Pharmacology of dextromethorphan: Relevance to dextromethorphan/quinidine (Nuedexta®) clinical use

Pharmacology and Therapeutics

Volumn 164, Issue , 2016, Pages 170-182

  Taylor, Charles P ^a   Traynelis, Stephen F ^b   Siffert, Joao ^c   Pope, Laura E ^c   Matsumoto, Rae R ^d  

^a CpTaylor Consulting   (United States)

^b EMORY UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c AVANIR PHARMACEUTICALS   (United States)

^d TOURO UNIVERSITY CALIFORNIA   (United States)

Author keywords

Nicotinic receptor; NMDA receptors; Pharmacokinetics; Pseudobulbar affect; Serotonin transporter; Sigma receptor

Indexed keywords

BRAIN RECEPTOR; DEXTROMETHORPHAN; DEXTROMETHORPHAN PLUS QUINIDINE; DEXTRORPHAN; G PROTEIN COUPLED RECEPTOR; N METHYL DEXTRO ASPARTIC ACID RECEPTOR; NICOTINIC RECEPTOR; NICOTINIC RECEPTOR ALPHA3BETA4; NORADRENALIN; SEROTONIN TRANSPORTER; SIGMA 1 OPIATE RECEPTOR; UNCLASSIFIED DRUG; DRUG COMBINATION; QUINIDINE; SIGMA OPIATE RECEPTOR; SIGMA-1 RECEPTOR;

DRUG BLOOD LEVEL; DRUG METABOLISM; DRUG RECEPTOR BINDING; HUMAN; NONHUMAN; PHARMACOKINETICS; PRIORITY JOURNAL; REVIEW; AGONISTS; ANIMAL; DRUG COMBINATION; DRUG EFFECTS; DRUG POTENTIATION; METABOLISM;

ANIMALS; DEXTROMETHORPHAN; DRUG COMBINATIONS; DRUG SYNERGISM; HUMANS; NOREPINEPHRINE; QUINIDINE; RECEPTORS, N-METHYL-D-ASPARTATE; RECEPTORS, NICOTINIC; RECEPTORS, SIGMA; SEROTONIN PLASMA MEMBRANE TRANSPORT PROTEINS;

EID: 84966593333     PISSN: 01637258     EISSN: 1879016X     Source Type: Journal    
DOI: 10.1016/j.pharmthera.2016.04.010     Document Type: Review

References (150)

1. Ahtee, L., Dextromethorphan inhibits 5-hydroxytryptamine uptake by human blood platelets and decreases 5-hydroxyindoleacetic acid content in rat brain. J Pharm Pharmacol 27 (1975), 177–180.
2. Albers, G.W., Saenz, R.E., Moses, J.A. Jr., Tolerability of oral dextromethorphan in patients with a history of brain ischemia. Clin Neuropharmacol 15 (1992), 509–514.
3. Anderson, T.R., Andrew, R.D., Spreading depression: imaging and blockade in the rat neocortical brain slice. J Neurophysiol 88 (2002), 2713–2725.
4. Avanir Pharmaceuticals, Inc, Nuedexta (dextromethorphan hydrobromide and quinidine sulfate) capsules: highlights of prescribing information., 2010 Aliso Viejo, CA https://www.nuedexta.com/pdf/Prescribing%20Information.pdf (Accessed Nov. 14, 2015).
5. Balasuriya, D., Stewart, A.P., Edwardson, J.M., The sigma-1 receptor interacts directly with GluN1 but not GluN2A in the GluN1/GluN2A NMDA receptor. J Neurosci 33 (2013), 18219–18224.
6. Bermack, J.E., Debonnel, G., The role of sigma receptors in depression. J Pharmacol Sci 97 (2005), 317–336.
7. Bernard-Marissal, N., Medard, J.J., Azzedine, H., Chrast, R., Dysfunction in endoplasmic reticulum–mitochondria crosstalk underlies SIGMAR1 loss of function mediated motor neuron degeneration. Brain 138 (2015), 875–890.
8. Blomqvist, O., Hernandez-Avila, C.A., Van Kirk, J., Rose, J.E., Kranzler, H.R., Mecamylamine modifies the pharmacokinetics and reinforcing effects of alcohol. Alcohol Clin Exp Res 26 (2002), 326–331.
9. Bouchard, P., Quirion, R., [3H]1,3-di(2-tolyl)guanidine and [3H](+)pentazocine binding sites in the rat brain: autoradiographic visualization of the putative sigma1 and sigma2 receptor subtypes. Neuroscience 76 (1997), 467–477.
10. Bresink, I., Danysz, W., Parsons, C.G., Mutschler, E., Different binding affinities of NMDA receptor channel blockers in various brain regions — indication of NMDA receptor heterogeneity. Neuropharmacology 34 (1995), 533–540.
11. Brooks, B.R., Thisted, R.A., Appel, S.H., Bradley, W.G., Olney, R.K., Berg, J.E. Group, A.-A. S., Treatment of pseudobulbar affect in ALS with dextromethorphan/quinidine: a randomized trial. Neurology 63 (2004), 1364–1370.
12. Brown, C., Fezoui, M., Selig, W.M., Schwartz, C.E., Ellis, J.L., Antitussive activity of sigma-1 receptor agonists in the guinea-pig. Br J Pharmacol 141 (2004), 233–240.
13. Brynne, L., Bresell, A., Sjogren, N., Effective visualization of integrated knowledge and data to enable informed decisions in drug development and translational medicine. J Transl Med, 11, 2013, 250.
14. Buzzi, M.G., Moskowitz, M.A., Evidence for 5-HT1B/1D receptors mediating the antimigraine effect of sumatriptan and dihydroergotamine. Cephalalgia 11 (1991), 165–168.
15. Campos-Caro, A., Smillie, F.I., Dominguez del Toro, E., Rovira, J.C., Vicente-Agullo, F., Chapuli, J. Criado, M., Neuronal nicotinic acetylcholine receptors on bovine chromaffin cells: cloning, expression, and genomic organization of receptor subunits. J Neurochem 68 (1997), 488–497.
16. Canning, B.J., Mori, N., An essential component to brainstem cough gating identified in anesthetized guinea pigs. FASEB J 24 (2010), 3916–3926.
17. Canoll, P.D., Smith, P.R., Gottesman, S., Musacchio, J.M., Autoradiographic localization of [3H]dextromethorphan in guinea pig brain: allosteric enhancement by ropizine. J Neurosci Res 24 (1989), 311–328.
18. Carpenter, C.L., Marks, S.S., Watson, D.L., Greenberg, D.A., Dextromethorphan and dextrorphan as calcium channel antagonists. Brain Res 439 (1988), 372–375.
19. Catterall, W.A., Molecular properties of a superfamily of plasma-membrane cation channels. Curr Opin Cell Biol 6 (1994), 607–615.
20. Changeux, J.P., Nicotine addiction and nicotinic receptors: lessons from genetically modified mice. Nat Rev Neurosci 11 (2010), 389–401.
21. Chapman, A.G., Meldrum, B.S., Non-competitive N-methyl-D-aspartate antagonists protect against sound-induced seizures in DBA/2 mice. Eur J Pharmacol 166 (1989), 201–211.
22. Chen, Z.R., Somogyi, A.A., Bochner, F., Simultaneous determination of dextromethorphan and three metabolites in plasma and urine using high-performance liquid chromatography with application to their disposition in man. Ther Drug Monit 12 (1990), 97–104.
23. Chen, S.L., Huang, E.Y., Chow, L.H., Tao, P.L., Dextromethorphan differentially affects opioid antinociception in rats. Br J Pharmacol 144 (2005), 400–404.
24. Chevallier, N., Keller, E., Maurice, T., Behavioural phenotyping of knockout mice for the sigma-1 (sigma(1)) chaperone protein revealed gender-related anxiety, depressive-like and memory alterations. J Psychopharmacol 25 (2011), 960–975.
25. Chi, H., de Wit, H., Mecamylamine attenuates the subjective stimulant-like effects of alcohol in social drinkers. Alcohol Clin Exp Res 27 (2003), 780–786.
26. Chou, Y.C., Liao, J.F., Chang, W.Y., Lin, M.F., Chen, C.F., Binding of dimemorfan to sigma-1 receptor and its anticonvulsant and locomotor effects in mice, compared with dextromethorphan and dextrorphan. Brain Res 821 (1999), 516–519.
27. Church, J., Shacklock, J.A., Baimbridge, K.G., Dextromethorphan and phencyclidine receptor ligands: differential effects on K(+)- and NMDA-evoked increases in cytosolic free Ca2 + concentration. Neurosci Lett 124 (1991), 232–234.
28. Codd, E.E., Shank, R.P., Schupsky, J.J., Raffa, R.B., Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception. J Pharmacol Exp Ther 274 (1995), 1263–1270.
29. Cummings, J.L., Lyketsos, C.G., Peskind, E.R., Porsteinsson, A.P., Mintzer, J.E., Scharre, D.W., et al. Effect of dextromethorphan–quinidine on agitation in patients with Alzheimer disease dementia. A randomized clinical trial. JAMA 314 (2015), 1242–1254.
30. Damaj, M.I., Flood, P., Ho, K.K., May, E.L., Martin, B.R., Effect of dextromethorphan and dextrorphan on nicotine and neuronal nicotinic receptors: in vitro and in vivo selectivity. J Pharmacol Exp Ther 312 (2005), 780–785.
31. Danysz, W., Essmann, U., Bresink, I., Wilke, R., Glutamate antagonists have different effects on spontaneous locomotor activity in rats. Pharmacol Biochem Behav 48 (1994), 111–118.
32. Derijks, H.J., Heerdink, E.R., Janknegt, R., De Koning, F.H.P., Olivier, B., Loonen, A.J.M., Egberts, A.C.G., Visualizing pharmacological activities of antidepressants: a novel approach. Open Pharmacol J 2 (2008), 54–62.
33. Dingledine, R., Borges, K., Bowie, D., Traynelis, S.F., The glutamate receptor ion channels. Pharmacol Rev 51 (1999), 7–61.
34. Donaldson, Z.R., Nautiyal, K.M., Ahmari, S.E., Hen, R., Genetic approaches for understanding the role of serotonin receptors in mood and behavior. Curr Opin Neurobiol 23 (2013), 399–406.
35. Dravid, S.M., Erreger, K., Yuan, H., Nicholson, K., Le, P., Lyuboslavsky, P. Traynelis, S.F., Subunit-specific mechanisms and proton sensitivity of NMDA receptor channel block. J Physiol 581 (2007), 107–128.
36. Duedahl, T.H., Dirks, J., Petersen, K.B., Romsing, J., Larsen, N.E., Dahl, J.B., Intravenous dextromethorphan to human volunteers: relationship between pharmacokinetics and anti-hyperalgesic effect. Pain 113 (2005), 360–368.
37. Ehret, G.B., Daali, Y., Chabert, J., Rebsamen, M., Wolff, A., Forster, A. Desmeules, J.A., Influence of CYP2D6 activity on pre-emptive analgesia by the N-methyl-D-aspartate antagonist dextromethorphan in a randomized controlled trial of acute pain. Pain Physician 16 (2013), 45–56.
38. Ferrer-Montiel, A.V., Merino, J.M., Planells-Cases, R., Sun, W., Montal, M., Structural determinants of the blocker binding site in glutamate and NMDA receptor channels. Neuropharmacology 37 (1998), 139–147.
39. Fishback, J.A., Robson, M.J., Xu, Y.T., Matsumoto, R.R., Sigma receptors: potential targets for a new class of antidepressant drug. Pharmacol Ther 127 (2010), 271–282.
40. Fishback, J.A., Rosen, A., Bhat, R., McCurdy, C.R., Matsumoto, R.R., A 96-well filtration method for radioligand binding analysis of sigma receptor ligands. J Pharm Biomed Anal 71 (2012), 157–161.
41. Fisher, R.S., Cysyk, B.J., Lesser, R.P., Pontecorvo, M.J., Ferkany, J.T., Schwerdt, P.R. Gordon, B., Dextromethorphan for treatment of complex partial seizures. Neurology 40 (1990), 547–549.
42. Gaginella, T.S., Bertko, R.J., Kachur, J.F., Effect of dextromethorphan and levomethorphan on gastric emptying and intestinal transit in the rat. J Pharmacol Exp Ther 240 (1987), 388–391.
43. Gao, Z., Milnes, J.T., Choisy, S.C., Leach, M.J., Hancox, J.C., James, A.F., The neuroprotective agent sipatrigine blocks multiple cardiac ion channels and causes triangulation of the ventricular action potential. Clin Exp Pharmacol Physiol 32 (2005), 1088–1096.
44. Glick, S.D., Maisonneuve, I.M., Kitchen, B.A., Fleck, M.W., Antagonism of alpha 3 beta 4 nicotinic receptors as a strategy to reduce opioid and stimulant self-administration. Eur J Pharmacol 438 (2002), 99–105.
45. Goetz, A.S., King, H.K., Ward, S.D., True, T.A., Rimele, T.J., Saussy, D.L. Jr., BMY 7378 is a selective antagonist of the D subtype of alpha 1-adrenoceptors. Eur J Pharmacol 272 (1995), R5–R6.
46. Grady, S.R., Moretti, M., Zoli, M., Marks, M.J., Zanardi, A., Pucci, L. Gotti, C., Rodent habenulo-interpeduncular pathway expresses a large variety of uncommon nAChR subtypes, but only the alpha3beta4* and alpha3beta3beta4* subtypes mediate acetylcholine release. J Neurosci 29 (2009), 2272–2282.
47. Gredal, O., Werdelin, L., Bak, S., Christensen, P.B., Boysen, G., Kristensen, M.O. Jensen, T.S., A clinical trial of dextromethorphan in amyotrophic lateral sclerosis. Acta Neurol Scand 96 (1997), 8–13.
48. Gundlach, A.L., Largent, B.L., Snyder, S.H., Autoradiographic localization of sigma receptor binding sites in guinea pig and rat central nervous system with (+)3H-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine. J Neurosci 6 (1986), 1757–1770.
49. Ha, Y., Saul, A., Tawfik, A., Williams, C., Bollinger, K., Smith, R. Smith, S.B., Late-onset inner retinal dysfunction in mice lacking sigma receptor 1 (sigmaR1). Invest Ophthalmol Vis Sci 52 (2011), 7749–7760.
50. Haiman, G., Pratt, H., Miller, A., Effects of dextromethorphan/quinidine on auditory event-related potentials in multiple sclerosis patients with pseudobulbar affect. J Clin Psychopharmacol 29 (2009), 444–452.
51. Hanner, M., Moebius, F.F., Flandorfer, A., Knaus, H.G., Striessnig, J., Kempner, E., Glossmann, H., Purification, molecular cloning, and expression of the mammalian sigma1-binding site. Proc Natl Acad Sci U S A 93 (1996), 8072–8077.
52. Hardingham, G.E., Bading, H., Synaptic versus extrasynaptic NMDA receptor signalling: implications for neurodegenerative disorders. Nat Rev Neurosci 11 (2010), 682–696.
53. Hashimoto, K., Activation of sigma-1 receptor chaperone in the treatment of neuropsychiatric diseases and its clinical implication. J Pharmacol Sci 127 (2015), 6–9.
54. Hayashi, T., Sigma-1 receptor: the novel intracellular target of neuropsychotherapeutic drugs. J Pharmacol Sci 127 (2015), 2–5.
55. Hayashi, T., Su, T.P., Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca(2 +) signaling and cell survival. Cell 131 (2007), 596–610.
56. Hernandez, S.C., Bertolino, M., Xiao, Y., Pringle, K.E., Caruso, F.S., Kellar, K.J., Dextromethorphan and its metabolite dextrorphan block alpha3beta4 neuronal nicotinic receptors. J Pharmacol Exp Ther, 293, 2000, 962-927.
57. Ilkjaer, S., Bach, L.F., Nielsen, P.A., Wernberg, M., Dahl, J.B., Effect of preoperative oral dextromethorphan on immediate and late postoperative pain and hyperalgesia after total abdominal hysterectomy. Pain 86 (2000), 19–24.
58. Ishibashi, H., Kuwano, K., Takahama, K., Inhibition of the 5-HT(1A) receptor-mediated inwardly rectifying K(+) current by dextromethorphan in rat dorsal raphe neurones. Neuropharmacology 39 (2000), 2302–2308.
59. Ishibashi, H., Eto, K., Arimura, Y., Yamada, J., Hatano, Y., Nishikawa, M. Takahama, K., Inhibition of the serotonin-induced inward current by dextromethorphan in rat nodose ganglion neurons. Brain Res 1097 (2006), 65–70.
60. Jaffe, D.B., Marks, S.S., Greenberg, D.A., Antagonist drug selectivity for radioligand binding sites on voltage-gated and N-methyl-D-aspartate receptor-gated Ca2 + channels. Neurosci Lett 105 (1989), 227–232.
61. Kachur, J.F., Morgan, D.W., Gaginella, T.S., Effect of dextromethorphan on guinea pig ileal contractility in vitro: comparison with levomethorphan, loperamide and codeine. J Pharmacol Exp Ther 239 (1986), 661–667.
62. Kamei, J., Tanihara, H., Igarashi, H., Kasuya, Y., Effects of N-methyl-D-aspartate antagonists on the cough reflex. Eur J Pharmacol 168 (1989), 153–158.
63. Kazis, A., Kimiskidis, V., Niopas, I., Pharmacokinetics of dextromethorphan and dextrorphan in epileptic patients. Acta Neurol Scand 93 (1996), 94–98.
64. Kekuda, R., Prasad, P.D., Fei, Y.J., Leibach, F.H., Ganapathy, V., Cloning and functional expression of the human type 1 sigma receptor (hSigmaR1). Biochem Biophys Res Commun 229 (1996), 553–558.
65. Kelly, T.F., Lieberman, D.Z., The utility of the combination of dextromethorphan and quinidine in the treatment of bipolar II and bipolar NOS. J Affect Disord 167 (2014), 333–335.
66. Kim, H.C., Bing, G., Jhoo, W.K., Kim, W.K., Shin, E.J., Im, D.H. Ko, K.H., Metabolism to dextrorphan is not essential for dextromethorphan's anticonvulsant activity against kainate in mice. Life Sci 72 (2003), 769–783.
67. Kim, J.Y., Kim, J.-Y., Park, S.Y., Jung, W.S., Kwak, H.-J., Effect of low dose ketamine to prevent remifentanil-induced cough: a randomized, double-blind, placebo controlled trial. Korean J Anesthesiol 56 (2009), 624–627.
68. Kimiskidis, V.K., Mirtsou-Fidani, V., Papaioannidou, P.G., Niopas, I., Georgiadis, G., Constadinidis, T.C., Kazis, A.D., A phase I clinical trial of dextromethorphan in intractable partial epilepsy. Methods Find Exp Clin Pharmacol 21 (1999), 673–678.
69. Klein, M., Musacchio, J.M., High affinity dextromethorphan binding sites in guinea pig brain. Effect of sigma ligands and other agents. J Pharmacol Exp Ther 251 (1989), 207–215.
70. 2 + imparts NMDA receptor subtype selectivity to the Alzheimer's drug memantine. J Neurosci 29 (2009), 2774–2779.
71. Kulak, J.M., McIntosh, J.M., Yoshikami, D., Olivera, B.M., Nicotine-evoked transmitter release from synaptosomes: functional association of specific presynaptic acetylcholine receptors and voltage-gated calcium channels. J Neurochem 77 (2001), 1581–1589.
72. Lau, C.G., Zukin, R.S., NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders. Nat Rev Neurosci 8 (2007), 413–426.
73. Lauterbach, E.C., An extension of hypotheses regarding rapid-acting, treatment-refractory, and conventional antidepressant activity of dextromethorphan and dextrorphan. Med Hypotheses 78 (2012), 693–702.
74. Lauterbach, E.C., Cummings, J.L., Kuppuswamy, P.S., Toward a more precise, clinically-informed pathophysiology of pathological laughing and crying. Neurosci Biobehav Rev 37 (2013), 1893–1916.
75. Le Meur, K., Galante, M., Angulo, M.C., Audinat, E., Tonic activation of NMDA receptors by ambient glutamate of non-synaptic origin in the rat hippocampus. J Physiol 580 (2007), 373–383.
76. Lee, J.H., Choi, S.H., Shin, T.J., Lee, B.H., Hwang, S.H., Kim, H.C., Nah, S.Y., Effect of dextromethorphan on human K(v)1.3 channel activity: involvement of C-type inactivation. Eur J Pharmacol 651 (2011), 122–127.
77. Lester, H.A., Miwa, J.M., Srinivasan, R., Psychiatric drugs bind to classical targets within early exocytotic pathways: therapeutic effects. Biol Psychiatry 72 (2012), 907–915.
78. Leveille, F., El Gaamouch, F., Gouix, E., Lecocq, M., Lobner, D., Nicole, O., Buisson, A., Neuronal viability is controlled by a functional relation between synaptic and extrasynaptic NMDA receptors. FASEB J 22 (2008), 4258–4271.
79. Lipton, S.A., Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond. Nat Rev Drug Discov 5 (2006), 160–170.
80. Lutz, J.D., Isoherranen, N., Prediction of relative in vivo metabolite exposure from in vitro data using two model drugs: dextromethorphan and omeprazole. Drug Metab Dispos 40 (2012), 159–168.
81. Mamo, D., Graff, A., Mizrahi, R., Shammi, C.M., Romeyer, F., Kapur, S., Differential effects of aripiprazole on D(2), 5-HT(2), and 5-HT(1A) receptor occupancy in patients with schizophrenia: a triple tracer PET study. Am J Psychiatry 164 (2007), 1411–1417.
82. Martina, M., Turcotte, M.E., Halman, S., Bergeron, R., The sigma-1 receptor modulates NMDA receptor synaptic transmission and plasticity via SK channels in rat hippocampus. J Physiol 578 (2007), 143–157.
83. Maurice, T., Su, T.P., The pharmacology of sigma-1 receptors. Pharmacol Ther 124 (2009), 195–206.
84. Mavlyutov, T.A., Nickells, R.W., Guo, L.W., Accelerated retinal ganglion cell death in mice deficient in the Sigma-1 receptor. Mol Vis 17 (2011), 1034–1043.
85. McLean, S., Weber, E., Autoradiographic visualization of haloperidol-sensitive sigma receptors in guinea-pig brain. Neuroscience 25 (1988), 259–269.
86. McQuay, H.J., Carroll, D., Jadad, A.R., Glynn, C.J., Jack, T., Moore, R.A., Wiffeh, P.J., Dextromethorphan for the treatment of neuropathic pain: a double-blind randomised controlled crossover trial with integral n-of-1 design. Pain 59 (1994), 127–133.
87. Miller, O.H., Yang, L., Wang, C.C., Hargroder, E.A., Zhang, Y., Delpire, E., Hall, B.J., GluN2B-containing NMDA receptors regulate depression-like behavior and are critical for the rapid antidepressant actions of ketamine. Elife, 3, 2014, e03581.
88. Mori, T., Hayashi, T., Su, T.P., Compromising sigma-1 receptors at the endoplasmic reticulum render cytotoxicity to physiologically relevant concentrations of dopamine in a nuclear factor-kappaB/Bcl-2-dependent mechanism: potential relevance to Parkinson's disease. J Pharmacol Exp Ther 341 (2012), 663–671.
89. Musacchio, J.M., Klein, M., Paturzo, J.J., Effects of dextromethorphan site ligands and allosteric modifiers on the binding of (+)-[3H]3-(-3-hydroxyphenyl)-N-(1-propyl)piperidine. Mol Pharmacol 35 (1989), 1–5.
90. Netzer, R., Pflimlin, P., Trube, G., Dextromethorphan blocks N-methyl-D-aspartate-induced currents and voltage-operated inward currents in cultured cortical neurons. Eur J Pharmacol 238 (1993), 209–216.
91. Nguyen, L., Robson, M.J., Healy, J.R., Scandinaro, A.L., Matsumoto, R.R., Involvement of sigma-1 receptors in the antidepressant-like effects of dextromethorphan. PLoS One, 9, 2014, e89985.
92. Nguyen, L., Matsumoto, R.R., Involvement of AMPA receptors in the antidepressant-like effects of dextromethorphan in mice. Behav Brain Res, 2015.
93. Nguyen, L., Lucke-Wold, B.P., Mookerjee, S.A., Cavendish, J.Z., Robson, M.J., Scandinaro, A.L., Matsumoto, R.R., Role of sigma-1 receptors in neurodegenerative diseases. J Pharmacol Sci 127 (2015), 17–29.
94. Oh, S.J., Han, K.S., Park, H., Woo, D.H., Kim, H.Y., Traynelis, S.F., Lee, C.J., Protease activated receptor 1-induced glutamate release in cultured astrocytes is mediated by Bestrophin-1 channel but not by vesicular exocytosis. Mol Brain, 5, 2012, 38.
95. Okamoto, S., Pouladi, M.A., Talantova, M., Yao, D., Xia, P., Ehrnhoefer, D.E. Lipton, S.A., Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin. Nat Med 15 (2009), 1407–1413.
96. Ondo, W.G., Dextromethorphan/quinidine for chorea: an open-label assessment. Clin Neuropharmacol 35 (2012), 53–54.
97. Pabba, M., Wong, A.Y., Ahlskog, N., Hristova, E., Biscaro, D., Nassrallah, W. Bergeron, R., NMDA receptors are upregulated and trafficked to the plasma membrane after sigma-1 receptor activation in the rat hippocampus. J Neurosci 34 (2014), 11325–11338.
98. Pan, Y.X., Mei, J., Xu, J., Wan, B.L., Zuckerman, A., Pasternak, G.W., Cloning and characterization of a mouse sigma1 receptor. J Neurochem 70 (1998), 2279–2285.
99. Panitch, H.S., Thisted, R.A., Smith, R.A., Wynn, D.R., Wymer, J.P., Achiron, A. Psuedobulbar Affect in Multiple Sclerosis Study, G., Randomized, controlled trial of dextromethorphan/quinidine for pseudobulbar affect in multiple sclerosis. Ann Neurol 59 (2006), 780–787.
100. Papouin, T., Oliet, S.H., Organization, control and function of extrasynaptic NMDA receptors. Philos Trans R Soc Lond Ser B Biol Sci, 369, 2014, 20130601.
101. Paquette, M.A., Martinez, A.A., Macheda, T., Meshul, C.K., Johnson, S.W., Berger, S.P., Giuffrida, A., Anti-dyskinetic mechanisms of amantadine and dextromethorphan in the 6-OHDA rat model of Parkinson's disease: role of NMDA vs. 5-HT1A receptors. Eur J Neurosci 36 (2012), 3224–3234.
102. Parsons, C.G., Quack, G., Bresink, I., Baran, L., Przegalinski, E., Kostowski, W. Danysz, W., Comparison of the potency, kinetics and voltage-dependency of a series of uncompetitive NMDA receptor antagonists in vitro with anticonvulsive and motor impairment activity in vivo. Neuropharmacology 34 (1995), 1239–1258.
103. Parsons, C.G., Stoffler, A., Danysz, W., Memantine: a NMDA receptor antagonist that improves memory by restoration of homeostasis in the glutamatergic system — too little activation is bad, too much is even worse. Neuropharmacology 53 (2007), 699–723.
104. Parvizi, J., Anderson, S.W., Martin, C.O., Damasio, H., Damasio, A.R., Pathological laughter and crying: a link to the cerebellum. Brain 124 (2001), 1708–1719.
105. Parvizi, J., Coburn, K.L., Shillcutt, S.D., Coffey, C.E., Lauterbach, E.C., Mendez, M.F., Neuroanatomy of pathological laughing and crying: a report of the American Neuropsychiatric Association Committee on Research. J Neuropsychiatry Clin Neurosci 21 (2009), 75–87.
106. Pike, V.W., PET radiotracers: crossing the blood–brain barrier and surviving metabolism. Trends Pharmacol Sci 30 (2009), 431–440.
107. Pioro, E.P., Brooks, B.R., Cummings, J., Schiffer, R., Thisted, R.A., Wynn, D. Efficacy Results Trial of, A. V. P. i. P. B. A. I, Dextromethorphan plus ultra low-dose quinidine reduces pseudobulbar affect. Ann Neurol 68 (2010), 693–702.
108. Pope, L.E., Khalil, M.H., Berg, J.E., Stiles, M., Yakatan, G.J., Sellers, E.M., Pharmacokinetics of dextromethorphan after single or multiple dosing in combination with quinidine in extensive and poor metabolizers. J Clin Pharmacol 44 (2004), 1132–1142.
109. Pubill, D., Gasulla, D., Sureda, F.X., Camins, A., Pallas, M., Escubedo, E., Camarasa, J., Characterization of [3H]nisoxetine binding in rat vas deferens membranes: modulation by sigma and PCP ligands. Life Sci 62 (1998), 763–773.
110. Purves, D., Augustine, G.J., Fitzpatrick, D., et al. (eds.) Glutamate Receptors. Neuroscience, 2nd ed., 2001, Sinauer Associates, Sunderland (MA) (Available from: http://www.ncbi.nlm.nih.gov/books/NBK10802/).
111. Redwine, K.E., Trujillo, K.A., Effects of NMDA receptor antagonists on acute mu-opioid analgesia in the rat. Pharmacol Biochem Behav 76 (2003), 361–372.
112. Reid, M.S., Mickalian, J.D., Delucchi, K.L., Berger, S.P., A nicotine antagonist, mecamylamine, reduces cue-induced cocaine craving in cocaine-dependent subjects. Neuropsychopharmacology 20 (1999), 297–307.
113. Rivers, N., Horner, B., Possible lethal reaction between Nardil and dextromethorphan. Can Med Assoc J, 103, 1970, 85.
114. Rogers, C., Lemaire, S., Role of the sigma receptor in the inhibition of [3H]-noradrenaline uptake in brain synaptosomes and adrenal chromaffin cells. Br J Pharmacol 103 (1991), 1917–1922.
115. Rose, J.E., Behm, F.M., Westman, E.C., Levin, E.D., Stein, R.M., Ripka, G.V., Mecamylamine combined with nicotine skin patch facilitates smoking cessation beyond nicotine patch treatment alone. Clin Pharmacol Ther 56 (1994), 86–99.
116. Ruscher, K., Wieloch, T., The involvement of the sigma-1 receptor in neurodegeneration and neurorestoration. J Pharmacol Sci 127 (2015), 30–35.
117. Sabino, V., Cottone, P., Parylak, S.L., Steardo, L., Zorrilla, E.P., Sigma-1 receptor knockout mice display a depressive-like phenotype. Behav Brain Res 198 (2009), 472–476.
118. Sah, P., Hestrin, S., Nicoll, R.A., Tonic activation of NMDA receptors by ambient glutamate enhances excitability of neurons. Science 246 (1989), 815–818.
119. Sanberg, P.R., Shytle, R.D., Silver, A.A., Treatment of Tourette's syndrome with mecamylamine. Lancet 352 (1998), 705–706.
120. Seth, P., Fei, Y.J., Li, H.W., Huang, W., Leibach, F.H., Ganapathy, V., Cloning and functional characterization of a sigma receptor from rat brain. J Neurochem 70 (1998), 922–931.
121. Sha, S., Hong, J., Qu, W.J., Lu, Z.H., Li, L., Yu, W.F., Chen, L., Sex-related neurogenesis decrease in hippocampal dentate gyrus with depressive-like behaviors in sigma-1 receptor knockout mice. Eur Neuropsychopharmacol 25 (2015), 1275–1286.
122. Shaibani, A.I., Pope, L.E., Thisted, R., Hepner, A., Efficacy and safety of dextromethorphan/quinidine at two dosage levels for diabetic neuropathic pain: a double-blind, placebo-controlled, multicenter study. Pain Med 13 (2012), 243–254.
123. Shin, E.J., Nah, S.Y., Kim, W.K., Ko, K.H., Jhoo, W.K., Lim, Y.K. Kim, H.C., The dextromethorphan analog dimemorfan attenuates kainate-induced seizures via sigma1 receptor activation: comparison with the effects of dextromethorphan. Br J Pharmacol 144 (2005), 908–918.
124. Shin, E.J., Nah, S.Y., Chae, J.S., Bing, G., Shin, S.W., Yen, T.P. Kim, H.C., Dextromethorphan attenuates trimethyltin-induced neurotoxicity via sigma1 receptor activation in rats. Neurochem Int 50 (2007), 791–799.
125. Silver, A.A., Shytle, R.D., Sheehan, K.H., Sheehan, D.V., Ramos, A., Sanberg, P.R., Multicenter, double-blind, placebo-controlled study of mecamylamine monotherapy for Tourette's disorder. J Am Acad Child Adolesc Psychiatry 40 (2001), 1103–1110.
126. Sinclair, J.G., Dextromethorphan–monoamine oxidase inhibitor interaction in rabbits. J Pharm Pharmacol 25 (1973), 803–808.
127. Sovner, R., Wolfe, J., Interaction between dextromethorphan and monoamine oxidase inhibitor therapy with isocarboxazid. N Engl J Med, 319, 1988, 1671.
128. Steinberg, G.K., Bell, T.E., Yenari, M.A., Dose escalation safety and tolerance study of the N-methyl-D-aspartate antagonist dextromethorphan in neurosurgery patients. J Neurosurg 84 (1996), 860–866.
129. Su, T.P., Hayashi, T., Maurice, T., Buch, S., Ruoho, A.E., The sigma-1 receptor chaperone as an inter-organelle signaling modulator. Trends Pharmacol Sci 31 (2010), 557–566.
130. Su, T.P., Hayashi, T., Maurice, T., Buch, S., Ruoho, A.E., The sigma-1 receptor chaperone as an inter-organelle signaling modulator. Trends Pharmacol Sci 31 (2011), 557–566.
131. Szekely, J.I., Sharpe, L.G., Jaffe, J.H., Induction of phencyclidine-like behavior in rats by dextrorphan but not dextromethorphan. Pharmacol Biochem Behav 40 (1991), 381–386.
132. Tachikawa, E., Mizuma, K., Kudo, K., Kashimoto, T., Yamato, S., Ohta, S., Characterization of the functional subunit combination of nicotinic acetylcholine receptors in bovine adrenal chromaffin cells. Neurosci Lett 312 (2001), 161–164.
133. Takahama, K., Fukushima, H., Isohama, Y., Kai, H., Miyata, T., Inhibition of glycine currents by dextromethorphan in neurones dissociated from the guinea-pig nucleus tractus solitarii. Br J Pharmacol 120 (1997), 690–694.
134. Taraschenko, O.D., Panchal, V., Maisonneuve, I.M., Glick, S.D., Is antagonism of alpha3beta4 nicotinic receptors a strategy to reduce morphine dependence?. Eur J Pharmacol 513 (2005), 207–218.
135. Tortella, F.C., Pellicano, M., Bowery, N.G., Dextromethorphan and neuromodulation: old drug coughs up new activities. Trends Pharmacol Sci 10 (1989), 501–507.
136. Trube, G., Netzer, R., Dextromethorphan: cellular effects reducing neuronal hyperactivity. Epilepsia 35:Suppl. 5 (1994), S62–S67.
137. Verhagen Metman, L., Blanchet, P.J., van den Munckhof, P., Del Dotto, P., Natte, R., Chase, T.N., A trial of dextromethorphan in parkinsonian patients with motor response complications. Mov Disord 13 (1998), 414–417.
138. Vieta, E., Thase, M.E., Naber, D., D'Souza, B., Rancans, E., Lepola, U. Eriksson, H., Efficacy and tolerability of flexibly-dosed adjunct TC-5214 (dexmecamylamine) in patients with major depressive disorder and inadequate response to prior antidepressant. Eur Neuropsychopharmacol 24 (2014), 564–574.
139. Vollrath, J.T., Sechi, A., Dreser, A., Katona, I., Wiemuth, D., Vervoorts, J. Goswami, A., Loss of function of the ALS protein SigR1 leads to ER pathology associated with defective autophagy and lipid raft disturbances. Cell Death Dis, 5, 2014, e1290.
140. Walker, F.O., Hunt, V.P., An open label trial of dextromethorphan in Huntington's disease. Clin Neuropharmacol 12 (1989), 322–330.
141. Wang, L., Duncan, G., Silencing of sigma-1 receptor induces cell death in human lens cells. Exp Cell Res 312 (2006), 1439–1446.
142. Wankerl, K., Weise, D., Gentner, R., Rumpf, J.J., Classen, J., L-type voltage-gated Ca2 + channels: a single molecular switch for long-term potentiation/long-term depression-like plasticity and activity-dependent metaplasticity in humans. J Neurosci 30 (2010), 6197–6204.
143. Werling, L.L., Lauterbach, E.C., Calef, U., Dextromethorphan as a potential neuroprotective agent with unique mechanisms of action. Neurologist 13 (2007), 272–293.
144. Werling, L.L., Keller, A., Frank, J.G., Nuwayhid, S.J., A comparison of the binding profiles of dextromethorphan, memantine, fluoxetine and amitriptyline: treatment of involuntary emotional expression disorder. Exp Neurol 207 (2007), 248–257.
145. Witherow, L.E., Houston, J.B., Sigmoidal kinetics of CYP3A substrates: an approach for scaling dextromethorphan metabolism in hepatic microsomes and isolated hepatocytes to predict in vivo clearance in rat. J Pharmacol Exp Ther 290 (1999), 58–65.
146. Wu, D., Otton, S.V., Kalow, W., Sellers, E.M., Effects of route of administration on dextromethorphan pharmacokinetics and behavioral response in the rat. J Pharmacol Exp Ther 274 (1995), 1431–1437.
147. Xia, P., Chen, H.S., Zhang, D., Lipton, S.A., Memantine preferentially blocks extrasynaptic over synaptic NMDA receptor currents in hippocampal autapses. J Neurosci 30 (2010), 11246–11250.
148. Yamashita, H., Ohno, K., Amada, Y., Hattori, H., OzawaFunatsu, Y., Toya, T. Yamaguchi, T., Effects of 2-[N-(4-chlorophenyl)-N-methylamino]-4H-pyrido[3.2-e]-1,3-thiazin-4-one (YM928), an orally active alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, in models of generalized epileptic seizure in mice and rats. J Pharmacol Exp Ther 308 (2004), 127–133.
149. Yokotani, K., Okada, S., Nakamura, K., Characterization of functional nicotinic acetylcholine receptors involved in catecholamine release from the isolated rat adrenal gland. Eur J Pharmacol 446 (2002), 83–87.
150. Young, E.C., Smith, J.A., Pharmacologic therapy for cough. Curr Opin Pharmacol 11 (2011), 224–230.