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Epothilone D prevents binge methamphetamine‐mediated loss of striatal dopaminergic markers
Author(s) -
Killinger Bryan A,
Moszczynska Anna
Publication year - 2016
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13391
Subject(s) - meth , methamphetamine , substantia nigra , dopaminergic , dopamine transporter , dopamine , pars compacta , striatum , tyrosine hydroxylase , ventral tegmental area , pharmacology , biology , neuroscience , medicine , chemistry , endocrinology , monomer , organic chemistry , acrylate , polymer
Exposure to binge methamphetamine ( METH ) can result in a permanent or transient loss of dopaminergic ( DA ergic) markers such as dopamine ( DA ), dopamine transporter, and tyrosine hydroxylase ( TH ) in the striatum. We hypothesized that the METH ‐induced loss of striatal DA ergic markers was, in part, due to a destabilization of microtubules ( MT s) in the nigrostriatal DA pathway that ultimately impedes anterograde axonal transport of these markers. To test this hypothesis, adult male Sprague–Dawley rats were treated with binge METH or saline in the presence or absence of epothilone D (EpoD), a MT ‐stabilizing compound, and assessed 3 days after the treatments for the levels of several DA ergic markers as well as for the levels of tubulins and their post‐translational modifications ( PMT s). Binge METH induced a loss of stable long‐lived MT s within the striatum but not within the substantia nigra pars compacta (SNpc). Treatment with a low dose of EpoD increased the levels of markers of stable MT s and prevented METH ‐mediated deficits in several DA ergic markers in the striatum. In contrast, administration of a high dose of EpoD appeared to destabilize MT s and potentiated the METH ‐induced deficits in several DA ergic markers. The low‐dose EpoD also prevented the METH ‐induced increase in striatal DA turnover and increased behavioral stereotypy during METH treatment. Together, these results demonstrate that MT dynamics plays a role in the development of METH ‐induced losses of several DA ergic markers in the striatum and may mediate METH ‐induced degeneration of terminals in the nigrostriatal DA pathway. Our study also demonstrates that MT ‐stabilizing drugs such as EpoD have a potential to serve as useful therapeutic agents to restore function of DA ergic nerve terminals following METH exposure when administered at low doses.Administration of binge methamphetamine (METH) negatively impacts neurotransmission in the nigrostriatal dopamine (DA) system. The effects of METH include decreasing the levels of DAergic markers in the striatum. We have determined that high‐dose METH destabilizes microtubules in this pathway, which is manifested by decreased levels of acetylated (Acetyl) and detyrosinated (Detyr) α‐tubulin (I). A microtubule stabilizing agent epothilone D protects striatal microtubules form the METH‐induced loss of DAergic markers (II). These findings provide a new strategy for protection form METH ‐ restoration of proper axonal transport.