Advertisement

Neurotoxicity Research

, Volume 34, Issue 1, pp 62–73 | Cite as

The Effects of Quinine on Neurophysiological Properties of Dopaminergic Neurons

  • Li Zou
  • Yingchao Xue
  • Michael Jones
  • Thomas Heinbockel
  • Mingyao Ying
  • Xiping Zhan
ORIGINAL ARTICLE

Abstract

Quinine is an antimalarial drug that is toxic to the auditory system by commonly inducing hearing loss and tinnitus, presumably due to its ototoxic effects on disruption of cochlear hair cells and blockade of ion channels of neurons in the auditory system. To a lesser extent, quinine also causes ataxia, tremor, and dystonic reactions. As dopaminergic neurons are implicated to play a role in all of these diseases, we tested the toxicity of quinine on induced dopaminergic (iDA) neurons derived from human pluripotent stem cells (iPSCs) and primary dopaminergic (DA) neurons of substantia nigra from mice brain slices. Patch clamp recordings and combined drug treatments were performed to examine key physiological properties of the DA neurons. We found that quinine (12.5–200 μM) depolarized the resting membrane potential and attenuated the amplitudes of rebound spikes induced by hyperpolarization. Action potentials were also broadened in spontaneously spiking neurons. In addition to quinine attenuating hyperpolarization-dependent conductance, the tail currents following withdrawal of hyperpolarizing currents were also attenuated. Taken together, we found that iPSC-derived DA neurons recapitulated all the tested physiological properties of human DA neurons, and quinine had distinct effects on the physiology of both iDA and primary DA neurons. This toxicity of quinine may be the underlying mechanism for the movement disorders of cinchonism or quinism and may play a role in tinnitus modulation.

Keywords

Dopaminergic neuron iPS cell Hyperpolarization Quinine 

Abbreviations

ACSF

Artificial cerebrospinal fluid

4-AP

4-Aminopyridine

DA neuron

Dopaminergic neuron

Ih

Hyperpolarization-dependent inward current

iDA neuron

Induced dopaminergic neuron

iPSCs

Induced pluripotent stem cells

ITail

Tail currents

TEA

Tetraethylammonium

TH

Tyrosine hydroxylase

TTX

Tetrodotoxin

Notes

Acknowledgements

This work was supported by the Howard University BFPSAP grant (X.Z.), the Hearing Heath Foundation (X.Z.), Maryland Stem Cell Research Fund (M.Y.), and Latham Trust Fund (T.H.). ML252 were kindly provided by Dr. Craig W. Lindsley (Vanderbilt University).

Compliance with Ethical Standards

The experimental protocols involving human iPSCs were approved by Howard University Institutional Biosafety Committee and Johns Hopkins Medicine Institutional Review Boards. Animal use and experimental protocols were approved by the Institutional Animal Care and Use Committee of the Howard University College of Medicine.

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. Amendola J, Woodhouse A, Martin-Eauclaire MF, Goaillard JM (2012) Ca(2)(+)/cAMP-sensitive covariation of I(A) and I(H) voltage dependences tunes rebound firing in dopaminergic neurons. J Neurosci 32(6):2166–2181.  https://doi.org/10.1523/JNEUROSCI.5297-11.2012 CrossRefPubMedGoogle Scholar
  2. Antonini A, Moresco RM, Gobbo C, De Notaris R, Panzacchi A, Barone P, Calzetti S, Negrotti A, Pezzoli G, Fazio F (2001) The status of dopamine nerve terminals in Parkinson’s disease and essential tremor: a PET study with the tracer [11-C]FE-CIT. Neurol Sci 22(1):47–48.  https://doi.org/10.1007/s100720170040 CrossRefPubMedGoogle Scholar
  3. Atzori M, Kanold PO, Pineda JC, Flores-Hernandez J, Paz RD (2005) Dopamine prevents muscarinic-induced decrease of glutamate release in the auditory cortex. Neuroscience 134(4):1153–1165.  https://doi.org/10.1016/j.neuroscience.2005.05.005 CrossRefPubMedGoogle Scholar
  4. Bikson M, Id Bihi R, Vreugdenhil M, Kohling R, Fox JE, Jefferys JG (2002) Quinine suppresses extracellular potassium transients and ictal epileptiform activity without decreasing neuronal excitability in vitro. Neuroscience 115(1):251–261.  https://doi.org/10.1016/S0306-4522(02)00320-2 CrossRefPubMedGoogle Scholar
  5. Charlton CG, Crowell B Jr (1995) Striatal dopamine depletion, tremors, and hypokinesia following the intracranial injection of S-adenosylmethionine: a possible role of hypermethylation in parkinsonism. Mol Chem Neuropathol 26(3):269–284.  https://doi.org/10.1007/BF02815143 CrossRefPubMedGoogle Scholar
  6. Clement EM, Grahame-Smith DG, Elliott JM (1998) Investigation of the presynaptic effects of quinine and quinidine on the release and uptake of monoamines in rat brain tissue. Neuropharmacology 37(7):945–951.  https://doi.org/10.1016/S0028-3908(98)00075-6 CrossRefPubMedGoogle Scholar
  7. Dirkx MF, den Ouden HE, Aarts E, Timmer MH, Bloem BR, Toni I, Helmich RC (2017) Dopamine controls Parkinson’s tremor by inhibiting the cerebellar thalamus. Brain aww331.  https://doi.org/10.1093/brain/aww331
  8. FDA_Data_Access (2008) QUALAQUIN®, quinine sulfate, [Online] Available from. https://www.accessdatafdagov/drugsatfda_docs/label/2008/021799s008lbl.pdf. Accessed: 19th March 2017
  9. Freedman JE, Weight FF (1989) Quinine potently blocks single K+ channels activated by dopamine D-2 receptors in rat corpus striatum neurons. Eur J Pharmacol 164(2):341–346.  https://doi.org/10.1016/0014-2999(89)90475-5 CrossRefPubMedGoogle Scholar
  10. Gambardella C, Pignatelli A, Belluzzi O (2012) The h-current in the substantia nigra pars compacta neurons: a re-examination. PLoS One 7(12):e52329.  https://doi.org/10.1371/journal.pone.0052329 CrossRefPubMedPubMedCentralGoogle Scholar
  11. Gittelman JX, Perkel DJ, Portfors CV (2013) Dopamine modulates auditory responses in the inferior colliculus in a heterogeneous manner. J Assoc Res Otolaryngol 14(5):719–729.  https://doi.org/10.1007/s10162-013-0405-0 CrossRefPubMedPubMedCentralGoogle Scholar
  12. Glavinovic MI, Trifaro JM (1988) Quinine blockade of currents through Ca2+−activated K+ channels in bovine chromaffin cells. J Physiol 399(1):139–152.  https://doi.org/10.1113/jphysiol.1988.sp017072 CrossRefPubMedPubMedCentralGoogle Scholar
  13. Gopal KV, Gross GW (2004) Unique responses of auditory cortex networks in vitro to low concentrations of quinine. Hear Res 192(1-2):10–22.  https://doi.org/10.1016/j.heares.2004.01.016 CrossRefPubMedGoogle Scholar
  14. Guzman JN, Sanchez-Padilla J, Chan CS, Surmeier DJ (2009) Robust pacemaking in substantia nigra dopaminergic neurons. J Neurosci 29(35):11011–11019.  https://doi.org/10.1523/JNEUROSCI.2519-09.2009 CrossRefPubMedPubMedCentralGoogle Scholar
  15. Imai S, Suzuki T, Sato K, Tokimasa T (1999) Effects of quinine on three different types of potassium currents in bullfrog sympathetic neurons. Neurosci Lett 275(2):121–124.  https://doi.org/10.1016/S0304-3940(99)00775-2 CrossRefPubMedGoogle Scholar
  16. Jarboe JK, Hallworth R (1999) The effect of quinine on outer hair cell shape, compliance and force. Hear Res 132(1-2):43–50.  https://doi.org/10.1016/S0378-5955(99)00031-3 CrossRefPubMedGoogle Scholar
  17. Jastreboff PJ, Brennan JF, Sasaki CT (1991) Quinine-induced tinnitus in rats. Arch Otolaryngol Head Neck Surg 117(10):1162–1166.  https://doi.org/10.1001/archotol.1991.01870220110020 CrossRefPubMedGoogle Scholar
  18. Kim JM, Lee JY, Kim HJ, Kim JS, Kim YK, Park SS, Kim SE, Jeon BS (2010) The wide clinical spectrum and nigrostriatal dopaminergic damage in spinocerebellar ataxia type 6. J Neurol Neurosurg Psychiatry 81(5):529–532.  https://doi.org/10.1136/jnnp.2008.166728 CrossRefPubMedGoogle Scholar
  19. Klueva J, Lima AD, Meis S, Voigt T, Munsch T (2012) Hyperpolarization-activated cation current contributes to spontaneous network activity in developing neocortical cultures. Neurosignals 20(1):35–47.  https://doi.org/10.1159/000330813 CrossRefPubMedGoogle Scholar
  20. Kotani S, Hasegawa J, Meng H, Suzuki T, Sato K, Sakakibara M, Takiguchi M, Tokimasa T (2001) Hyperpolarizing shift by quinine in the steady-state inactivation curve of delayed rectifier-type potassium current in bullfrog sympathetic neurons. Neurosci Lett 300(2):87–90.  https://doi.org/10.1016/S0304-3940(01)01554-3 CrossRefPubMedGoogle Scholar
  21. Koyama S, Appel SB (2006) A-type K+ current of dopamine and GABA neurons in the ventral tegmental area. J Neurophysiol 96(2):544–554.  https://doi.org/10.1152/jn.01318.2005 CrossRefPubMedGoogle Scholar
  22. LaHoste GJ, Wigal T, King BH, Schuck SE, Crinella FM, Swanson JM (2000) Carbamazepine reduces dopamine-mediated behavior in chronic neuroleptic-treated and untreated rats: implications for treatment of tardive dyskinesia and hyperdopaminergic states. Exp Clin Psychopharmacol 8(1):125–132.  https://doi.org/10.1037/1064-1297.8.1.125 CrossRefPubMedGoogle Scholar
  23. Lee CH, MacKinnon R (2017) Structures of the human HCN1 hyperpolarization-activated channel. Cell 168(1-2):111–120.e111.  https://doi.org/10.1016/j.cell.2016.12.023 CrossRefPubMedPubMedCentralGoogle Scholar
  24. Levy F, Swanson JM (2001) Timing, space and ADHD: the dopamine theory revisited. Aust N Z J Psychiatry 35(4):504–511.  https://doi.org/10.1046/j.1440-1614.2001.00923.x CrossRefPubMedGoogle Scholar
  25. Lin X, Chen S, Tee D (1998) Effects of quinine on the excitability and voltage-dependent currents of isolated spiral ganglion neurons in culture. J Neurophysiol 79(5):2503–2512.  https://doi.org/10.1152/jn.1998.79.5.2503 CrossRefPubMedGoogle Scholar
  26. Lopez-Gonzalez MA, Santiago AM, Esteban-Ortega F (2007) Sulpiride and melatonin decrease tinnitus perception modulating the auditolimbic dopaminergic pathway. J Otolaryngol 36(04):213–219.  https://doi.org/10.2310/7070.2007.0018 CrossRefPubMedGoogle Scholar
  27. Mulders WH, Robertson D (2004) Dopaminergic olivocochlear neurons originate in the high frequency region of the lateral superior olive of guinea pigs. Hear Res 187(1-2):122–130.  https://doi.org/10.1016/S0378-5955(03)00308-3 CrossRefPubMedGoogle Scholar
  28. Nimitvilai S, You C, Arora DS, McElvain MA, Vandegrift BJ, Brodie MS, Woodward JJ (2016) Differential effects of toluene and ethanol on dopaminergic neurons of the ventral tegmental area. Front Neurosci 10:434CrossRefPubMedPubMedCentralGoogle Scholar
  29. Ochi K, Eggermont JJ (1997) Effects of quinine on neural activity in cat primary auditory cortex. Hear Res 105(1-2):105–118.  https://doi.org/10.1016/S0378-5955(96)00201-8 CrossRefPubMedGoogle Scholar
  30. Paxinos G, Franklin KBJ (2012) Paxinos and Franklin’s the Mouse Brain in stereotaxic coordinates, 4th Edition. AcademicGoogle Scholar
  31. Pizzagalli DA (2014) Depression, stress, and anhedonia: toward a synthesis and integrated model. Annu Rev Clin Psychol 10(1):393–423.  https://doi.org/10.1146/annurev-clinpsy-050212-185606 CrossRefPubMedPubMedCentralGoogle Scholar
  32. Robinson SK, Viirre ES, Stein MB (2007) Antidepressant therapy in tinnitus. Hear Res 226(1-2):221–231.  https://doi.org/10.1016/j.heares.2006.08.004 CrossRefPubMedGoogle Scholar
  33. Sagal J, Zhan X, Xu J, Tilghman J, Karuppagounder SS, Chen L, Dawson VL, Dawson TM, Laterra J, Ying M (2014) Proneural transcription factor Atoh1 drives highly efficient differentiation of human pluripotent stem cells into dopaminergic neurons. Stem Cells Transl Med 3(8):888–898.  https://doi.org/10.5966/sctm.2013-0213 CrossRefPubMedPubMedCentralGoogle Scholar
  34. Schicknick H, Reichenbach N, Smalla KH, Scheich H, Gundelfinger ED, Tischmeyer W (2012) Dopamine modulates memory consolidation of discrimination learning in the auditory cortex. Eur J Neurosci 35(5):763–774.  https://doi.org/10.1111/j.1460-9568.2012.07994.x CrossRefPubMedGoogle Scholar
  35. Shi L, Bian X, Qu Z, Ma Z, Zhou Y, Wang K, Jiang H, Xie J (2013) Peptide hormone ghrelin enhances neuronal excitability by inhibition of Kv7/KCNQ channels. Nat Commun 4:1435.  https://doi.org/10.1038/ncomms2439 CrossRefPubMedGoogle Scholar
  36. Shi Y, Burchiel KJ, Anderson VC, Martin WH (2009) Deep brain stimulation effects in patients with tinnitus. Otolaryngol Head Neck Surg 141(2):285–287.  https://doi.org/10.1016/j.otohns.2009.05.020 CrossRefPubMedGoogle Scholar
  37. Silamut K, White NJ, Looareesuwan S, Warrell DA (1985) Binding of quinine to plasma proteins in falciparum malaria. Am J Trop Med Hyg 34(4):681–686.  https://doi.org/10.4269/ajtmh.1985.34.681 CrossRefPubMedGoogle Scholar
  38. Sullivan MD, Dobie RA, Sakai CS, Katon WJ (1989) Treatment of depressed tinnitus patients with nortriptyline. Ann Otol Rhinol Laryngol 98(11):867–872.  https://doi.org/10.1177/000348948909801107 CrossRefPubMedGoogle Scholar
  39. Swanson JM, Sunohara GA, Kennedy JL, Regino R, Fineberg E, Wigal T, Lerner M, Williams L, LaHoste GJ, Wigal S (1998) Association of the dopamine receptor D4 (DRD4) gene with a refined phenotype of attention deficit hyperactivity disorder (ADHD): a family-based approach. Mol Psychiatry 3(1):38–41.  https://doi.org/10.1038/sj.mp.4000354 CrossRefPubMedGoogle Scholar
  40. Taylor WR, White NJ (2004) Antimalarial drug toxicity: a review. Drug Saf 27(1):25–61.  https://doi.org/10.2165/00002018-200427010-00003 CrossRefPubMedGoogle Scholar
  41. Thompson AJ, Lochner M, Lummis SC (2007) The antimalarial drugs quinine, chloroquine and mefloquine are antagonists at 5-HT3 receptors. Br J Pharmacol 151(5):666–677.  https://doi.org/10.1038/sj.bjp.0707238 CrossRefPubMedPubMedCentralGoogle Scholar
  42. Wanwimolruk S, Denton JR (1992) Plasma protein binding of quinine: binding to human serum albumin, alpha 1-acid glycoprotein and plasma from patients with malaria. J Pharm Pharmacol 44(10):806–811.  https://doi.org/10.1111/j.2042-7158.1992.tb03210.x CrossRefPubMedGoogle Scholar
  43. White NJ, Looareesuwan S, Warrell DA, Warrell MJ, Bunnag D, Harinasuta T (1982) Quinine pharmacokinetics and toxicity in cerebral and uncomplicated falciparum malaria. Am J Med 73(4):564–572.  https://doi.org/10.1016/0002-9343(82)90337-0 CrossRefPubMedGoogle Scholar
  44. Zheng J, Ren T, Parthasarathi A, Nuttall AL (2001) Quinine-induced alterations of electrically evoked otoacoustic emissions and cochlear potentials in guinea pigs. Hear Res 154(1-2):124–134.  https://doi.org/10.1016/S0378-5955(01)00229-5 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2017

Authors and Affiliations

  1. 1.Department of Physiology and BiophysicsHoward University College of MedicineWashington, DCUSA
  2. 2.Department of Neurology, Hugo W. Moser Research Institute at Kennedy KriegerJohns Hopkins University School of MedicineBaltimoreUSA
  3. 3.Department of AnatomyHoward University College of MedicineWashington, DCUSA

Personalised recommendations