Methamphetamine affects cell proliferation in the medial prefrontal cortex: A new niche for toxicity
Introduction
Substance use disorders, particularly, methamphetamine addiction is a significant social, economic, and public health problems worldwide. Clinical studies in humans who were under the influence of moderate to heavy methamphetamine use demonstrated a variety of fronto-cortical-dependent cognitive deficits that could persist for days after abuse (Nestor et al., 2011, Yin et al., 2012, Bernacer et al., 2013), as well as considerable levels of neuro- and glio-toxicity that could not be recovered during abstinence (Morales et al., 2012, Sung et al., 2013, Tong et al., 2014). Therefore, it appears that the neuronal and glial disturbances in the frontal cortex of methamphetamine addicts could contribute to the development and subsequent consequences of methamphetamine addiction, and suggests a potential role of gliogenesis (generation of glial cells from progenitors and precursor cells) in the medial prefrontal cortex (mPFC) in such functional changes (Jentsch et al., 2000, Rhodes et al., 2005).
Recent evidence has shown that some aspects of mPFC gliogenesis could be involved in the altered glioplasticity that underlies methamphetamine addiction. Clinically relevant models of intravenous self-administration of methamphetamine in rodents that produce maladaptive patterns of methamphetamine intake (Kitamura et al., 2006) demonstrate the negative impact on the proliferation and survival of glial progenitors (Mandyam et al., 2007b). Proliferation of progenitors is measured via Ki-67 or 5-bromo-2′-deoxyuridine (BrdU) immunoreactivity. Ki-67 is a transcription factor which is expressed in proliferating progenitors in S, G2, M, and parts of G1 phases of the cell cycle (Gerdes et al., 1984), whereas a single injection of BrdU labels S-phase cells, and the age of the cell at the time of euthanasia determines proliferation, differentiation, and maturation stages; (Eisch and Mandyam, 2007). Self-administration of methamphetamine (42 days of limited (1 h/day: short access (ShA)) or extended access (6 h/day: long access (LgA)) to methamphetamine) decreased (BrdU) labeled cells in the mPFC that were 28-days-old post BrdU injection, suggesting that methamphetamine inhibited the survival and maturation of glial progenitors (Mandyam et al., 2007b). Self-administration of methamphetamine (42 days of limited and extended access) also decreased Ki-67-labeled proliferating cells indicating that methamphetamine inhibits the proliferation of glial progenitors (Mandyam et al., 2007b). Experimenter-delivered and self-administered methamphetamine produces cell death in the mPFC (Prudencio et al., 2002, Kadota and Kadota, 2004, Mandyam et al., 2007b, Abekawa et al., 2008, Abekawa et al., 2011a, Abekawa et al., 2011b, Nakato et al., 2011), which suggests the potential role of cell death in producing the glial disturbance associated with chronic methamphetamine exposure (Mandyam et al., 2007b, Tong et al., 2014). However, it needs to be determined whether methamphetamine-induced inhibition of proliferation occurs at a time frame earlier than 42 days of methamphetamine self-administration as this will allow us to demonstrate that the glial disturbance in the mPFC is relative to the amount of methamphetamine consumed, and whether a reduction in the number of proliferating cells at earlier time points correlates with changes in cell death. Therefore, in this study, we tested the hypothesis that fewer sessions of methamphetamine self-administration differentially affects the number of proliferating cells in the mPFC via Ki-67 labeling and the number of cells in the process of apoptosis via activated caspase-3 labeling over a time course of methamphetamine exposure.
Mechanistic studies demonstrate that the mPFC plays a role in relapse to methamphetamine seeking (Hiranita et al., 2006). Withdrawal from methamphetamine self-administration enhances methamphetamine seeking following priming in animals given extended access (but not limited access) to methamphetamine self-administration, suggesting that the magnitude of methamphetamine seeking is directly related to the amount of intake during prolonged methamphetamine self-administration (Yan et al., 2007, Rogers et al., 2008, Recinto et al., 2012). Furthermore, enhanced methamphetamine seeking following withdrawal correlated with increases in neuronal activation in the mPFC (Recinto et al., 2012). This suggests that alterations in glial plasticity produced by methamphetamine may impact the activation of neurons in the mPFC (Kim et al., 2014). Some recent advances have been made to determine whether withdrawal from methamphetamine differentially influences the proliferation and survival of progenitors in the hippocampus when compared with methamphetamine exposure (Recinto et al., 2012). Emerging evidence demonstrates that withdrawal from methamphetamine enhances proliferation and survival of newly born progenitors in the hippocampus, and enhanced survival of progenitors could be responsible for the enhanced neurogenesis during protracted withdrawal after methamphetamine (or cocaine) self-administration (Noonan et al., 2008, Deschaux et al., 2014, Recinto et al., 2012). However, it needs to be determined whether the increases in the number of progenitors in methamphetamine withdrawn animals are specific to the hippocampus (a region rich in neural progenitors) or is general to the progenitor pool in the brain (e.g. the mPFC, which is rich in glial progenitors). Consequently, in this study, we tested the hypothesis that withdrawal from methamphetamine self-administration alters the number of proliferating cells in the mPFC.
Section snippets
Animals
Surgical and experimental procedures were carried out in strict adherence to the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH publication number 85-23, revised 1996) and approved by the Institutional Animal Care and Use Committee of The Scripps Research Institute. Seventy-seven adult, male Wistar rats (Charles River), weighing 200–250 g at the start of the experiment, were housed two per cage in a temperature-controlled vivarium under a reverse light/dark
Ki-67 labeled cells in the mPFC are actively dividing progenitors
In the mPFC, we expected most of the Ki-67 cells to be actively dividing; the colabeling data of Ki-67 and BrdU fit well with expectations based on previous studies in the granule cell layer of the hippocampus (Dayer et al., 2003, Mandyam et al., 2007a). Qualitative analysis indicates that nearly all (82.3 ± 2.6%) of the Ki-67-labeled cells in the mPFC expressed BrdU 2 h after BrdU injection (Fig. 1b-e), as expected if Ki-67 is expressed by all dividing cells (Scholzen and Gerdes, 2000, Kee et
Discussion
The goal of this study was to determine if fewer sessions of methamphetamine self-administration differentially affected the number of proliferating cells in the mPFC when compared with 42 sessions of methamphetamine in a model of methamphetamine dependence. Consistent with our hypothesis, in the extended access animals, the number of proliferating cells was increased with 4 sessions (LgA-4), unaltered with 13–22 sessions (LgA-13 and -22) and reduced with 42 sessions (LgA-42). Similarly, the
Acknowledgements
This work was supported by National Institute on Drug Abuse Grants DA022473 and DA034140 (C.D.M). We thank Dr. Sunmee Wee (TSRI, Florida) for her assistance with surgery and self-administration behavior. We acknowledge the excellent technical assistance of Drs. Clara Yuan and Patrick Recinto from the College of Pharmacy at the University of California, San Diego; Anjali Samant, Mike Pham, Hanan Jammal, Krisha Begalla, Roxanne Kotzebue and Matthew Soleiman from the independent study program at
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