How does methamphetamine (meth) damage neurons?

Question

Meth is considered to be neurotoxic by forming reactive oxygen species and oxidizing the neurons. But unlike dopamine, which, by the way, is neurotoxic due to ROS induced dopaminergic stress, meth does not have any oxygen atom, and thus cannot be the direct cause of ROS.

So, how exactly does meth exert its neurotoxic effects?

Answer 1

Nice question! I will directly begin with the process through which methamphetamine causes damage to neurons, putting in as much details as are known, and adding appropriate citations wherever required.

Methamphetamine (METH) is known to act by increasing concentration of dopamine in brain¹. When excess of dopamine is produced, it causes oxidative damage to axon terminals². This is because direct oxidation of dopamine leading to quinone formation³, iron-catalyzed dopamine metabolism via Fenton reaction⁴, and metabolism of dopamine by monoamine oxidase-A⁵ contribute to production of superoxide and hydrogen peroxide.

Methamphetamine is known to increase concentration of glutamate. This (supposedly) happens as: high concentration of methamphetamine D₁-mediated striatonigral GABAergic transmission, which in turn activates GABA-A receptors in substantia nigra pars reticulata (SNr), leading to increase in GABAergic nigro-thalamic activity which increases corticostriatal glutamate release⁶ (since I can't explain all those terms in a single answer). Now, excessive glutamate activates the glutamate-activated NMDA and AMPA receptors which, in turn, increases activity of nitric oxide synthase⁷. Activation of nitric oxide synthase generates reactive nitrogen species which create an oxidative stress⁸.

Oxidative stress is further increased because of depletion of antioxidant enzymes due to methamphetamine itself⁹. Now, the oxidative stress has to be manifested somehow. This is done by lipid peroxidation and protein carbonyl formation¹⁰, and also by specific nitration and nitrosylation of proteins important for monoamine synthesis and release, including VMAT-2 and tyrosine & tryptophan hydroxylase^7,11,12. Oxidative modification of these proteins restricts their activity and contributes to their degradation, thus playing a major role in neurotoxicity. Researches substantiate the significant contribution of oxidative stress to the neurotoxicity of substituted amphetamines antioxidant treatments have also been shown to be neuroprotective against the damage produced by methamphetamine or methylenedioxymethamphetamine^13,14,15.

P.S.: oxidative damage is not the only way through which methamphetamine causes neurotoxicity. Other possible ways include altered metabolism¹⁶, damage to mitochondria¹⁷, peripheral organ damage¹⁸ due to oxidative modification of hepatocellular mitochondrial proteins¹⁹, activation of microglia in striatum, cortex and hippocampus²⁰, etc. Also, cannabinoids are known to suppress inflammatory processes and damage during methamphetamine exposure²¹. But since this is out-of-scope for this question, I won't go into their details.

References:

_{1. Cadet JL, Brannock C, Jayanthi S, Krasnova IN (2015). "Transcriptional and epigenetic substrates of methamphetamine addiction and withdrawal: evidence from a long-access self-administration model in the rat". Mol. Neurobiol. 51 (2): 696–717. doi:10.1007/s12035-014-8776-8. PMC 4359351Freely accessible. PMID 24939695.}

_{2. Schmidt CJ, Ritter JK, Sonsalla PK, Hanson GR, Gibb JW. Role of dopamine in the neurotoxic effects of methamphetamine. The Journal of pharmacology and experimental therapeutics. 1985;233:539–544}

_{3. Graham DG. Oxidative pathways for catecholamines in the genesis of neuromelanin and cytotoxic quinones. Molecular pharmacology. 1978;14:633–643}

_{4. Yamamoto BK, Zhu W. The effects of methamphetamine on the production of free radicals and oxidative stress. J Pharmacol Exp Ther. 1998;287:107–114}

_{5. LaVoie MJ, Hastings TG. Dopamine quinone formation and protein modification associated with the striatal neurotoxicity of methamphetamine: evidence against a role for extracellular dopamine. J Neurosci. 1999;19:1484–1491}

_{6. Mark K. A., Soghomonian J.-J., Yamamoto B. K., High-dose methamphetamine acutely activates the striatonigral pathway to increase striatal glutamate and mediate long-term dopamine toxicity. J. Neurosci. 24, 11449–11456 (2004)}

_{7. Eyerman DJ, Yamamoto BK. A rapid oxidation and persistent decrease in the vesicular monoamine transporter 2 after methamphetamine. J Neurochem. 2007;103:1219–1227}

_{8. Imam SZ, Islam F, Itzhak Y, Slikker W, Jr, Ali SF. Prevention of dopaminergic neurotoxicity by targeting nitric oxide and peroxynitrite: implications for the prevention of methamphetamine-induced neurotoxic damage. Annals of the New York Academy of Sciences. 2000;914:157–171}

_{9. Jayanthi S, Ladenheim B, Cadet JL. Methamphetamine-induced changes in antioxidant enzymes and lipid peroxidation in copper/zinc-superoxide dismutase transgenic mice. Annals of the New York Academy of Sciences. 1998;844:92–102}

_{10. Gluck MR, Moy LY, Jayatilleke E, Hogan KA, Manzino L, Sonsalla PK. Parallel increases in lipid and protein oxidative markers in several mouse brain regions after methamphetamine treatment. J Neurochem. 2001;79:152–160}

_{11. Kuhn DM, Aretha CW, Geddes TJ. Peroxynitrite inactivation of tyrosine hydroxylase: mediation by sulfhydryl oxidation, not tyrosine nitration. The Journal of neuroscience : the official journal of the Society for Neuroscience. 1999;19:10289–10294}

_{12. Kuhn DM, Geddes TJ. Peroxynitrite inactivates tryptophan hydroxylase via sulfhydryl oxidation. Coincident nitration of enzyme tyrosyl residues has minimal impact on catalytic activity. The Journal of biological chemistry. 1999;274:29726–29732}

_{13. Gudelsky GA. Effect of ascorbate and cysteine on the 3,4-methylenedioxymethamphetamine-induced depletion of brain serotonin. J Neural Transm. 1996;103:1397–1404}

_{14. Sanchez V, Camarero J, O’Shea E, Green AR, Colado MI. Differential effect of dietary selenium on the long-term neurotoxicity induced by MDMA in mice and rats. Neuropharmacology. 2003;44:449–461}

_{15. Fukami G, Hashimoto K, Koike K, Okamura N, Shimizu E, Iyo M. Effect of antioxidant N-acetyl-L-cysteine on behavioral changes and neurotoxicity in rats after administration of methamphetamine. Brain research. 2004;1016:90–95}

_{16. Pontieri FE, Crane AM, Seiden LS, Kleven MS, Porrino LJ. Metabolic mapping of the effects of intravenous methamphetamine administration in freely moving rats. Psychopharmacology. 1990;102:175–182}

_{17. Burrows KB, Gudelsky G, Yamamoto BK. Rapid and transient inhibition of mitochondrial function following methamphetamine or 3,4-methylenedioxymethamphetamine administration. European journal of pharmacology. 2000;398:11–18}

_{18. Smith DE, Fischer CM. An analysis of 310 cases of acute high-dose methamphetamine toxicity in Haight-Ashbury. Clin Toxicol. 1970;3:117–124}

_{19. Moon KH, Upreti VV, Yu LR, Lee IJ, Ye X, Eddington ND, Veenstra TD, Song BJ. Mechanism of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy)-mediated mitochondrial dysfunction in rat liver. Proteomics. 2008;8:3906–3918}

_{20. Pubill D, Canudas AM, Pallas M, Camins A, Camarasa J, Escubedo E. Different glial response to methamphetamine- and methylenedioxymethamphetamine-induced neurotoxicity. Naunyn-Schmiedeberg’s archives of pharmacology. 2003;367:490–499}

_{21. Yiangou Y, Facer P, Durrenberger P, Chessell IP, Naylor A, Bountra C, Banati RR, Anand P. COX-2, CB2 and P2X7-immunoreactivities are increased in activated microglial cells/macrophages of multiple sclerosis and amyotrophic lateral sclerosis spinal cord. BMC neurology. 2006;6:12}