Adolescence, Impulsivity, and Drug Abuse: Sex/Hormones

描述(由申请人提供)：这个项目的总体目标是使用创新的动物模型来研究作为药物滥用关键易感因素出现的个体差异(冲动、青春期、性别、荷尔蒙状况和对非药物奖励的热衷)。要解决的主要问题是，冲动是青春期的一个决定性特征，是否与青春期(与成年相比)更容易受到药物滥用的脆弱性有关，以及冲动是否与这一发育关键阶段性腺激素的增加有关。冲动的行为模型；例如，延迟折扣(选择小的立即奖励与大延迟的奖励)，以及去/不去任务(在有信号的无奖励与奖励期间的行为抑制)将被使用。其他行为将与冲动测试的结果进行比较，以确定它们是否与冲动行为相同，并具有预测价值；例如，寻求毒品行为的消失和恢复(Ext/Reinst)(复发)。最后，冲动性测量将与毒品(如可卡因、海洛因)和非毒品(如跑轮子和摄入蔗糖)奖励的新奇行为的各种指数有关。以下是与拟议的四个实验相对应的具体目标：1)解决冲动在多大程度上是青少年相对于成年人易受药物滥用影响的主要因素。雄性和雌性青春期和成年大鼠将在组内和组间在两个冲动指标上进行比较，延迟折扣(DD)和食物或静脉注射可卡因的Go/No Go任务。2)调查冲动型青少年是否会因可卡因和食物奖励而使用DD和Go/No-Go程序而成为冲动型成年人。低(Lol)和高(Hil)冲动的男性和女性也将在寻找可卡因行为的Ext/Reinst上进行比较。3)为了确定使用DD或Go/No-Go程序的青少年和成人在冲动和/或药物滥用方面的性别差异是由于循环性腺激素的增加还是先天发育/组织差异，将比较5组：a)去卵巢女性(OVX)，b)去卵巢+雌激素替代(OVX+E)，c)去势男性(CAST)，d)假手术女性(Sham)和e)假男性。4)研究冲动与与冲动相关的因素在预测药物滥用中的关系。大鼠将被选为HIL和LOL(DD和Go/No-Go)，并在其他测量以及其他奖励维持的行为方面进行测试。其他组将被选为因毒品(可卡因、海洛因)和非毒品(跑轮、蔗糖)奖励而强化的行为的高和低组，并对冲动性进行测试，以双向比较对毒品或非药物奖励的冲动性和亲和力。研究吸毒行为中的冲动行为，将有助于我们更好地了解毒品滥用的病因、预防和治疗。

DESCRIPTION (provided by applicant): The overall objective of this project is to use innovative animal models to study individual differences that have emerged as key vulnerability factors in drug abuse (impulsivity, adolescence, sex, hormonal status, and avidity for nondrug rewards). The main question to be addressed is whether impulsivity, a defining characteristic of adolescence, is related to the enhanced vulnerability to drug abuse that is seen more in adolescence (versus adulthood), and whether impulsivity is related to the increase in gonadal hormones that occurs during this critical phase of development. Behavioral models of impulsivity; such as, delay discounting (choosing a small-immediate versus a large-delayed reward), and the Go/No-go task (inhibition of behavior during signaled nonreward versus reward periods) will be used. Other behaviors will be compared to the results of the impulsivity tests to determine whether they covary with impulsive behavior and have predictive value; such as, extinction and reinstatement (Ext/Reinst) of drug-seeking behavior (relapse). Finally, impulsivity measures will be related to various indices of novelty-seeking behavior for drug (e.g., cocaine, heroin) and nondrug (e.g., wheel-running, and sucrose intake) rewards. The following are specific aims that correspond with the four proposed experiments: 1) to address the extent to which impulsivity is a major factor contributing to vulnerability to drug abuse in adolescents versus adults. Male and female adolescent and adult rats will be compared within and between groups on two measures of impulsivity, delay-discounting (DD) and the Go/No- go tasks for food or IV cocaine. 2) To investigate the question of whether impulsive adolescents become impulsive adults using the DD and Go/No-go procedures for cocaine and food rewards. Low (Lol) and high (Hil) impulsive male and female groups will also be compared on Ext/Reinst of cocaine-seeking behavior. 3) To determine whether it is an increase in circulating gonadal hormones or innate developmental/ organizational differences that account for the sex differences in impulsivity and/or drug abuse in adolescents and adults using the DD or Go/No-go procedure, 5 groups will be compared: a) ovariectomized females (OVX), b) OVX with estrogen replacement (OVX + E), c) castrated males (CAST), d) sham-operated females (SHAM) and e) SHAM males. 4) To examine the relationship between impulsivity and factors that covary with impulsivity in predicting drug abuse. Rats will be selected for Hil and Lol (DD and Go/No-go) and tested on the other measure as well as for behavior maintained by other rewards. Other groups will be selected as high and low for behaviors reinforced by drug (cocaine, heroin) and nondrug (wheel-running, sucrose) rewards and tested on measures of impulsivity for a bidirectional comparison of impulsivity and avidity for drugs or nondrug rewards. The study of impulsivity in drug-seeking behavior will increase our understanding of the etiology, prevention, and treatment of drug abuse.