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个体差异，这些差异已成为药物滥用的关键脆弱因素（冲动，青春期，性别，激素状态和对非药物奖励的渴望）。要解决的主要问题是，冲动性，青春期的一个定义性特征，是否与更容易在青春期（与成年期相比）看到的药物滥用有关，以及冲动性是否与发生在这一关键发展阶段的性腺激素增加有关。冲动的行为模型例如，延迟折扣（选择小的立即奖励与大的延迟奖励），以及Go/No-go任务（在信号非奖励与奖励期间的行为抑制）将被使用。将其他行为与冲动性测试的结果进行比较，以确定它们是否与冲动行为协变并具有预测价值;例如，寻求药物行为（复发）的消退和恢复（Ext/Reinst）。最后，冲动性测量将与药物新奇寻求行为的各种指数相关（例如，可卡因、海洛因）和非药物（例如，轮跑和蔗糖摄入）奖励。以下是与四项拟议实验相对应的具体目标：1）解决冲动性在多大程度上是青少年与成人相比更容易吸毒的主要因素。将在组内和组间比较雄性和雌性青春期和成年大鼠的冲动性、延迟折扣（DD）和食物或IV可卡因的Go/No-go任务的两个测量值。2)探讨冲动青少年是否会因可卡因和食物奖励而使用DD和Go/No-go程序而成为冲动成年人。低（Lol）和高（Hil）冲动的男性和女性组也将比较可卡因寻求行为的Ext/Reinst。3)为了确定使用DD或Go/No-go程序的青少年和成人中冲动和/或药物滥用的性别差异是否是循环性腺激素增加或先天发育/组织差异所致，将比较5组：a）卵巢切除雌性（OVX），B）OVX+雌激素替代（OVX + E），c）去势雄性（CAST），d）假手术雌性（SHAM）和e）SHAM雄性。4)探讨冲动性与冲动性协变因子在预测药物滥用中的关系。将选择大鼠进行Hil和Lol（DD和Go/No-go），并对其他措施以及其他奖励所维持的行为进行测试。其他组将被选择为高和低的药物（可卡因，海洛因）和非药物（车轮运行，蔗糖）奖励强化的行为，并测试冲动的措施，以双向比较冲动和对药物或非药物奖励的渴望。对觅药行为中冲动性的研究将有助于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.