EFFECTS OF ALCOHOL ON MESOACCUMBAL DOPAMINE LEVELS

点击翻译按钮获取中文摘要

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.