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  • Addiction, Drugs
  • Information from Lay-Language Summaries is Embargoed Until the Conclusion of the Scientific Presentation

    157—Drugs of Abuse: Toxicity and Structural Plasticity

    Sunday, November 10, 2013, 8:00 am - 12:00 noon

    157.07: Striatal glial proliferation following methamphetamine-induced dopamine neurotoxicity

    Location: Halls B-H

    *D. M. FRIEND1, C. C. CHAU2, F. G. STRATHMANN3, K. A. KEEFE4;
    1Interdepartmental Program in Neurosci., 3Pathology, 4Interdepartmental Program in Neurosci. and Pharmacol. and Toxicology, 2Univ. of Utah, Salt Lake City, UT

    Abstract Body: Previous work has suggested that a single bolus regimen of methamphetamine (METH) increases the number of proliferating cells in striatum and that some proliferating cells co-localize with beta-III tubulin, suggesting a neuronal fate. However, the identity of these cells has not been clearly elucidated. Also, the extent to which such proliferation is induced simply by exposure to METH or is associated with METH-induced neurotoxicity has not been examined. Data from our lab and others indicate that rats with partial dopamine (DA) loss resulting from prior exposure to METH are resistant to further decreases in striatal DA when re-exposed to METH 30 days later. This experimental paradigm allows for examination of factors associated with METH-induced toxicity in animals matched for acute METH exposure, but differentiated with respect to acute METH-induced neurotoxicity. To this end, rats were pretreated with saline or a neurotoxic regimen of METH at postnatal day (PND)60. Animals recovered for 30 days and were then challenged at PND90 with either METH or saline, resulting in four treatment groups: Saline:Saline, METH:Saline, Saline:METH, and METH:METH. Therefore, the current work examined cellular proliferation (BrdU and Ki67) in striata of animals administered saline or a neurotoxic regimen of METH on postnatal days 60 and/or 90. Our data confirm that rats with prior exposure to a neurotoxic regimen of METH are protected against further DA depletion. Furthermore, consistent with previous work, we found that animals exposed to METH and acutely experiencing toxicity (Saline:METH) showed an increase in striatal proliferation compared to all other treatment groups. Using double-label immunohistochemistry, we determined that a large proportion of the proliferating cells in the Saline:METH treatment group were microglia (CD11b+), with only small proportions of proliferating cells double staining for GFAP (astrocytes) or NeuN (neurons). These results are consistent with previous reports in that we observed an increase in proliferation following METH exposure. However, we extend the current knowledge by demonstrating that a large proportion of these proliferating cells appear to be microglia, suggesting a significant contribution of glial proliferation to the total amount of METH-induced proliferation. Furthermore, we show that the increase in proliferation only occurs in animals exposed to METH and experiencing acute toxicity (Saline:METH) but not in animals exposed to METH and not experiencing acute toxicity (METH:METH) suggesting that microglia reactivity and proliferation parallels METH-induced neurotoxicity.

    Lay Language Summary: Our work demonstrates that exposure to methamphetamine results not only in neuronal damage, but also in important changes to immune cells in the brain known as glia.
    Methamphetamine abuse continues to be a significant public health concern. Recently, other work has shown that individuals with a history of hospitalization for methamphetamine abuse are at greater risk for developing Parkinson’s Disease. Because symptoms of Parkinsonism arise later in life, this observation suggests that methamphetamine exposure results in long-term dopamine damage that may not be fully appreciated until many years later. Therefore, there is a clear need for research determining the mechanism through which methamphetamine damages dopamine systems in order to foster the development of potential therapeutic intervention.
    There is evidence that methamphetamine not only damages neurons, but also alters the function of other cells in the brain called glia. In general there are two kinds of glia, microglia and astrocytes. Microglia and astrocytes are the immune cells of the brain, and their function and structure changes following central nervous system injuries such as stroke, traumatic brain injury, and infection. When astrocytes and microglia change their shape and function we call them reactive. Although it is known that these cells change following methamphetamine exposure, the role that these cells play in long-term methamphetamine-induced dopamine damage is not clear.
    Prior data from our lab has shown that after rats are exposed to methamphetamine, they have less dopamine than healthy rats in a region of the brain known as the striatum. However, when the same rats are re-exposed to methamphetamine 30 days later, their striatal dopamine levels do not decrease further. We can thus compare changes in the brain following a single exposure to methamphetamine, when damage to dopamine neurons occurs, to changes in the brain of animals that were re-exposed to methamphetamine for a second time and do not have further dopamine neuron damage. This approach allows us to determine what factors are related to methamphetamine exposure but not further neuronal damage (animals re-exposed to methamphetamine) and what factors are related to methamphetamine-induced neuronal damage (animals exposed at a single time point). In this context we examined changes in glia in animals experiencing methamphetamine-induced neuronal damage (exposed at a single time point) compared to animals re-exposed to methamphetamine but not undergoing further dopamine neuronal damage (animals re-exposed to methamphetamine) to further characterize how microglia and astrocytes change after methamphetamine exposure, and to answer questions regarding what functions microglia and astrocytes may play in methamphetamine-induced neurotoxicity.
    We found that while astrocytes appear to become reactive and stay reactive for weeks after methamphetamine-induced neuron damage, microglia only become reactive in animals acutely experiencing methamphetamine-induced neuron damage (animals exposed at a single time point). Additionally, we also show that the number of newly born cells increases only in animals experiencing methamphetamine-induced neuron damage (animals exposed at a single time point), and approximately 40 percent of these cells are microglia, suggesting that new microglial cells are born only when methamphetamine-induced neuron damage occurs.
    These results are important because they indicate that methamphetamine not only damages dopamine neurons, but also alters glial function. These data also suggest that microglia may play an important role in methamphetamine-induced neurotoxicity. Additionally, these data suggest that astrocytes could play an important role in the resistance to methamphetamine-induced damage to dopamine neurons that is observed; that is, they may help prevent further damage to neurons in animals re-exposed to methamphetamine. Future studies will use genetic models or specific pharmacological manipulations of these cell types in order to more fully elucidate their role in methamphetamine-induced neurotoxicity.