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

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.