Stress-Induced Marijuana Self-Administration: Role of Sex and Oxytocin

描述（由申请人提供）：使用马兜铃（MJ）是普遍的，并具有严重的公共卫生后果，包括快速发展到依赖和从事其他危险行为的可能性更大。这对女性尤其重要，因为她们在MJ吸烟者中所占的比例越来越大，而且比男性更容易复发。MJ吸烟者的治疗选择目前有限，提高对可能引发MJ使用的机制的理解以及从MJ使用到依赖的过渡至关重要。这项拨款提案的总体目标是阐明介导MJ使用过程中的性别差异，在非寻求治疗，非依赖性MJ的常规用户-一组谁是在发展MJ依赖的风险很大。因此，在男性和女性MJ吸烟者中，我们将测量1）对压力的反应，这是一个经常与药物滥用有关的因素，使用标准化的心理压力源，以及2）压力诱导的MJ自我给药。作为概念验证方法，我们将鼻内（i.n.）催产素，以测试催产素，一种与抑制应激反应有关的激素，在女性中可能更有效，是否会减少应激和应激诱导的MJ自我给药。具体而言，在MJ吸烟者中，我们将确定（1）通过使用自然MJ自我给药范例，与无压力（无压力测试~ NST）条件相比，暴露于社会压力（Trier社会压力测试~ TSST）后行为和生理压力反应（Aim 1a）和随后MJ自我给药（Aim 1b）的性别差异，以及（2）i.n.与安慰剂相比，催产素给药对TSST与NST（目标2a）的行为反应以及随后雄性与雌性（目标2c）相比的MJ自我给药（目标2b）。该项目的结果将为MJ吸烟者这一特别高危群体提供关键信息，以更好地为性别特异性干预措施的发展提供信息。催产素的管理，如果有效地减轻压力的行为反应，将强烈支持我们提出的机制假说，并支持进一步探索可能的干预技术，压力诱导的MJ使用。这项调查的结果也将为进一步研究持续使用MJ和MJ使用者以及其他滥用药物使用者依赖性进展的行为和机制因素奠定重要基础。

DESCRIPTION (provided by applicant): Marijuana (MJ) use is prevalent, and has serious public health consequences, including a fast progression to dependence and a greater likelihood of engaging in other risky behaviors. This is of particular importance to women, who comprise a growing proportion of MJ smokers and are more likely to relapse than men. Treatment options for MJ smokers are currently limited and improved understanding of mechanisms that may trigger MJ use and the transition from MJ use to dependence is critical. The overarching goal of this grant proposal is to elucidate sex differences in processes mediating MJ use in non-treatment seeking, non-dependent regular users of MJ~ a group who is at great risk for developing MJ dependence. Therefore, in male and female MJ smokers, we will measure 1) the response to stress, a factor often implicated in drug abuse, using a standardized psychological stressor, and 2) stress-induced MJ self-administration. As a proof-of-concept approach we will administer intranasal (i.n.) oxytocin to test whether oxytocin, a hormone linked to the inhibition of stress response and potentially more effective in women, decreases stress and stress-induced MJ self-administration. Specifically, in MJ smokers, we will determine (1) sex differences in the behavioral and physiological stress response (Aim 1a) and subsequent MJ self-administration (Aim 1b) after exposure to a social stressor (Trier Social Stress Test~ TSST) compared to a stress-free (No Stress Test~ NST) condition through use of a naturalistic MJ self-administration paradigm~ and (2) the effects of i.n. oxytocin administratio compared with placebo on the behavioral response to TSST vs. NST (Aim 2a) and subsequent MJ self-administration (Aim 2b) in males compared to females (Aim 2c). Findings from this project will provide critical information for this particularly at-risk group of MJ smokers to bettr inform development of sex-specific interventions. Oxytocin administration, if effective in mitigating the behavioral response to stress, would strongly support our proposed mechanistic hypothesis and would support further exploration of possible intervention techniques for stress-induced MJ use. Results from this investigation will also lay critical groundwork for further research of behavioral and mechanistic factors underlying the continued use of MJ and the progression to dependence in MJ users, as well as users of other drugs of abuse.