Original Article | Published:

Methamphetamine Induces Dopamine Release in the Nucleus Accumbens Through a Sigma Receptor-Mediated Pathway

Neuropsychopharmacology volume 43, pages 14051414 (2018) | Download Citation

Abstract

Methamphetamine (METH) is a drug with a high addictive potential that is widely abused across the world. Although it is known that METH dysregulates both dopamine transmission and dopamine reuptake, the specific mechanism of action remains obscure. One promising target of METH is the sigma receptor, a chaperone protein located on the membrane of the endoplasmic reticulum. Using fast-scan cyclic voltammetry, we show that METH-enhancement of evoked dopamine release and basal efflux is dependent on sigma receptor activation. METH-induced activation of sigma receptors results in oxidation of a cysteine residue on VMAT2, which decreases transporter function. Unilateral injections of the sigma receptor antagonist BD-1063 prior to METH administration increased dopamine-related ipsilateral circling behavior, indicating the involvement of sigma receptors. These findings suggest that interactions between METH and the sigma receptor lead to oxidative species (most likely superoxide) that in turn oxidize VMAT2. Altogether, these findings show that the sigma receptor has a key role in METH dysregulation of dopamine release and dopamine-related behaviors.

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References

  1. , , (1995). Drug-induced circling preference in rats. Correlation with monoamine levels. Mol Neurobiol 11: 145–154.

  2. , , , , , (2015). Mitochondria: key players in the neurotoxic effects of amphetamines. Arch Toxicol 89: 1695–1725.

  3. , , , (2009). Regulation and function of selenoproteins in human disease. Biochem J 422: 11–22.

  4. , , , , , (2014). Benomyl, aldehyde dehydrogenase, DOPAL, and the catecholaldehyde hypothesis for the pathogenesis of Parkinson's disease. Chem Res Toxicol 27: 1359–1361.

  5. , , , , , et al (2008). Differential regional effects of methamphetamine on dopamine transport. Eur J Pharmacol 590: 105–110.

  6. , , , (1994). Release of dopamine via the human transporter. Molecular Pharmacology 45: 312–316.

  7. , , , , , (2004). Dopamine release evoked by beta scorpion toxin, tityus gamma, in prefrontal cortical slices is mediated by intracellular calcium stores. Cell Mol Neurobiol 24: 757–767.

  8. , , (2009). Psychostimulant-induced alterations in vesicular monoamine transporter-2 function: neurotoxic and therapeutic implications. Neuropharmacology 56(Suppl 1): 133–138.

  9. , , (1990). Partial purification and characterization of the vacuolar H(+)-ATPase of mammalian synaptic vesicles. J Neurochem 55: 1663–1670.

  10. , , (2014). Is there a role for nitric oxide in methamphetamine-induced dopamine terminal degeneration? Neurotox Res 25: 153–160.

  11. , , , , , et al (2016). Mechanisms of amphetamine action illuminated through optical monitoring of dopamine synaptic vesicles in Drosophila brain. Nat Commun 7: 10652.

  12. , , (2015). The role of SIGMAR1 gene mutation and mitochondrial dysfunction in amyotrophic lateral sclerosis. J Pharmacol Sci 127: 36–41.

  13. , , (2013). Spontaneous inhibitory synaptic currents mediated by a g protein-coupled receptor. Neuron 78: 807–812.

  14. , (2006). Comparison of the monoamine transporters from human and mouse in their sensitivities to psychostimulant drugs. BMC Pharmacol 6: 6.

  15. , , (2011). Nitric oxide donors enhance the frequency dependence of dopamine release in nucleus accumbens. Neuropsychopharmacology 36: 1811–1822.

  16. , , , , (2013). Stimulants as specific inducers of dopamine-independent sigma agonist self-administration in rats. J Pharmacol Exp Ther 347: 20–29.

  17. , , , , , (2013). Oxidative stress status in recently abstinent methamphetamine abusers. Psychiatry Clin Neurosci 67: 92–100.

  18. , , , (2007). A vehicle injection into the right core of the nucleus accumbens both reverses the region-specificity and alters the type of contralateral turning elicited by unilateral stimulation of dopamine D2/D3 and D1 receptors in the left core of the nucleus accumbens. Eur J Pharmacol 577: 64–70.

  19. , , , , , et al (2001a). Methamphetamine-induced dopaminergic neurotoxicity: role of peroxynitrite and neuroprotective role of antioxidants and peroxynitrite decomposition catalysts. Ann N Y Acad Sci 939: 366–380.

  20. , , , , , et al (2001b). Peroxynitrite plays a role in methamphetamine-induced dopaminergic neurotoxicity: evidence from mice lacking neuronal nitric oxide synthase gene or overexpressing copper-zinc superoxide dismutase. J Neurochem 76: 745–749.

  21. , , (2002). Dopamine transporter-mediated conductances increase excitability of midbrain dopamine neurons. Nat Neurosci 5: 971–978.

  22. (1993). Repeated methamphetamine-treatment alters brain sigma receptors. Eur J Pharmacol 230: 243–244.

  23. , , , (2017). A novel GLP-1/GIP dual receptor agonist protects from 6-OHDA lesion in a rat model of Parkinson's disease. Neuropharmacology 117: 238–248.

  24. , , , , , et al (2015). Involvement of reactive oxygen species in cocaine-taking behaviors in rats. Addict Biol 20: 663–675.

  25. , , , , , et al (2017). The role of reactive oxygen species in methamphetamine self-administration and dopamine release in the nucleus accumbens. Addict Biol. 22: 1304–1315.

  26. , , , , , et al (2006). Cognitive function and nigrostriatal markers in abstinent methamphetamine abusers. Psychopharmacology 185: 327–338.

  27. , (2007). Voltammetric characterization of the effect of monoamine uptake inhibitors and releasers on dopamine and serotonin uptake in mouse caudate-putamen and substantia nigra slices. Neuropharmacology 52: 1596–1605.

  28. , , , , , (1998a). Profound neuronal plasticity in response to inactivation of the dopamine transporter. Proc Natl Acad Sci USA 95: 4029–4034.

  29. , , , (1998b). Mechanisms of amphetamine action revealed in mice lacking the dopamine transporter. J Neurosci 18: 1979–1986.

  30. , , , , , et al (1994). Endothelin-3 stimulates inositol 1,4,5-trisphosphate production and Ca2+ influx to produce biphasic dopamine release from rat striatal slices. Cell Mol Neurobiol 14: 271–280.

  31. , , , , , et al (2011) A role for sigma receptors in stimulant self administration and addiction Pharmaceuticals Basel 4: 880–914.

  32. , , , , , et al (2012). AC927, a sigma receptor ligand, blocks methamphetamine-induced release of dopamine and generation of reactive oxygen species in NG108-15 cells. Mol Pharmacol 81: 299–308.

  33. , , , , (1999). Hydroxyl radical formation following methamphetamine administration to rats. Pharmacol Toxicol 85: 133–137.

  34. , , , , , (2004). Amphetamine modulates human incentive processing. Neuron 43: 261–269.

  35. , (1999). Dopamine quinone formation and protein modification associated with the striatal neurotoxicity of methamphetamine: evidence against a role for extracellular dopamine. J Neurosci 19: 1484–1491.

  36. , , , , , et al (2015). Increased vesicular monoamine transporter 2 (VMAT2; Slc18a2) protects against methamphetamine toxicity. ACS Chem Neurosci 6: 790–799.

  37. , , , (2014). Sigma (sigma) receptors as potential therapeutic targets to mitigate psychostimulant effects. Adv Pharmacol 69: 323–386.

  38. , (2009). The pharmacology of sigma-1 receptors. Pharmacol Ther 124: 195–206.

  39. , , , (2015). Prior methamphetamine self-administration attenuates the dopaminergic deficits caused by a subsequent methamphetamine exposure. Neuropharmacology 93: 146–154.

  40. , , , , (2005). Involvement of sigma (sigma) receptors in the acute actions of methamphetamine: receptor binding and behavioral studies. Neuropharmacology 49: 638–645.

  41. , , , (2014). Sigma receptors as potential therapeutic targets for neuroprotection. Eur J Pharmacol 743: 42–47.

  42. , (1993). The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res Brain Res Rev 18: 247–291.

  43. , , , (2006). Protein S-glutathionylation and platelet anti-aggregating activity of disulfiram. Biochem Pharmacol 72: 608–615.

  44. , (2003). Monoamine transporters and psychostimulant drugs. Eur J Pharmacol 479: 23–40.

  45. , (2015). The involvement of the sigma-1 receptor in neurodegeneration and neurorestoration. J Pharmacol Sci 127: 30–35.

  46. , , , (1993). Reevaluation of the two-component hypothesis for turning behaviour by manipulating activities in the striatum and the nucleus accumbens of intact rats. Eur J Pharmacol 237: 161–168.

  47. , , , , (2001). Amphetamine distorts stimulation-dependent dopamine overflow: effects on D2 autoreceptors, transporters, and synaptic vesicle stores. J Neurosci 21: 5916–5924.

  48. , , , , , (2011). In vivo imaging of mitochondrial function in methamphetamine-treated rats. Neuroimage 57: 866–872.

  49. , , , (2014). Biphasic mechanisms of amphetamine action at the dopamine terminal. J Neurosci 34: 5575–5582.

  50. , , , , , (1998). Carrier-mediated release, transport rates, and charge transfer induced by amphetamine, tyramine, and dopamine in mammalian cells transfected with the human dopamine transporter. J Neurochem 71: 1289–1297.

  51. , , , (2014). Oxidative stress and lipid peroxidation in prolonged users of methamphetamine. Drug Metab Lett 7: 79–82.

  52. , , , , , et al (2008). Cocaine disinhibits dopamine neurons in the ventral tegmental area via use-dependent blockade of GABA neuron voltage-sensitive sodium channels. Eur J Neurosci 28: 2028–2040.

  53. , , , , (2010). The sigma-1 receptor chaperone as an inter-organelle signaling modulator. Trends Pharmacol Sci 31: 557–566.

  54. (2011). How addictive drugs disrupt presynaptic dopamine neurotransmission. Neuron 69: 628–649.

  55. , , , (2005). Mechanisms of neurotransmitter release by amphetamines: a review. Prog Neurobiol 75: 406–433.

  56. , , (2014). Glutathione and redox signaling in substance abuse. Biomed Pharmacother 68: 799–807.

  57. , , , , , et al (2014). Total antioxidant capacity is significantly lower in cocaine-dependent and methamphetamine-dependent patients relative to normal controls: results from a preliminary study. Hum Psychopharmacol 29: 537–543.

  58. , (2016). S-glutathionylation and redox protein signaling in drug addiction. Prog Mol Biol Transl Sci 137: 87–121.

  59. , (2000). Intra-accumbens amphetamine increases the conditioned incentive salience of sucrose reward: enhancement of reward "wanting" without enhanced "liking" or response reinforcement. J Neurosci 20: 8122–8130.

  60. , , (2011). Demon voltammetry and analysis software: analysis of cocaine-induced alterations in dopamine signaling using multiple kinetic measures. J Neurosci Methods 202: 158–164.

  61. , , (2017). Cholinergic interneurons underlie spontaneous dopamine release in nucleus accumbens. J Neurosci 37: 2086–2096.

  62. , , , , (2015). Recent advances in methamphetamine neurotoxicity mechanisms and its molecular pathophysiology. Behav Neurol 2015: 103969.

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Acknowledgements

We would like to thank the personnel who contributed to this project, namely Dr. Jacqueline Womersley, Dr. Bryan Blummel, Andrew Perez, Christopher Schow, Gilbert Marchant, Spencer McCarthy, and Mark Woodbury. We would like to dedicate this work in memory of Samuel I. Shin.

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Affiliations

  1. Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah, USA

    • David M Hedges
    •  & Vajira K Weerasekara
  2. Department of Psychology and Neuroscience, Brigham Young University, Provo, UT, USA

    • J Daniel Obray
    • , Jordan T Yorgason
    • , Eun Young Jang
    •  & Scott C Steffensen
  3. Department of Cell and Molecular Pharmacology, Medical University of South Carolina, Charleston, SC, USA

    • Joachim D Uys
  4. Department of Cell and Molecular Biology, University of Hawaii at Manoa, Honolulu, HI, USA

    • Frederick P Bellinger

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Correspondence to Scott C Steffensen.

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DOI

https://doi.org/10.1038/npp.2017.291

Supplementary Information accompanies the paper on the Neuropsychopharmacology website (http://www.nature.com/npp)