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The effects of methamphetamine self-administration on hippocampal serotonergic sy

甲基苯丙胺自我给药对海马血清素能系统的影响

基本信息

批准号：
8450968
负责人：
LISA M MCFADDEN
金额：
$ 5.39万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8450968
关键词：
Abstinence Acute Aftercare Alleles Animals Attention Attenuated Behavior Behavioral Behavioral Symptoms Brain Brain region Brain-Derived Neurotrophic Factor Cell Line Cell Survival Cell Volumes Clinical Data Depressed mood Disease Exhibits Hippocampus (Brain)Human Knock-out Knowledge Lead Link Literature Major Depressive Disorder Mental Depression Messenger RNA Methamphetamine Neurobehavioral Manifestations Patients Pharmacological Treatment Play Predisposition Proteins Psychotropic Drugs Public Health Rattus Relapse Reporting Research Research Personnel Rodent Rodent Model Role Selective Serotonin Reuptake Inhibitor Self Administration Self-Administered Serotonin Symptoms System Testing Time common treatment depressive symptoms drug of abuse insight methamphetamine abuse methamphetamine exposure neurochemistry neurogenesis novel pre-clinical preclinical study research study serotonin transporter skills theories therapeutic target uptake

项目摘要

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.

描述(由申请人提供)：几个因素可能会导致严重的抑郁障碍。这些症状包括但不限于：1)海马区体积缩小(Sheline等人，1999年)；2)脑源性神经营养因子水平降低(BDNF；Dwivedi等人，2010年)；以及3)5-羟色胺转运体异常(SERT；Caspi等人，2003年)。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是人类抑郁症的一种常见治疗方法，它可以增加海马区BDNF水平并减少抑郁症状(Sillaber等人，2008年)。与严重抑郁障碍类似，甲基苯丙胺(冰毒)在人类中的滥用与：1)较小的海马体体积(Thompson等人，2004年)；以及2)禁欲使用者的抑郁症状(Glasner-Edwards等人，2009年)。此外，临床前研究表明，实验者服用冰毒会导致海马区SERT功能和5-羟色胺含量下降(Heh等人，2000年；Cadet等人，2009年)。SERT功能、脑源性神经营养因子、海马体体积和使用冰毒后抑郁症状之间的潜在相互作用几乎没有受到关注。因此，目前的建议将检验这一假设，即自身服用冰毒会降低SERT功能，从而导致海马区BDNF水平的降低。BDNF的这些减少反过来可能导致神经发生和细胞存活率的减少，这可能导致海马体体积的丧失，并增加抑郁症状。值得注意的是，初步数据表明，SERT功能和海马内BDNF的下降都发生在自我注射冰毒短短5天后。这些研究的结果有可能极大地有助于理解与冰毒滥用相关的抑郁症的治疗目标，以及潜在的治疗靶点。