Post-SSRI Sexual Dysfunction: A Bioelectric Mechanism?
Abstract
Selective serotonin reuptake inhibitor (SSRI) drugs, targeting serotonin transport, are widely used. A puzzling and biomedically important phenomenon concerns the persistent sexual dysfunction following SSRI use seen in some patients. What could be the mechanism of a persistent physiological state brought on by a transient exposure to serotonin transport blockers? In this study, we briefly review the clinical facts concerning this side effect of serotonin reuptake inhibitors and suggest a possible mechanism. Bioelectric circuits (among neural or non-neural cells) could persistently maintain alterations of bioelectric cell properties (resting potential), resulting in long-term changes in electrophysiology and signaling. We present new data revealing this phenomenon in planarian flatworms, in which brief SSRI exposures induce long-lasting changes in resting potential profile. We also briefly review recent data linking neurotransmitter signaling to developmental bioelectrics. Further study of tissue bioelectric memory could enable the design of ionoceutical interventions to counteract side effects of SSRIs and similar drugs.
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References
1. Healy D. Psychiatric Drugs Explained. Edinburgh: Elsevier, 2016.
2. Healy D, Le Noury J, Mangin D. Enduring sexual dysfunction after treatment with antidepressants, 5alpha-reductase inhibitors and isotretinoin: 300 cases. Int J Risk Saf Med 2018;29:125–134.
3. Csoka AB, Shipko S. Persistent sexual side effects after SSRI discontinuation. Psychother Psychosom 2006;75:187–188.
4. Bahrick AS. Post SSRI sexual dysfunction. American Society for the Advancement of Pharmacotherapy Tablet, 2006;7:2-3, 10–11.
5. Healy D. Citizen petition: Sexual side effects of SSRIs and SNRIs. Int J Risk Saf Med 2018;29:135–147.
6. Leiblum SR, Nathan SG. Persistent sexual arousal syndrome: a newly discovered pattern of female sexuality. J Sex Marital Ther 2001;27:365–380.
7. Irwig MS, Kolukula S. Persistent sexual side effects of finasteride for male pattern hair loss. J Sex Med 2011;8:1747–1753.
8. Hogan C, Le Noury J, Healy D, et al. One hundred and twenty cases of enduring sexual dysfunction following treatment. Int J Risk Saf Med 2014;26:109–116.
9. Healy D, Tranter R. Pharmacological stress diathesis syndromes. J Psychopharmacol 1999;13:287–290.
10. Johannesen L, Vicente J, Mason JW, et al. Late sodium current block for drug-induced long QT syndrome: Results from a prospective clinical trial. Clin Pharmacol Ther 2016;99:214–223.
11. Wang GK, Mitchell J, Wang SY. Block of persistent late Na+ currents by antidepressant sertraline and paroxetine. J Membr Biol 2008;222:79–90.
12. Mathews J, Levin M. The body electric 2.0: Recent advances in developmental bioelectricity for regenerative and synthetic bioengineering. Curr Opin Biotechnol 2018;52:134–144.
13. McLaughlin KA, Levin M. Bioelectric signaling in regeneration: Mechanisms of ionic controls of growth and form. Dev Biol 2018;433:177–189.
14. Bates E. Ion channels in development and cancer. Annu Rev Cell Dev Biol 2015;31:231–247.
15. Tuszynski J, Tilli TM, Levin M. Ion channel and neurotransmitter modulators as electroceutical approaches to the control of cancer. Curr Pharm Des 2017;23:4827–4841.
16. Moore D, Walker SI, Levin M. Cancer as a disorder of patterning information: Computational and biophysical perspectives on the cancer problem. Converg Sci Phys Oncol 2017;3:043001.
17. Chernet B, Levin M. Endogenous voltage potentials and the microenvironment: Bioelectric signals that reveal, induce and normalize cancer. J Clin Exp Oncol 2013;Suppl 1:S1-002.
18. Lobikin M, Chernet B, Lobo D, et al. Resting potential, oncogene-induced tumorigenesis, and metastasis: The bioelectric basis of cancer in vivo. Phys Biol 2012;9:065002.
19. Li C, Levin M, Kaplan DL. Bioelectric modulation of macrophage polarization. Sci Rep 2016;6:21044.
20. Sundelacruz S, Levin M, Kaplan DL. Comparison of the depolarization response of human mesenchymal stem cells from different donors. Sci Rep 2015;5:18279.
21. Sundelacruz S, Levin M, Kaplan DL. Role of membrane potential in the regulation of cell proliferation and differentiation. Stem Cell Rev Rep 2009;5:231–246.
22. Sundelacruz S, Levin M, Kaplan DL. Membrane potential controls adipogenic and osteogenic differentiation of mesenchymal stem cells. PLoS One 2008;3:e3737.
23. Urbina A, Godoy-Silva R, Hoyos M, et al. Morphological and electrical disturbances after split-flow fractionation in murine macrophages. J Chromatogr A 2019;1590:104–112.
24. Pare JF, Martyniuk CJ, Levin M. Bioelectric regulation of innate immune system function in regenerating and intact Xenopus laevis. NPJ Regen Med 2017;2:15.
25. Purnell MC, Skrinjar TJ. Bioelectric field enhancement: The influence on membrane potential and cell migration in vitro. Adv Wound Care (New Rochelle) 2016;5:539–545.
26. Abdul Kadir L, Stacey M, Barrett-Jolley R. Emerging roles of the membrane potential: action beyond the action potential. Front Physiol 2018;9:1661.
27. Hayakawa Y, Sakitani K, Konishi M, et al. Nerve growth factor promotes gastric tumorigenesis through aberrant cholinergic signaling. Cancer Cell 2017;31:21–34.
28. Cervera J, Pietak A, Levin M, et al. Bioelectrical coupling in multicellular domains regulated by gap junctions: A conceptual approach. Bioelectrochemistry 2018;123:45–61.
29. Pietak A, Levin M. Bioelectric gene and reaction networks: Computational modelling of genetic, biochemical and bioelectrical dynamics in pattern regulation. J R Soc Interface 2017;14:20170425.
30. Pietak A, Levin M. Exploring instructive physiological signaling with the bioelectric tissue simulation engine (BETSE). Front Bioeng Biotechnol 2016;4:55.
31. Cervera J, Manzanares JA, Mafe S, et al. Synchronization of bioelectric oscillations in networks of nonexcitable cells: From single-cell to multicellular states. J Phys Chem B 2019;123:3924–3934.
32. Pagan OR, Baker D, Deats S, et al. Planarians in pharmacology: Parthenolide is a specific behavioral antagonist of cocaine in the planarian Girardia tigrina. Int J Dev Biol 2012;56:193–196.
33. Pagan OR, Rowlands A, Fattore A, et al. A cembranoid from tobacco prevents the expression of nicotine-induced withdrawal behavior in planarian worms. Eur J Pharmacol 2009;615:118–124.
34. Rowlands AL, Pagan OR. Parthenolide prevents the expression of cocaine-induced withdrawal behavior in planarians. Eur J Pharmacol 2008;583:170–172.
35. Pagan OR, Rowlands A, Azam M, et al. Reversal of cocaine-induced planarian behavior by parthenolide and related sesquiterpene lactones. Pharmacol Biochem Behav 2008;89:160–170.
36. Rawls SM, Gerber K, Ding Z, et al. Agmatine: Identification and inhibition of methamphetamine, kappa opioid, and cannabinoid withdrawal in planarians. Synapse 2008;62:927–934.
37. Rawls SM, Gomez T, Stagliano GW, et al. Measurement of glutamate and aspartate in Planaria. J Pharmacol Toxicol Methods 2006;53:291–295.
38. Oviedo NJ, Morokuma J, Walentek P, et al. Long-range neural and gap junction protein-mediated cues control polarity during planarian regeneration. Dev Biol 2010;339:188–199.
39. Durant F, Bischof J, Fields C, et al. The role of early bioelectric signals in the regeneration of planarian anterior/posterior polarity. Biophys J 2019;116:948–961.
40. Durant F, Morokuma J, Fields C, et al. Long-term, stochastic editing of regenerative anatomy via targeting endogenous bioelectric gradients. Biophys J 2017;112:2231–2243.
41. Liu J, Martinez-Corral R, Prindle A, et al. Coupling between distant biofilms and emergence of nutrient time-sharing. Science 2017;356:638–642.
42. Lee DD, Prindle A, Liu J, et al. SnapShot: Electrochemical communication in biofilms. Cell 2017;170:214–214.e1.
43. Humphries J, Xiong L, Liu J, et al. Species-independent attraction to biofilms through electrical signaling. Cell 2017;168:200–209 e12.
44. Prindle A, Liu J, Asally M, et al. Ion channels enable electrical communication in bacterial communities. Nature 2015;527:59–63.
45. Belus MT, Rogers MA, Elzubeir A, et al. Kir2.1 is important for efficient BMP signaling in mammalian face development. Dev Biol 2018;444(Suppl 1):S297–S307.
46. Smith RS, Kenny CJ, Ganesh V, et al. Sodium channel SCN3A (NaV1.3) regulation of human cerebral cortical folding and oral motor development. Neuron 2018;99:905–913.e7.
47. Bauer CK, Calligari P, Radio FC, et al. Mutations in KCNK4 that affect gating cause a recognizable neurodevelopmental syndrome. Am J Hum Genet 2018;103:621–630.
48. Masotti A, Uva P, Davis-Keppen L, et al. Keppen-Lubinsky Syndrome Is Caused by Mutations in the inwardly rectifying K(+) channel encoded by KCNJ6. Am J Hum Genet 2015;96:295–300.
49. Litan A, Langhans SA. Cancer as a channelopathy: Ion channels and pumps in tumor development and progression. Front Cell Neurosci 2015;9:86.
50. Kortüm F, Caputo V, Bauer CK, et al. Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome. Nat Genet 2015;47:661–667.
51. Côté F, Fligny C, Bayard E, et al. Maternal serotonin is crucial for murine embryonic development. Proc Natl Acad Sci U S A 2007;104:329–334.
52. Ori M, De Lucchini S, Marras G, et al. Unraveling new roles for serotonin receptor 2B in development: Key findings from Xenopus. Int J Dev Biol 2013;57:707–714.
53. Gustafson T, Toneby MI. How genes control morphogenesis. Am Sci 1971;59:452–462.
54. Yuan I, Horng CT, Chen VCH, et al. Escitalopram oxalate inhibits proliferation and migration and induces apoptosis in non-small cell lung cancer cells. Oncol Lett 2018;15:3376–3382.
55. Bonnin A, Torii M, Wang L, et al. Serotonin modulates the response of embryonic thalamocortical axons to netrin-1. Nat Neurosci 2007;10:588–597.
56. Poopalasundaram S, Chambers D, Graham A, et al. Serotonin receptor 1A (HTR1A), a novel regulator of GnRH neuronal migration in chick embryo. Endocrinology 2016;157:4632–4640.
57. Kruk JS, Bermeo S, Skarratt KK, et al. The effect of antidepressants on mesenchymal stem cell differentiation. J Bone Metab 2018;25:43–51.
58. Oleskin AV, Kirovskaia TA, Botvinko IV, et al. Effect of serotonin (5-hydroxytryptamine) on the growth and differentiation of microorganisms [in Russian]. Mikrobiologiia 1998;67:305–312.
59. Maier L, Pruteanu M, Kuhn M, et al. Extensive impact of non-antibiotic drugs on human gut bacteria. Nature 2018;555:623–628.
60. Oswald I, Lewis SA, Dunleavy DLF, et al. Drugs of dependence though not of abuse: Fenfluramine and imipramine. Br Med J 1971;3:70–73.
61. Aldana BI, Sitges M. Sertraline inhibits pre-synaptic Na(+) channel-mediated responses in hippocampus-isolated nerve endings. J Neurochem 2012;121:197–205.
62. Lee HA, Kim KS, Hyun SA, et al. Wide spectrum of inhibitory effects of sertraline on cardiac ion channels. Korean J Physiol Pharmacol 2012;16:327–332.
63. Kim HS, Li H, Kim HW, et al. Selective serotonin reuptake inhibitor sertraline inhibits voltage-dependent K+ channels in rabbit coronary arterial smooth muscle cells. J Biosci 2016;41:659–666.
64. Lee HM, Hahn SJ, Choi BH. Blockade of Kv1.5 channels by the antidepressant drug sertraline. Korean J Physiol Pharmacol 2016;20:193–200.
65. Chan JD, Agbedanu PN, Zamanian M, et al. ‘Death and axes’: Unexpected Ca(2+) entry phenologs predict new anti-schistosomal agents. PLoS Pathog 2014;10:e1003942.
66. Nishimura K., Kitamura Y, Inoue T, et al. Identification and distribution of tryptophan hydroxylase (TPH)-positive neurons in the planarian Dugesia japonica. Neurosci Res 2007;59:101–106.
67. Saitoh O, Yuruzume E, Nakata H. Identification of planarian serotonin receptor by ligand binding and PCR studies. Neuroreport 1996;8:173–178.
68. Creti P, Capasso A, Grasso M, et al. Identification of a 5-HT1A receptor positively coupled to planarian adenylate cyclase. Cell Biol Int Rep 1992;16:427–432.
69. Ofoegbu PU, Lourenço J, Mendo S, et al. Effects of low concentrations of psychiatric drugs (carbamazepine and fluoxetine) on the freshwater planarian, Schmidtea mediterranea. Chemosphere 2019;217:542–549.
70. Cho M, Nayak SU, Jennings T, et al. Predator odor produces anxiety-like behavioral phenotype in planarians that is counteracted by fluoxetine. Physiol Behav 2019;206:181–184.
71. Welsh JH, Williams LD. Monoamine-containing neurons in planaria. J Comp Neurol 1970;138:103–115.
72. Oviedo NJ, Nicolas CL, Adams DS, et al. Live imaging of planarian membrane potential using DiBAC4(3). CSH Protoc 2008;2008:pdb.prot5055.
73. Fields C, Bischof J, Levin M. Morphological coordination: Unifying neural and non-neural signaling. Physiology 2020;35:16–30.
74. Levin M, Buznikov GA, Lauder JM. Of minds and embryos: Left-right asymmetry and the serotonergic controls of pre-neural morphogenesis. Dev Neurosci 2006;28:171–185.
75. Buznikov GA, Peterson RE, Nikitina LA, et al. The pre-nervous serotonergic system of developing sea urchin embryos and larvae: Pharmacologic and immunocytochemical evidence. Neurochem Res 2005;30:825–837.
76. Buznikov G, Shmukler Y, Lauder J. From oocyte to neuron: Do neurotransmitters function in the same way throughout development? Cell Mol Neurobiol 1996;16:537–559.
77. Sullivan KG, Levin M. Neurotransmitter signaling pathways required for normal development in Xenopus laevis embryos: A pharmacological survey screen. J Anat 2016;229:483–502.
78. De Lucchini S, Ori M, Cremisi F, et al. 5-HT2B-mediated serotonin signaling is required for eye morphogenesis in Xenopus. Mol Cell Neurosci 2005;29:299–312.
79. Ghavamabadi RT, Taghipour Z, Hassanipour M, et al. Effect of maternal fluoxetine exposure on lung, heart, and kidney development in rat neonates. Iran J Basic Med Sci 2018;21:417–421.
80. Vichier-Guerre C, Parker M, Pomerantz Y. Impact of selective serotonin reuptake inhibitors on neural crest stem cell formation. Toxicol Lett 2017;281:20–25.
81. Sari Y, Zhou FC/Serotonin and its transporter on proliferation of fetal heart cells. Int J Dev Neurosci 2003;21:417–424.
82. Nebigil CG, Maroteaux L. A novel role for serotonin in heart. Trends Cardiovasc Med 2001;11:329–335.
83. Nebigil CG, Hickel P, Messaddeq N, et al. Ablation of serotonin 5-HT(2B) receptors in mice leads to abnormal cardiac structure and function. Circulation 2001;103:2973–2979.
84. Nebigil CG, Etienne N, Schaerlinger B, et al. Developmentally regulated serotonin 5-HT2B receptors. Int J Dev Neurosci 2001;19:365–372.
85. Yavarone MS, Shuey DL, Tamir H, et al. Serotonin and cardiac morphogenesis in the mouse embryo. Teratology 1993;47:573–584.
86. Shuey DL, Sadler TW, Tamir H, et al. Serotonin and morphogenesis. Transient expression of serotonin uptake and binding protein during craniofacial morphogenesis in the mouse. Anat Embryol 1993;187:75–85.
87. Shuey DL, Yavarone M, Sadler TW, et al. Serotonin and morphogenesis in the cultured mouse embryo. Adv Exp Med Biol 1990;265:205–215.
88. Colas JF, Launay JM, Vonesch JL, et al. Serotonin synchronises convergent extension of ectoderm with morphogenetic gastrulation movements in Drosophila. Mech Dev 1999;87:77–91.
89. Colas JF, Launay JM, Kellermann O, et al. Drosophila 5-HT2 serotonin receptor: Coexpression with fushi-tarazu during segmentation. Proc Natl Acad Sci U S A 1995;92:5441–5445.
90. Fukumoto T, Kema IP, Levin M. Serotonin signaling is a very early step in patterning of the left-right axis in chick and frog embryos. Curr Biol 2005;15:794–803.
91. Fukumoto T, Blakely R, Levin M. Serotonin transporter function is an early step in left-right patterning in chick and frog embryos. Dev Neurosci 2005;27:349–363.
92. Adams DS, Robinson KR, Fukumoto T, et al. Early, H+-V-ATPase-dependent proton flux is necessary for consistent left-right patterning of non-mammalian vertebrates. Development 2006;133:1657–1671.
93. Vandenberg LN, Lemire JM, Levin M. Serotonin has early, cilia-independent roles in Xenopus left-right patterning. Dis Model Mech 2012;6:261–268.
94. Blackiston DJ, Vien K, Levin M. Serotonergic stimulation induces nerve growth and promotes visual learning via posterior eye grafts in a vertebrate model of induced sensory plasticity. NPJ Regen Med 2017;2:8.
95. Lobikin M, Lobo D, Blackiston DJ, et al. Serotonergic regulation of melanocyte conversion: A bioelectrically regulated network for stochastic all-or-none hyperpigmentation. Sci Signal 2015;8:ra99.
96. Blackiston DJ, Anderson GM, Rahman N, et al. A novel method for inducing nerve growth via modulation of host resting potential: Gap junction-mediated and serotonergic signaling mechanisms. Neurotherapeutics 2015;12:170–184.
97. Lobo D, Lobikin M, Levin M. Discovering novel phenotypes with automatically inferred dynamic models: A partial melanocyte conversion in Xenopus. Sci Rep 2017;7:41339.
98. Lobikin M, Paré JF, Kaplan DL, et al. Selective depolarization of transmembrane potential alters muscle patterning and muscle cell localization in Xenopus laevis embryos. Int J Dev Biol 2015;59:303–311.
99. Blackiston D, Adams DS, Lemire JM, et al. Transmembrane potential of GlyCl-expressing instructor cells induces a neoplastic-like conversion of melanocytes via a serotonergic pathway. Dis Model Mech 2011;4:67–85.
100. Nakatani Y, Amano T. Functional modulation of Nav1.2 voltage-gated sodium channels induced by escitalopram. Biol Pharm Bull 2018;41:1471–1474.
101. Hong DH, Li H, Kim HS, et al. The effects of the selective serotonin reuptake inhibitor fluvoxamine on voltage-dependent K(+) channels in rabbit coronary arterial smooth muscle cells. Biol Pharm Bull 2015;38:1208–1213.
102. Hernandez-Diaz S, Levin M. Alteration of bioelectrically-controlled processes in the embryo: A teratogenic mechanism for anticonvulsants. Reprod Toxicol 2014;47:111–114.
103. Norris GT, Kipnis J. Immune cells and CNS physiology: Microglia and beyond. J Exp Med 2019;216:60–70.
104. Lee FJ, Williams KB, Levin M, et al. The bacterial metabolite indole inhibits regeneration of the planarian flatworm Dugesia japonica. iScience 2018;10:135–148.
105. Levin M, Martyniuk CJ. The bioelectric code: An ancient computational medium for dynamic control of growth and form. Biosystems 2018;164:76–93.
106. Tang-Schomer MD, White JD, Tien LW, et al. Bioengineered functional brain-like cortical tissue. Proc Natl Acad Sci U S A 2014;111:13811–13816.
107. Churchill CDM, Winter P, Tuszyunski JA, et al. EDEn—Electroceutical Design Environment: An ion channel database with small molecule modulators and tissue expression information. iScience 2018;11:42–56.
108. Pai VP, Pietak A, Willocq V, et al. HCN2 rescues brain defects by enforcing endogenous voltage pre-patterns. Nat Commun 2018;9:998.
109. Oviedo NJ, Nicolas CL, Adams DS, et al. Establishing and maintaining a colony of planarians. CSH Protoc 2008;2008:pdb.prot5053.
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Bioelectricity
Volume 2 • Issue Number 1 • March 2020
Pages: 7 - 13
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Copyright 2020, Mary Ann Liebert, Inc., publishers.
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Published online: 18 March 2020
Published in print: March 2020
Published ahead of print: 12 December 2019
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All authors wrote the text; J.L. performed the experiments. All authors have reviewed and approved of the article before submission. The article has been submitted solely to this journal and is not published, in press, or submitted elsewhere.
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No competing financial interests exist.
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M.L. and J.L. gratefully acknowledge support by an Allen Discovery Center award from the Paul G. Allen Frontiers Group (No. 12171).
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