Adolescence, Impulsivity, and Drug Abuse: Sex/Hormones

描述（由申请人提供）：该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脆弱性因素的个体差异（冲动、青春期、性别、荷尔蒙状况和对非药物奖励的渴望）。要解决的主要问题是，作为青春期的一个决定性特征，冲动是否与青春期（与成年期相比）对药物滥用的脆弱性增强有关，以及冲动是否与性腺激素的增加有关，性腺激素在这个关键的发展阶段发生。冲动行为模型；例如，延迟折扣（选择小即时奖励与大延迟奖励）和Go/No-go任务（在信号无奖励和奖励期间的行为抑制）将被使用。其他行为将与冲动性测试的结果进行比较，以确定它们是否与冲动性行为共变并具有预测价值；例如，药物寻求行为（复发）的消失和恢复（Ext/Reinst）。最后，冲动性测量将与药物（如可卡因、海洛因）和非药物（如跑轮和蔗糖摄入）奖励的各种追求新奇行为指数相关。以下是与四个拟议实验相对应的具体目标：1)解决冲动在多大程度上是导致青少年与成人容易滥用药物的主要因素。雄性和雌性的青春期和成年大鼠将在组内和组间进行冲动性的两项测量，延迟折扣（DD）和对食物或静脉注射可卡因的Go/No- Go任务。2)探讨使用DD和Go/No-go程序获得可卡因和食物奖励后，冲动青少年是否会成为冲动成人。并比较低（Lol）和高（Hil）冲动男性和女性组的可卡因寻求行为的Ext/Reinst。3)为了确定是否是循环性腺激素的增加或先天发育/组织差异导致了使用DD或Go/No-go手术的青少年和成人冲动和/或药物滥用的性别差异，将比较5组：a)卵巢切除的女性（OVX）， b)雌激素替代的OVX （OVX + E), c)阉割的男性（CAST）， d）假手术的女性（SHAM）和E)假手术的男性。4)探讨冲动性与影响冲动性的因素在药物滥用预测中的关系。老鼠将被选择去玩Hil和Lol (DD和Go/No-go)，并在其他测量方法以及其他奖励维持的行为上进行测试。其他组将被选择为药物（可卡因，海洛因）和非药物（跑轮，蔗糖）奖励强化行为的高低，并对冲动性进行测试，以双向比较冲动性和对药物或非药物奖励的渴望。对药物寻求行为中的冲动性的研究将增加我们对药物滥用的病因、预防和治疗的理解。

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.