动物中，奖赏中的NAcc）已经有很好的记录。滥用药物，如酒精，会增加NAcc中的多巴胺（DA）水平。成年大鼠同样，在许多研究药物，预期已被证明，增加成年NAcc中的DA。因此，一些研究表明，这条通路是药物滥用的潜在神经基质。在人类中，药物虐待模式通常在青少年时期建立，而不是成年;这是尤其是酒精。有限数量的研究调查了在发育过程中对酒精的反应。建立一个动物模型来研究这种奖励系统在早期发展和青春期是关键。数据显示，吸毒开始于青春期左右并持续到成年期。此外，大脑的发育仍然是在此期间正在进行，这可能是至关重要的，在阐明成瘾的发展。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 来自幼鼠的NAcc。透析过程允许测量药物给药引起的神经化学变化。本研究建议使用体内微透析来检查：1.的影响乙醇对青春期前大鼠（出生后第25天; PND 25）NAcc的影响; 中边缘通路在青春期前的功能（PND 35，45），重复乙醇暴露后的成年动物（PND 60）（n=注射bidazole 在这些不同的发育时期，每个年龄4天）。的这些拟议研究的主要目标是：首先，分离乙醇暴露对雄性大鼠中脑边缘多巴胺通路的剂量效应和雌性青春期前大鼠，以确定适当的低剂量和高剂量用于重复给药实验;第二，检查急性与酒精对青春期前中脑边缘DA通路的重复作用相比，第三，观察这些过程是如何改变的。在重复给药后的青春期和成年动物中，酒精在青春期和成年期;和第四，以确定影响对中脑边缘DA系统功能的影响青春期前、青春期前和成年动物。我们将研究如何系统对乙醇管理的反应，这些反应在青春期前、青春期前后和成年动物，以及药物预期重复给药后足以引起相同的神经化学反应（即，是否有“预期诱导”的增加在重复乙醇后，对单独的盐水的响应）。这些研究将提供关于中脑边缘DA功能改变的见解，在大脑奖励系统被激活的时候，发展中国家我们以前曾报道乙醇诱导的DA流出增加，在青春期前大鼠的NAcc中。拟议的研究将使我们能够研究乙醇对年轻动物影响的潜在机制，为了理解这些过程如何控制初始化，毒品使用。此外，我们将能够比较不同年龄段的这些反应，这对于理解可能导致继续滥用乙醇。