Comparison of the Psychopharmacological Effects of Tiletamine and Ketamine in Rodents
Tóm tắt
The glutamate N-methyl-d-aspartate (NMDA) receptor antagonist ketamine (KET) produces rapid and sustained antidepressant effects in patients. Tiletamine (TIL; 2-ethylamino-2-thiophen-2-yl-cyclohexan-1-one) is another uncompetitive NMDA receptor antagonist, used in a medical (veterinary) setting as an anesthetic tranquilizer. Here, we compared the behavioral actions of KET and TIL in a variety of tests, focusing on antidepressant-like and dissociative-like effects in mice and rats. The minimum effective doses of KET and TIL were 10 mg/kg to reduce mouse forced swim test immobility and 15 mg/kg to reduce marble-burying behavior. However, at similar doses, both compounds diminished locomotor activity and disturbed learning processes in the mouse passive avoidance test and the rat novel object recognition test. KET and TIL also reduced social behavior and accompanying 50-kHz “happy” ultrasonic vocalizations (USVs) in rats. TIL (5–15 mg/kg) displayed additional anxiolytic-like effects in the four-plate test. Neither KET nor TIL affected pain response in the hot plate test. Examination of the “side effects” revealed that only at the highest doses investigated did both compounds produce motor deficits in the rotarod test in mice. While KET produced behavioral effects at doses comparable between species, in the rats, TIL was ~10 times more potent than in the mice. In summary, antidepressant-like properties of both KET and TIL are similar, as are their adverse effect liabilities. We suggest that TIL could be an alternative to KET as an antidepressant with an additional anxiolytic-like profile.
Tài liệu tham khảo
Ammar G, Naja WJ, Pelissolo A (2015) Treatment-resistant anxiety disorders: a literature review of drug therapy strategies. Encéphale 41:260–265
Bechtholt-Gompf AJ, Smith KL, John CS et al (2011) CD-1 and Balb/cJ mice do not show enduring antidepressant-like effects of ketamine in tests of acute antidepressant efficacy. Psychopharmacology 215:689–695
Berman RM, Cappiello A, Anand A et al (2000) Antidepressant effects of ketamine in depressed patients. Biol Psychiatry 47:351–354
Borsini F, Podhorna J, Marazziti D (2002) Do animal models of anxiety predict anxiolytic-like effects of antidepressants? Psychopharmacology 163:121–141
Bourin M, Masse F, Dailly E et al (2005) Anxiolytic-like effect of milnacipran in the four-plate test in mice: mechanism of action. Pharmacol Biochem Behav 81:645–656
Broekkamp CL, Rijk HW, Joly Gelouin D et al (1986) Major tranquillizers can be distinguished from minor tranquillizers on the basis of effects on marble burying and swim- induced grooming in mice. Eur J Pharmacol 126:223–229
Burgdorf J, Zhang XL, Nicholson KL, et al (2013) GLYX-13, a NMDA receptor glycine-site functional partial agonist, induces antidepressant-like effects without ketamine-like side effects. Neuropsychopharmacology 38
Chen G, Ensor CR, Bohner B (1969) The pharmacology of 2-(ethylamino)-2-(2-thienyl)-cyclohexanone-HCl (CI-634). J Pharmacol Exp Ther 168:171–179
Domino EF (2010) Taming the ketamine tiger. 1965. Anesthesiology 113:678–684
Ennaceur A, Delacour J (1988) A new one-trial test for neurobiological studies of memory in rats. 1: behavioral data. Behav Brain res 31:47–59
Eskelund A, Li Y, Budac DP, et al (2017) Drugs with antidepressant properties affect tryptophan metabolites differently in rodent models with depression-like behavior. J Neurochem
ffRench-Mullen JM, Lehmann J, Bohacek R et al (1987) Tiletamine is a potent inhibitor of N-methyl-aspartate-induced depolarizations in rat hippocampus and striatum. J Pharmacol ExpTher 243:915–920
Gargiulo S, Greco A, Gramanzini M et al (2012) Mice anesthesia, analgesia, and care, part I: anesthetic considerations in preclinical research. ILAR j 53:E55–E69
Glue P, Medlicott NJ, Harland S, et al (2017) Ketamine's dose-related effects on anxiety symptoms in patients with treatment refractory anxiety disorders. J Psychopharmacol: 269881117705089
Griffiths RR, Johnson MW, Carducci MA et al (2016) Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: a randomized double-blind trial. J Psychopharmacol 30:1181–1197
Gyertyan I (1995) Analysis of the marble burying response: marbles serve to measure digging rather than evoke burying. Behav Pharmacol 6:24–31
Hayase T, Yamamoto Y, Yamamoto K (2006) Behavioral effects of ketamine and toxic interactions with psychostimulants. BMCNeurosci 7:1–10
Holuj M, Popik P, Nikiforuk A (2015) Improvement of ketamine-induced social withdrawal in rats: the role of 5-HT7 receptors. Behav Pharmacol 26:766–775
Koike H, Iijima M, Chaki S (2011) Involvement of AMPA receptor in both the rapid and sustained antidepressant-like effects of ketamine in animal models of depression. Behav Brain res 224:107–111
Kornhuber J, Bormann J, Hubers M et al (1991) Effects of the 1-amino-adamantanes at the MK-801-binding site of the NMDA-receptor-gated ion channel: a human postmortem brain study. Eur J Pharmacol 206:297–300
Koros E, Rosenbrock H, Birk G et al (2007) The selective mGlu5 receptor antagonist MTEP, similar to NMDA receptor antagonists, induces social isolation in rats. Neuropsychopharmacology 32:562–576
Krystal JH, Karper LP, Seibyl JP et al (1994) Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Arch gen Psychiatry 51:199–214
Li X, Morrow D, Witkin JM (2006) Decreases in nestlet shredding of mice by serotonin uptake inhibitors: comparison with marble burying. Life Sci 78:1933–1939
Luby ED (1959) Study of a new schizophrenomimetic drug—Sernyl. AMAArchNeurolPsychiat 81:363–369
Luckenbaugh DA, Niciu MJ, Ionescu DF et al (2014) Do the dissociative side effects of ketamine mediate its antidepressant effects? J AffectDisord 159:56–61
Marinova Z, Chuang DM, Fineberg N (2017) Glutamate-modulating drugs as a potential therapeutic strategy in obsessive-compulsive disorder. Curr Neuropharmacol
Morris H, Wallach J (2014) From PCP to MXE: a comprehensive review of the non-medical use of dissociative drugs. Drug Test Anal 6:614–632
Moskal JR, Burch R, Burgdorf JS et al (2014) GLYX-13, an NMDA receptor glycine site functional partial agonist enhances cognition and produces antidepressant effects without the psychotomimetic side effects of NMDA receptor antagonists. Expert Opin Investig Drugs 23:243–254
Murrough JW (2016) Ketamine for depression: an update. Biol Psychiatry 80:416–418
Nikiforuk A, Popik P (2014) Ketamine prevents stress-induced cognitive inflexibility in rats. Psychoneuroendocrinology 40:119–122
Nikiforuk A, Fijal K, Potasiewicz A et al (2013a) The 5-hydroxytryptamine (serotonin) receptor 6 agonist EMD 386088 ameliorates ketamine-induced deficits in attentional set shifting and novel object recognition, but not in the prepulse inhibition in rats. J Psychopharmacol 27:469–476
Nikiforuk A, Kos T, Fijal K et al (2013b) Effects of the selective 5-HT7 receptor antagonist SB-269970, and amisulpride on ketamine-induced schizophrenia-like deficits in rats. PLoS One 8:e66695
Njung'e K, Handley SL (1991) Evaluation of marble-burying behavior as a model of anxiety. Pharmacol Biochem Behav 38:63–67
Papp M, Gruca P, Lason-Tyburkiewicz M et al (2017) Antidepressant, anxiolytic and procognitive effects of subacute and chronic ketamine in the chronic mild stress model of depression. Behav Pharmacol 28:1–8
Plesan A, Hedman U, Xu XJ et al (1998) Comparison of ketamine and dextromethorphan in potentiating the antinociceptive effect of morphine in rats. Anesth Analg 86:825–829
Popik P, Kos T, Sowa-Kucma M et al (2008) Lack of persistent effects of ketamine in rodent models of depression. Psychopharmacology 198:421–430
Porsolt RD, Le Pichon M, Jalfre M (1977) Depression: a new animal model sensitive to antidepressant treatments. Nature 266:730–732
Potasiewicz A, Holuj M, Kos T et al (2017) 3-Furan-2-yl-N-p-tolyl-acrylamide, a positive allosteric modulator of the alpha7 nicotinic receptor, reverses schizophrenia-like cognitive and social deficits in rats. Neuropharmacology 113:188–197
Preskorn SH, Baker B, Kolluri S et al (2008) An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective N-methyl-D-aspartate antagonist, CP-101,606, in patients with treatment-refractory major depressive disorder. J Clin Psychopharmacol 28:631–637
Quail MT, Weimersheimer P, Woolf AD et al (2001) Abuse of telazol: an animal tranquilizer. J Toxicol Clin Toxicol 39:399–402
Rao TS, Contreras PC, Cler JA et al (1991) Contrasting neurochemical interactions of tiletamine, a potent phencyclidine (PCP) receptor ligand, with the N-methyl-D-aspartate-coupled and -uncoupled PCP recognition sites. J Neurochem 56:890–897
Rodriguez CI, Kegeles LS, Levinson A et al (2013) Randomized controlled crossover trial of ketamine in obsessive-compulsive disorder: proof-of-concept. Neuropsychopharmacology 38:2475–2483
Salat K, Podkowa A, Kowalczyk P et al (2015a) Anticonvulsant active inhibitor of GABA transporter subtype 1, tiagabine, with activity in mouse models of anxiety, pain and depression. Pharmacol rep 67:465–472
Salat K, Podkowa A, Mogilski S et al (2015b) The effect of GABA transporter 1 (GAT1) inhibitor, tiagabine, on scopolamine-induced memory impairments in mice. Pharmacol Rep 67:1155–1162
Salat K, Siwek A, Starowicz G et al (2015c) Antidepressant-like effects of ketamine, norketamine and dehydronorketamine in forced swim test: role of activity at NMDA receptor. Neuropharmacology 99:301–307
Sams-Dodd F (2013) Is poor research the cause of the declining productivity of the pharmaceutical industry? An industry in need of a paradigm shift. Drug DiscovToday 18:211–217
Schatzberg AF (2014) A word to the wise about ketamine. Am J Psychiatry 171:262–264
Schneider T, Popik P (2007) Attenuation of estrous cycle-dependent marble burying in female rats by acute treatment with progesterone and antidepressants. Psychoneuroendocrinology 32:651–659
Silvestre JS, Nadal R, Pallares M et al (1997) Acute effects of ketamine in the holeboard, the elevated-plus maze, and the social interaction test in Wistar rats. DepressAnxiety 5:29–33
Skolnick P, Layer RT, Popik P et al (1996) Adaptation of the N-methyl-D-aspartate (NMDA) receptors following antidepressant treatment: implications for the pharmacotherapy of depression. Pharmacopsychiatry 29:23–26
Strekalova T, Spanagel R, Bartsch D et al (2004) Stress-induced anhedonia in mice is associated with deficits in forced swimming and exploration. Neuropsychopharmacology 29:2007–2017
Su LX, Shi XX, Yang P et al (2017) Effects of tiletamine on the adenosine monophosphate-activated protein kinase signaling pathway in the rat central nervous system. Res vet Sci 114:101–108
Trullas R, Skolnick P (1990) Functional antagonists at the NMDA receptor complex exhibit antidepressant actions. Eur J Pharmacol 185:1–10
Yang C, Qu Y, Abe M et al (2017) (R)-ketamine shows greater potency and longer lasting antidepressant effects than its metabolite (2R,6R)-hydroxynorketamine. Biol Psychiatry. doi:10.1016/j.biopsych.2016.12.020
Zanos P, Moaddel R, Morris PJ et al (2016) NMDAR inhibition-independent antidepressant actions of ketamine metabolites. Nature 533:481–486
Zarate CA Jr, Singh JB, Carlson PJ et al (2006a) A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch gen Psychiatry 63:856–864
Zarate CA, Singh JB, Quiroz JA et al (2006b) A double-blind, placebo-controlled study of memantine in the treatment of major depression. Am J Psychiatry 163:153–155
Zhu X, Ye G, Wang Z et al (2017) Sub-anesthetic doses of ketamine exert antidepressant-like effects and upregulate the expression of glutamate transporters in the hippocampus of rats. Neurosci Lett 639:132–137