Linked Life Data

18643795

Source:http://linkedlifedata.com/resource/pubmed/id/18643795

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
5
pubmed:dateCreated
2008-9-17
pubmed:abstractText
The vesicular monoamine transporter 2 (VMAT2) controls the loading of dopamine (DA) into vesicles and therefore determines synaptic properties such as quantal size, receptor sensitivity, and vesicular and cytosolic DA concentration. Impairment of proper DA compartmentalization is postulated to underlie the sensitivity of DA neurons to oxidative damage and degeneration. It is known that DA can auto-oxidize in the cytosol to form quinones and other oxidative species and that this production of oxidative stress is thought to be a critical factor in DA terminal loss after methamphetamine (METH) exposure. Using a mutant strain of mice (VMAT2 LO), which have only 5-10% of the VMAT2 expressed by wild-type animals, we show that VMAT2 is a major determinant of METH toxicity in the striatum. Subsequent to METH exposure, the VMAT2 LO mice show an exacerbated loss of dopamine transporter and tyrosine hydroxylase (TH), as well as enhanced astrogliosis and protein carbonyl formation. More importantly, VMAT2 LO mice show massive argyrophilic deposits in the striatum after METH, indicating that VMAT2 is a regulator of METH-induced neurodegeneration. The increased METH neurotoxicity in VMAT2 LO occurs in the absence of any significant difference in basal temperature or METH-induced hyperthermia. Furthermore, primary midbrain cultures from VMAT2 LO mice show more oxidative stress generation and a greater loss of TH positive processes than wild-type cultures after METH exposure. Elevated markers of neurotoxicity in VMAT2 LO mice and cultures suggest that the capacity to store DA determines the amount of oxidative stress and neurodegeneration after METH administration.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
1471-4159
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
106
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2205-17
pubmed:meshHeading
pubmed-meshheading:18643795-Amphetamine-Related Disorders, pubmed-meshheading:18643795-Animals, pubmed-meshheading:18643795-Astrocytes, pubmed-meshheading:18643795-Biological Markers, pubmed-meshheading:18643795-Brain, pubmed-meshheading:18643795-Cell Compartmentation, pubmed-meshheading:18643795-Cells, Cultured, pubmed-meshheading:18643795-Disease Models, Animal, pubmed-meshheading:18643795-Dopamine, pubmed-meshheading:18643795-Dopamine Plasma Membrane Transport Proteins, pubmed-meshheading:18643795-Dopamine Uptake Inhibitors, pubmed-meshheading:18643795-Down-Regulation, pubmed-meshheading:18643795-Fever, pubmed-meshheading:18643795-Gliosis, pubmed-meshheading:18643795-Methamphetamine, pubmed-meshheading:18643795-Mice, pubmed-meshheading:18643795-Mice, Knockout, pubmed-meshheading:18643795-Nerve Degeneration, pubmed-meshheading:18643795-Neurons, pubmed-meshheading:18643795-Oxidative Stress, pubmed-meshheading:18643795-Synaptic Vesicles, pubmed-meshheading:18643795-Vesicular Monoamine Transport Proteins
pubmed:year
2008
pubmed:articleTitle
Reduced vesicular storage of dopamine exacerbates methamphetamine-induced neurodegeneration and astrogliosis.
pubmed:affiliation
Center for Neurodegenerative Disease, Emory University, Atlanta, Georgia, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural