title: Methamphetamine-induced deficits of brain monoaminergic neuronal markers: distal axotomy or neuronal plasticity.
abstract: We examined the effects of methamphetamine (METH) on monoaminergic (i.e. dopamine and serotonin) axonal markers and glial cell activation in the rat brain. Our findings indicate that the loss of dopamine transporters (DAT), serotonin transporters (5-HTT), vesicular monoamine transporter type-2 (VMAT-2) and glial cell activation induced by METH in the striatum and in the central gray are consistent with a degenerative process. Our novel finding of METH effects on monoaminergic neurons in the central gray may have important implications on METH-induced hyperthermia. In other brain regions examined, DAT and 5-HTT deficits after METH administration were present in the absence of lasting changes in VMAT-2 levels or glial cell activation. Brain regions exhibiting protracted deficits in DAT and/or 5-HTT and VMAT-2 levels also expressed increased levels of [(3)H]-R-PK11195 binding to peripheral benzodiazepine receptors, a quantitative marker of glial cell activation. Immunohistochemical assessment of microglia and astrocytes confirmed the PBR results. Microglia activation was more pronounced than astrocytosis in affected regions in most METH-exposed brains with the exception of a small number of rats that were most severely affected by METH based on loss of body weight. In these rats, both microglia and astrocytes were highly activated and expressed a distinct regional pattern suggestive of widespread brain injury. The reason for the pattern of glial cell activation in this group of rats is not currently known but it may be associated with METH-induced hyperthermia. In summary, our findings suggest two neurotoxic endpoints in the brain of METH-exposed animals. Brain regions exhibiting DAT and 5-HTT deficits that co-localize with decreased VMAT-2 levels and glial cell activation may represent monoaminergic terminal degeneration. However, the DAT and 5-HTT deficits in brain regions lacking a deficit in VMAT-2 and glial cell activation may reflect drug-induced modulation of these plasma membrane proteins.
authors: Molecular Neurotoxicology Laboratory, Department of Environmental Health Sciences, 615 North Wolfe Street, Room W2001, The Johns Hopkins University, Bloomberg School of Public Health, Baltimore, MD 21205, USA. tguilart@jhsph.edu
authors: T R
authors: TR
authors: Guilarte
authors: M K
authors: MK
authors: Nihei
authors: J L
authors: JL
authors: McGlothan
authors: A S
authors: AS
authors: Howard
mesh_terms: D000818:Animals; D019771:Axotomy; D015415:Biomarkers / Q000032:analysis; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000032:analysis / Q000378:metabolism*; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis / Q000378:metabolism; D026901:Membrane Transport Proteins; D008694:Methamphetamine / Q000633:toxicity*; D009457:Neuroglia / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009479:Neuropeptides; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000032:analysis / Q000378:metabolism*; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins
chemical_list: D015415:Biomarkers; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009479:Neuropeptides; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; D012701:Serotonin; D008694:Methamphetamine; D004298:Dopamine