The effects of methamphetamine self-administration on hippocampal serotonergic sy

描述（由申请人提供）：有几个因素可能导致重度抑郁症。这些包括但不限于：1)海马体积变小（Sheline et al., 1999）；2)脑源性神经营养因子（BDNF; Dwivedi et al., 2010）水平降低；3)血清素转运体异常（SERT; Caspi et al, 2003）。值得注意的是，临床前研究表明，选择性5 -羟色胺再摄取抑制剂（人类抑郁症的常用治疗方法）可增加海马BDNF水平并减轻抑郁症状（Sillaber et al, 2008）。与重度抑郁症类似，人类滥用甲基苯丙胺（冰毒）与：1)海马体积较小有关（Thompson et al., 2004）；2)戒断使用者的抑郁症状（Glasner-Edwards et al., 2009）。此外，临床前研究表明，实验者给药甲基苯丙胺导致海马SERT功能和血清素含量下降（Haughey等人，2000；Cadet等人，2009）。甲基苯丙胺使用后SERT功能、BDNF、海马体积和抑郁症状之间的潜在相互作用很少受到关注。因此，目前的建议将测试自我管理甲基安非他明降低SERT功能的假设，因此，有助于海马内BDNF水平的降低。BDNF的减少反过来可能导致神经发生和细胞存活的减少，这可能导致海马体积的减少，并增加抑郁症状。值得注意的是，初步数据表明，自我给药5天后，SERT功能和海马内BDNF均出现下降。这些研究的结果有可能为理解与冰毒滥用有关的抑郁症的治疗做出重大贡献，并为治疗提供潜在的治疗目标。

DESCRIPTION (provided by applicant): Several factors may contribute to major depressive disorder. These include, but are not limited to: 1) smaller hippocampal volumes (Sheline et al., 1999); 2) decreased levels of brain derived neurotrophic factor (BDNF; Dwivedi et al., 2010); and 3) abnormalities in the serotonin transporter (SERT; Caspi et al, 2003). Of note, preclinical studies indicate that administration of selective serotonin reuptake inhibitors, a common treatment for depression in humans, increase hippocampal BDNF levels and decrease depressive symptoms (Sillaber et al., 2008). Similar to major depressive disorder, methamphetamine (METH) abuse in humans is associated with: 1) smaller hippocampal volumes (Thompson et al., 2004); and 2) depressive symptoms in abstinent users (Glasner-Edwards et al., 2009). Further, preclinical studies have shown experimenter-administered METH leads to decreased hippocampal SERT function and serotonin content (Haughey et al., 2000; Cadet et al., 2009). The potential interaction between SERT function, BDNF, hippocampal volumes, and depressive symptoms after METH use has received little attention. Accordingly, the current proposal will test the hypothesis that the self-administration of METH decreases SERT function and, consequently, contributes to decreases in BDNF levels within the hippocampus. These decreases in BDNF, in turn, may lead to decreases in neurogenesis and cell survival, which may contribute to the loss of hippocampal volume, and increases in depressive symptoms. Of note, preliminary data suggest that both decreases in SERT function and BDNF within the hippocampus occur after as little as 5 d of METH self-administration. The results of these studies have the potential to contribute significantly to the understanding of, an potential therapeutic targets for, the treatment of depression associated with METH abuse.