Gender differences in drug abuse

描述（由申请人提供）：女性开始使用可卡因，比男性更早进入治疗，并且在摄入可卡因时比男性更严重。因此，女性从最初使用到依赖的过程比男性要快。这种“伸缩”效应反映了依赖障碍的医学后果和行为/心理因素特征的发展过程较短。所提出的研究是理解在诱导和表达吸毒行为的结构-功能关系以及这种行为在男性和女性中的长期后果的根本重要的第一步。在这个提议中，我们试图确定荷尔蒙和发育事件，产生两性二态上升多巴胺系统，导致药物滥用倾向的性别差异，并确定一些相关的神经过程介导这些性别差异。在大脑的发育过程中，激素会影响大脑的组织，这一过程有两次。在大鼠中，这些发生在围产期和青春期前后。我们提出实验来验证这样的假设，即女性对可卡因滥用的脆弱性增强取决于关键的围产期性腺激素暴露的缺乏，以及随后在青春期周围暴露于卵巢激素。自我给药可卡因将作为主要的结果衡量标准。人类在青春期获得吸毒行为是成年后吸毒问题的一个强有力的预测因素。我们假设，在青春期前后开始的激素暴露有助于增加男性和女性对可卡因治疗的强化和/或长期后果的脆弱性。我们将确定青春期是否是雌性和雄性大鼠对自我使用可卡因的脆弱性增强的时期。另一种可能是，青少年并不是更容易受到精神运动兴奋剂的成瘾特性的影响，而是在青少年时期接触这些药物的长期后果导致成年后对这些药物的易感性增加，这种可能性也将被研究。最后，将通过观察纹状体和伏隔核透析液中的多巴胺来研究组织和发育对可卡因反应性别差异影响的神经基础。这些实验是探索可卡因滥用易感性的性别差异对纹状体和伏隔核影响程度的第一步。女性比男性更容易对可卡因上瘾。该实验将使用临床前模型研究导致药物滥用性别差异的神经发育过程。这个项目的长期目标是基于对成瘾易感性的神经基础的更好理解，为男性和女性制定更好的干预和治疗方案。

DESCRIPTION (provided by applicant): Women begin using cocaine, enter treatment at earlier ages than men, and have more severe cocaine use at intake than men. Thus, women progress from initial use to dependence faster than men do. This "telescoping" effect reflects a briefer time course for the development of medical consequences and behavioral/psychological factors characteristic of a dependence disorder. The studies proposed are a fundamentally important first step towards understanding structure-function relations in the induction and expression of drug-taking behavior and the long-term consequences of this behavior in both males and females. In this proposal we seek to identify the hormonal and developmental events that produce a sexually dimorphic ascending dopamine system that results in sex differences in drug abuse liability, and to identify some of the associated neural processes that mediate these sex differences. There are two times during development of the brain when hormones can influence its organization. In the rat these occur during the peri-natal period and again during the peri-pubertal period. Experiments are proposed to test the hypothesis that the enhanced vulnerability of females for cocaine abuse is dependent on the lack of exposure to gonadal hormones during the critical perinatal period, as well as subsequent exposure to ovarian hormones during the peripubertal period. Self-administration of cocaine will be used as the primary outcome measure. Acquisition of drug taking behavior during adolescence in humans is a strong predictor of drug abuse problems as an adult. We hypothesize that onset of hormone exposure during the peri-pubertal period contributes to increased vulnerability for the reinforcing and/or long-term consequences of cocaine treatment in both males and females. We will determine whether adolescence is a period of enhanced vulnerability for female vs. male rats to self-administer cocaine. Alternatively, it is possible that adolescents aren't more vulnerable to the addictive properties of the psychomotor stimulants, but that the long-term consequences of exposure to these drugs during adolescence result in increased susceptibility as an adult, this possibility will be examined as well. Finally, the neural basis of the organizational and developmental influences on sex differences in the response to cocaine will be examined by looking at dopamine in dialysate from striatum and nucleus accumbens. These experiments are a first step towards exploring the extent that sex differences in vulnerability for cocaine abuse impacts the striatum and nucleus accumbens. Women are more vulnerable to becoming addicted to cocaine than are men. The experiments proposed will investigate the neurodevelopmental processes that contribute to this gender difference in drug abuse using a preclinical model. The long-term goal of this project is to develop better intervention and treatment protocols for both men and women based on an improved understanding of neural basis of vulnerability to addiction.