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Molecular Footprints of Neurotoxic Amphetamine Action
Author(s) -
KUHN DONALD M.,
GEDDES TIMOTHY J.
Publication year - 2000
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2000.tb05187.x
Subject(s) - methamphetamine , chemistry , amphetamine , neurotoxicity , meth , tryptophan hydroxylase , reactive nitrogen species , pharmacology , dopamine , reactive oxygen species , mdma , biochemistry , tyrosine hydroxylase , nitric oxide , serotonin , enzyme , toxicity , biology , neuroscience , serotonergic , receptor , monomer , organic chemistry , acrylate , polymer
Methamphetamine (METH) and 3,4‐methylenedioxymethamphetamine (MDMA or Ecstasy) are amphetamine analogs with high abuse potential. These drugs also cause damage to dopamine and serotonin nerve terminals in vivo. The mechanisms by which these drugs cause neurotoxicity are not known, but a great deal of attention has been focused on reactive oxygen species (ROS) and reactive nitrogen species (RNS) as mediators of this toxicity. ROS and RNS have very short biological half‐lives in vivo , and it is virtually impossible to measure them in brain directly. However, ROS and RNS are also characterized by their extreme reactivity with proteins and nucleotides. Tryptophan hydroxylase (TPH) and tyrosine hydroxylase (TH), the initial and rate limiting enzymes in the synthesis of serotonin and dopamine, respectively, are identified targets for the actions of METH and MDMA. Using recombinant forms of these proteins, we have found that nitric oxide, catechol‐quinones, and peroxynitrite, all of which are potentially produced by the neurotoxic amphetamines, covalently modify both TPH and TH. The ROS and RNS cause reductions in catalytic function of these enzymes in a manner that is consistent with the effects of METH and MDMA in vivo. Protein‐bound ROS or RNS may serve as molecular footprints of neurotoxic amphetamine action.