The Effects of Quinine on Neurophysiological Properties of Dopaminergic Neurons
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.
KeywordsDopaminergic neuron iPS cell Hyperpolarization Quinine
Artificial cerebrospinal fluid
- DA neuron
Hyperpolarization-dependent inward current
- iDA neuron
Induced dopaminergic neuron
Induced pluripotent stem cells
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.
- 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
- 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
- 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
- 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
- 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
- FDA_Data_Access (2008) QUALAQUIN®, quinine sulfate, [Online] Available from. https://www.accessdatafdagov/drugsatfda_docs/label/2008/021799s008lbl.pdf. Accessed: 19th March 2017
- 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
- 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
- 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/10.1037/1064-1218.104.22.168 CrossRefPubMedGoogle Scholar
- Paxinos G, Franklin KBJ (2012) Paxinos and Franklin’s the Mouse Brain in stereotaxic coordinates, 4th Edition. AcademicGoogle Scholar
- 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
- 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
- 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
- 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