Methamphetamine Induced Neuroplasticity and Female Reproductive Health

描述（由申请人提供）：甲基苯丙胺（METH）是一种精神兴奋剂，与女性和男性的性欲和行为增加密切相关。尽管男性和女性同样有可能对METH上瘾或使用METH，但性行为的研究通常集中在男性使用者身上。当人们考虑到甲基苯丙胺与艾滋病毒/艾滋病等性传播疾病和计划外怀孕的高度相关性时，审查甲基苯丙胺对妇女影响的研究很少，这一点令人极为关切。事实上，为什么甲基如此深刻地增加性欲是未知的，据我们所知，相对未被探索。在我们最近的工作中，我们采用啮齿动物模型来研究METH对女性性行为和潜在神经回路的影响。我们发现METH增强了女性的性动机，但这种增强依赖于孕酮。此外，卵巢激素（雌二醇和孕酮）和METH的联合给药增强了内侧杏仁核和下丘脑腹内侧核的神经元激活，这两个脑核与女性性行为有关。因此，本申请的广泛、长期目标是了解介导女性药物-性关系的细胞和分子机制。我们将采用一种新的方法，利用病变技术，选择性地靶向参与介导METH效应的神经元，从而建立它们在药物-性关系中的作用。目前建议的具体目标是（i）确定内侧杏仁核神经元的特定亚群是否负责METH增强女性性动机，（ii）确定METH和卵巢激素是否诱导内侧杏仁核的结构和神经化学可塑性，以及（iii）研究药物-性关系的细胞和分子机制。推进我们对女性性动机和METH使用之间联系的神经生物学的理解的重要性在于，有可能揭示女性成瘾的生物学基础的新基础，这些基础涉及卵巢激素、自然奖励和药物诱导奖励的交叉。

DESCRIPTION (provided by applicant): Methamphetamine (METH) is a psychomotor stimulant that is strongly associated with increases in sexual drive and behavior in both women and men. Even though men and women are equally as likely to be addicted to or use METH, studies of sexual behavior often focus on male users. The paucity in studies examining the effect of METH in women is of great concern, when one considers the high correlation with sexually transmitted diseases such as HIV/AIDS and unplanned pregnancies. In fact, why METH so profoundly increases sexual drive is unknown and, to our knowledge, relatively unexplored. In our recent work, we have employed a rodent model to examine the effects of METH on female sexual behavior and the underlying neural circuitry. We found that METH enhances sexual motivation in females, but this enhancement is dependent upon progesterone. Additionally, the combined administration of ovarian hormones (estradiol and progesterone) and METH enhances the neuronal activation in the medial amygdala and the ventromedial nucleus of the hypothalamus, two brain nuclei implicated in female sexual behaviors. Thus, the broad, long-term objective of the current application is to understand the cellular and molecular mechanisms mediating the drug-sex nexus in females. We will employ a novel approach that utilizes a lesion technique that selectively targets neurons involved in mediating the effects of METH, thus establishing their role in the drug-sex nexus. The specific aims of the current proposal are to (i) establish whether a specific subpopulation of medial amygdala neurons is responsible for METH enhanced female sexual motivation, (ii) determine if METH and ovarian hormones induce structural and neurochemical plasticity in medial amygdala and (iii) investigate the cellular and molecular mechanisms underlying the drug- sex nexus. The significance of advancing our understanding of the neurobiology that links female sexual motivation and METH use is the potential to uncover new foundations for the biological basis of addiction in women that involve the intersection of ovarian hormones, natural reward and drug-induced reward.