NMDAR inhibition-independent antidepressant actions of ketamine metabolites
Panos Zanos, Ruin Moaddel, Patrick J Morris, Polymnia Georgiou, Jonathan Fischell, Greg I Elmer, Manickavasagom Alkondon, Peixiong Yuan, Heather J Pribut, Nagendra S Singh, Katina S S Dossou, Yuhong Fang, Xi-Ping Huang, Cheryl L Mayo, Irving W Wainer, Edson X Albuquerque, Scott M Thompson, Craig J Thomas, Carlos A Zarate Jr, Todd D Gould, Panos Zanos, Ruin Moaddel, Patrick J Morris, Polymnia Georgiou, Jonathan Fischell, Greg I Elmer, Manickavasagom Alkondon, Peixiong Yuan, Heather J Pribut, Nagendra S Singh, Katina S S Dossou, Yuhong Fang, Xi-Ping Huang, Cheryl L Mayo, Irving W Wainer, Edson X Albuquerque, Scott M Thompson, Craig J Thomas, Carlos A Zarate Jr, Todd D Gould
Abstract
Major depressive disorder affects around 16 per cent of the world population at some point in their lives. Despite the availability of numerous monoaminergic-based antidepressants, most patients require several weeks, if not months, to respond to these treatments, and many patients never attain sustained remission of their symptoms. The non-competitive, glutamatergic NMDAR (N-methyl-d-aspartate receptor) antagonist (R,S)-ketamine exerts rapid and sustained antidepressant effects after a single dose in patients with depression, but its use is associated with undesirable side effects. Here we show that the metabolism of (R,S)-ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential for its antidepressant effects, and that the (2R,6R)-HNK enantiomer exerts behavioural, electroencephalographic, electrophysiological and cellular antidepressant-related actions in mice. These antidepressant actions are independent of NMDAR inhibition but involve early and sustained activation of AMPARs (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors). We also establish that (2R,6R)-HNK lacks ketamine-related side effects. Our data implicate a novel mechanism underlying the antidepressant properties of (R,S)-ketamine and have relevance for the development of next-generation, rapid-acting antidepressants.
Figures
References
- Kessler RC, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R) JAMA. 2003;289:3095–3105.
- Trivedi MH, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163:28–40.
- Rush AJ, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905–1917.
- Zarate CA, Jr., et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Archives of general psychiatry. 2006;63:856–864.
- Berman RM, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47:351–354.
- Diazgranados N, et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Archives of general psychiatry. 2010;67:793–802.
- Lally N, et al. Anti-anhedonic effect of ketamine and its neural correlates in treatment-resistant bipolar depression. Transl Psychiatry. 2014;4:e469.
- Murrough JW, et al. Antidepressant efficacy of ketamine in treatment-resistant major depression: a two-site randomized controlled trial. Am J Psychiatry. 2013;170:1134–1142.
- Morgan CJ, Curran HV. Ketamine use: a review. Addiction. 2012;107:27–38.
- Newport DJ, et al. Ketamine and Other NMDA Antagonists: Early Clinical Trials and Possible Mechanisms in Depression. American Journal of Psychiatry. 2015;172:950–966.
- Leung LY, Baillie TA. Comparative pharmacology in the rat of ketamine and its two principal metabolites, norketamine and (Z)-6-hydroxynorketamine. J Med Chem. 1986;29:2396–2399.
- Moaddel R, et al. Sub-anesthetic concentrations of (R,S)-ketamine metabolites inhibit acetylcholine-evoked currents in alpha7 nicotinic acetylcholine receptors. Eur J Pharmacol. 2013;698:228–234.
- Ebert B, Mikkelsen S, Thorkildsen C, Borgbjerg FM. Norketamine, the main metabolite of ketamine, is a non-competitive NMDA receptor antagonist in the rat cortex and spinal cord. Eur J Pharmacol. 1997;333:99–104.
- Yang C, et al. R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects. Transl Psychiatry. 2015;5:e632.
- Maeng S, et al. Cellular mechanisms underlying the antidepressant effects of ketamine: role of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol Psychiatry. 2008;63:349–352.
- Autry AE, et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature. 2011;475:91–95.
- Desta Z, et al. Stereoselective and regiospecific hydroxylation of ketamine and norketamine. Xenobiotica. 2012;42:1076–1087.
- Adams JD, Jr., Baillie TA, Trevor AJ, Castagnoli N., Jr. Studies on the biotransformation of ketamine. 1-Identification of metabolites produced in vitro from rat liver microsomal preparations. Biomed Mass Spectrom. 1981;8:527–538.
- Zarate CA, Jr., et al. Relationship of ketamine's plasma metabolites with response, diagnosis, and side effects in major depression. Biol Psychiatry. 2012;72:331–338.
- Carrier N, Kabbaj M. Sex differences in the antidepressant-like effects of ketamine. Neuropharmacology. 2013;70:27–34.
- Franceschelli A, Sens J, Herchick S, Thelen C, Pitychoutis PM. Sex differences in the rapid and the sustained antidepressant-like effects of ketamine in stress-naive and "depressed" mice exposed to chronic mild stress. Neuroscience. 2015;290:49–60.
- Irifune M, Shimizu T, Nomoto M, Fukuda T. Involvement of N-methyl-D-aspartate (NMDA) receptors in noncompetitive NMDA receptor antagonist-induced hyperlocomotion in mice. Pharmacol Biochem Behav. 1995;51:291–296.
- Gant TG. Using deuterium in drug discovery: leaving the label in the drug. J Med Chem. 2014;57:3595–3611.
- Duman RS, Aghajanian GK, Sanacora G, Krystal JH. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med. 2016;22:238–249.
- Li N, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329:959–964.
- Koike H, Iijima M, Chaki S. Involvement of AMPA receptor in both the rapid and sustained antidepressant-like effects of ketamine in animal models of depression. Behav Brain Res. 2011;224:107–111.
- Koike H, Chaki S. Requirement of AMPA receptor stimulation for the sustained antidepressant activity of ketamine and LY341495 during the forced swim test in rats. Behav Brain Res. 2014;271:111–115.
- Whittington MA, Traub RD, Kopell N, Ermentrout B, Buhl EH. Inhibition-based rhythms: experimental and mathematical observations on network dynamics. Int J Psychophysiol. 2000;38:315–336.
- Cunningham MO, Davies CH, Buhl EH, Kopell N, Whittington MA. Gamma oscillations induced by kainate receptor activation in the entorhinal cortex in vitro. J Neurosci. 2003;23:9761–9769.
- Muthukumaraswamy SD, et al. Evidence that Subanesthetic Doses of Ketamine Cause Sustained Disruptions of NMDA and AMPA-Mediated Frontoparietal Connectivity in Humans. J Neurosci. 2015;35:11694–11706.
- Lepack AE, Fuchikami M, Dwyer JM, Banasr M, Duman RS. BDNF release is required for the behavioral actions of ketamine. Int J Neuropsychopharmacol. 2015:18.
- De Vry J, Jentzsch KR. Role of the NMDA receptor NR2B subunit in the discriminative stimulus effects of ketamine. Behav Pharmacol. 2003;14:229–235.
- Moaddel R, et al. The distribution and clearance of (2S,6S)-hydroxynorketamine, an active ketamine metabolite, in Wistar rats. Pharmacol Res Perspect. 2015;3:e00157.
- Donahue RJ, Muschamp JW, Russo SJ, Nestler EJ, Carlezon WA., Jr. Effects of striatal DeltaFosB overexpression and ketamine on social defeat stress-induced anhedonia in mice. Biol Psychiatry. 2014;76:550–558.
- Malkesman O, et al. The female urine sniffing test: a novel approach for assessing reward-seeking behavior in rodents. Biol Psychiatry. 2010;67:864–871.
- Zanos P, et al. The Prodrug 4-Chlorokynurenine Causes Ketamine-Like Antidepressant Effects, but Not Side Effects, by NMDA/GlycineB-Site Inhibition. J Pharmacol Exp Ther. 2015;355:76–85.
- Chiu J, et al. Chronic ethanol exposure alters MK-801 binding sites in the cerebral cortex of the near-term fetal guinea pig. Alcohol. 1999;17:215–221.
- Raver SM, Haughwout SP, Keller A. Adolescent cannabinoid exposure permanently suppresses cortical oscillations in adult mice. Neuropsychopharmacology. 2013;38:2338–2347.
- Bokil H, Andrews P, Kulkarni JE, Mehta S, Mitra PP. Chronux: a platform for analyzing neural signals. J Neurosci Methods. 2010;192:146–151.
Source: PubMed