Molecular footprints of neurotoxic amphetamine action
by
Kuhn DM, Geddes TJ
Department of Psychiatry and Behavioral Neurosciences,
Wayne State University School of Medicine, Detroit,
Michigan 48201, USA.
donald.kuhn@wayne.edu
Ann N Y Acad Sci 2000; 914:92-103

ABSTRACT

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 MDMNA in vivo. Protein-bound ROS or RNS may serve as molecular footprints of neurotoxic amphetamine action.

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A toxic intraneuronal metabolite of serotonin?
Electrophysiological evidence of 5-HT damage
Non-neurotoxic and neurotoxic serotonin-releasers
Ecstasy-induced toxicity and the dopamine transporter
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5-HT, 5-HIAA, norepinephrine, epinephrine and dopamine
Lack of serotonin neurotoxicity after intracerebral Ecstasy microinjection
Molecular and cellular mechanisms of MDMA (Ecstasy)-induced neurotoxicity
No neurotoxicity? Brain serotonin transporter binding in former users of MDMA (Ecstasy)

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