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

描述(由申请人提供)：大麻(MJ)的使用很普遍，并具有严重的公共健康后果，包括迅速发展成依赖和更有可能从事其他危险行为。这对女性尤其重要，她们在MJ吸烟者中所占的比例越来越大，而且比男性更有可能复发。目前对MJ吸烟者的治疗选择有限，对可能引发MJ使用的机制的了解有所改善，从MJ使用过渡到依赖是至关重要的。这项拨款提案的首要目标是阐明在非寻求治疗、非依赖的MJ~a群体中使用MJ的过程中的性别差异，这些群体有很大的MJ依赖发展风险。因此，在男性和女性MJ吸烟者中，我们将使用标准化的心理应激源来测量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自我管理。作为一种概念验证方法，我们将对鼻腔(I.N.)催产素是一种与抑制压力反应有关的激素，对女性来说可能更有效，它是否可以减少压力和压力诱导的MJ自我给药。具体地说，在MJ吸烟者中，我们将通过使用自然主义的MJ自我管理范式来确定(1)暴露在社会应激源(Trier Social Stress Test，TSST)与无压力(No Stress Test，NST)条件下相比，暴露于社会应激源(Trier Social Stress Test，TSST)后的行为和生理应激反应(Aim 1a)和随后的MJ自我管理(Aim 1b)的性别差异。比较催产素和安慰剂对TSST和NST的行为反应(目标2a)，以及随后的MJ自我给药(目标2b)与女性(目标2c)的比较。该项目的研究结果将为这一特别高危的MJ吸烟者群体提供关键信息，以便更好地为制定针对性别的干预措施提供信息。如果催产素在减轻应激的行为反应方面有效，将有力地支持我们提出的机械论假说，并将支持进一步探索可能的应激诱导MJ使用的干预技术。这项调查的结果也将为进一步研究MJ持续使用的行为和机制因素以及MJ使用者和其他滥用药物使用者的依赖进展奠定关键基础。

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.