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

描述（由申请人提供）：大麻（MJ）的使用是普遍的，并有严重的公共卫生后果，包括快速发展到依赖和更大的可能性从事其他危险行为。这对女性尤其重要，因为女性烟民的比例越来越大，而且比男性更容易复吸。目前，MJ吸烟者的治疗选择有限，提高对MJ使用机制的理解以及从MJ使用到依赖的转变是至关重要的。这项拨款提案的总体目标是阐明在非寻求治疗、非依赖MJ的常规使用者中MJ使用过程的性别差异，MJ是一个有很大风险发展成MJ依赖的群体。因此，在男性和女性MJ吸烟者中，我们将使用标准化的心理压力源来测量1)对压力的反应，这是一个经常与药物滥用有关的因素，以及2)压力诱导的MJ自我给药。作为一种概念验证方法，我们将使用鼻内催产素来测试催产素（一种与抑制应激反应有关的激素，对女性可能更有效）是否能减少压力和应激诱导的MJ自我给药。特别是在MJ吸烟者中，我们将通过使用自然的MJ自我给药范式来确定(1)暴露于社会压力源（Trier social stress Test~ TSST）与无压力（No stress Test~ NST）条件下的行为和生理应激反应（Aim 1a）和随后的MJ自我给药（Aim 1b）的性别差异；(2)与安慰剂相比，催产素给药对TSST与NST （Aim 2a）和随后的MJ的行为反应的影响男性自我给药（Aim 2b）与女性（Aim 2c）相比。该项目的研究结果将为MJ吸烟者这一特别危险的群体提供关键信息，以更好地为性别特异性干预措施的发展提供信息。如果催产素能够有效地缓解应激行为反应，将有力地支持我们提出的机制假说，并支持进一步探索应激诱导MJ使用的可能干预技术。这项调查的结果也将为进一步研究MJ使用者以及其他滥用药物的使用者持续使用MJ并发展为依赖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.