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.

Public Health Relevance

Methamphetamine abuse is a debilitating disorder that is often associated with depressive symptoms during abstinence that can, in turn, contribute to relapse. The proposed studies will investigate factors that may contribute to these symptoms including alterations in hippocampal volumes, brain derived neurotrophic factor, and serotonergic function. The findings of the proposed studies will provide important insight into depression associated with methamphetamine use and identify potential therapeutic targets for treatment that may be applicable to not only methamphetamine associated depression, but also depression associated with abstinence from other stimulant drugs of abuse.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32DA033097-01
Application #
8254079
Study Section
Special Emphasis Panel (ZRG1-F02A-J (20))
Program Officer
Avila, Albert
Project Start
2012-04-01
Project End
2015-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
1
Fiscal Year
2012
Total Cost
$52,190
Indirect Cost
Name
University of Utah
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
McFadden, Lisa M; Vieira-Brock, Paula L; Hanson, Glen R et al. (2014) Methamphetamine self-administration attenuates hippocampal serotonergic deficits: role of brain-derived neurotrophic factor. Int J Neuropsychopharmacol 17:1315-20
McFadden, Lisa M; Hanson, Glen R; Fleckenstein, Annette E (2013) The effects of methamphetamine self-administration on cortical monoaminergic deficits induced by subsequent high-dose methamphetamine administrations. Synapse 67:875-81