N-Methyl-D-aspartate receptor antagonist d-methadone produces rapid, mTORC1-dependent antidepressant effects.
Animals
Antidepressive Agents
/ administration & dosage
Dendritic Spines
/ drug effects
Excitatory Postsynaptic Potentials
/ drug effects
Ketamine
/ administration & dosage
Male
Mechanistic Target of Rapamycin Complex 1
/ metabolism
Methadone
/ administration & dosage
Prefrontal Cortex
/ drug effects
Rats, Sprague-Dawley
Receptors, N-Methyl-D-Aspartate
/ antagonists & inhibitors
Signal Transduction
/ drug effects
Journal
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
ISSN: 1740-634X
Titre abrégé: Neuropsychopharmacology
Pays: England
ID NLM: 8904907
Informations de publication
Date de publication:
12 2019
12 2019
Historique:
received:
21
06
2019
accepted:
20
08
2019
revised:
16
08
2019
pubmed:
28
8
2019
medline:
9
7
2020
entrez:
28
8
2019
Statut:
ppublish
Résumé
Currently available antidepressants have a delayed onset and limited efficacy, highlighting the need for new, rapid and more efficacious agents. Ketamine, an NMDA receptor antagonist, has emerged as a new rapid-acting antidepressant, effective even in treatment resistant patients. However, ketamine induces undesired psychotomimetic and dissociative side effects that limit its clinical use. The d-stereoisomer of methadone (dextromethadone; REL-1017) is a noncompetitive NMDA receptor antagonist with an apparently favorable safety and tolerability profile. The current study examined the rapid and sustained antidepressant actions of d-methadone in several behavioral paradigms, as well as on mTORC1 signaling and synaptic changes in the medial prefrontal cortex (mPFC). A single dose of d-methadone promoted rapid and sustained antidepressant responses in the novelty-suppressed feeding test (NSFT), a measure of anxiety, and in the female urine sniffing test (FUST), a measure of motivation and reward. D-methadone also produced a rapid reversal of the sucrose preference deficit, a measure of anhedonia, in rats exposed to chronic unpredictable stress. D-methadone increased phospho-p70S6 kinase, a downstream target of mTORC1 in the mPFC, and intra-mPFC infusion of the selective mTORC1 inhibitor rapamycin blocked the antidepressant actions of d-methadone in the FUST and NSFT. D-methadone administration also increased levels of the synaptic proteins, PSD95, GluA1, and Synapsin 1 and enhanced synaptic function in the mPFC. Studies in primary cortical cultures show that d-methadone also increases BDNF release, as well as phospho-p70S6 kinase. These findings indicate that d-methadone induces rapid antidepressant actions through mTORC1-mediated synaptic plasticity in the mPFC similar to ketamine.
Identifiants
pubmed: 31454827
doi: 10.1038/s41386-019-0501-x
pii: 10.1038/s41386-019-0501-x
pmc: PMC6898593
doi:
Substances chimiques
Antidepressive Agents
0
D-methadone
0
Receptors, N-Methyl-D-Aspartate
0
Ketamine
690G0D6V8H
Mechanistic Target of Rapamycin Complex 1
EC 2.7.11.1
Methadone
UC6VBE7V1Z
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2230-2238Références
Kessler RC, Chiu WT, Demler O, Merikangas KR, Walters EE. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62:617–27.
pubmed: 15939839
pmcid: 2847357
Mueller TI, Leon AC, Keller MB, Solomon DA, Endicott J, Coryell W, et al. Recurrence after recovery from major depressive disorder during 15 years of observational follow-up. Am J Psychiatry. 1999;156:1000–6.
pubmed: 10401442
Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163:1905–17.
pubmed: 17074942
Berman RM, Cappiello A, Anand A, Oren DA, Heninger GR, Charney DS, et al. Antidepressant effects of ketamine in depressed patients. Biol Psychiatry. 2000;47:351–4.
pubmed: 10686270
Zarate CA Jr., Singh JB, Carlson PJ, Brutsche NE, Ameli R, Luckenbaugh DA, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. 2006;63:856–64.
pubmed: 16894061
Maeng S, Zarate CA Jr., Du J, Schloesser RJ, McCammon J, Chen G, 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;63:349–52.
pubmed: 17643398
Lepack AE, Bang E, Lee B, Dwyer JM, Duman RS. Fast-acting antidepressants rapidly stimulate ERK signaling and BDNF release in primary neuronal cultures. Neuropharmacology. 2016;111:242–52.
pubmed: 27634096
pmcid: 5075989
Lepack AE, Fuchikami M, Dwyer JM, Banasr M, Duman RS. BDNF release is required for the behavioral actions of ketamine. Int J Neuropsychopharmacol. 2014;18:pii: pyu033.
Duman RS, Aghajanian GK, Sanacora G, Krystal JH. Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants. Nat Med. 2016;22:238–49.
pubmed: 26937618
pmcid: 5405628
Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science. 2010;329:959–64.
pubmed: 20724638
pmcid: 3116441
Liu RJ, Lee FS, Li XY, Bambico F, Duman RS, Aghajanian GK. Brain-derived neurotrophic factor Val66Met allele impairs basal and ketamine-stimulated synaptogenesis in prefrontal cortex. Biol Psychiatry. 2012;71:996–1005.
pubmed: 22036038
Harward SC, Hedrick NG, Hall CE, Parra-Bueno P, Milner TA, Pan E, et al. Autocrine BDNF-TrkB signalling within a single dendritic spine. Nature. 2016;538:99–103.
pubmed: 27680698
pmcid: 5398094
Liu RJ, Fuchikami M, Dwyer JM, Lepack AE, Duman RS, Aghajanian GK. GSK-3 inhibition potentiates the synaptogenic and antidepressant-like effects of subthreshold doses of ketamine. Neuropsychopharmacology. 2013;38:2268–77.
pubmed: 23680942
pmcid: 3773678
Short B, Fong J, Galvez V, Shelker W, Loo CK. Side-effects associated with ketamine use in depression: a systematic review. Lancet Psychiatry. 2018;5:65–78.
pubmed: 28757132
Bernstein G, Davis K, Mills C, Wang L, McDonnell M, Oldenhof J, et al. Characterization of the safety and pharmacokinetic profile of D-methadone, a novel N-methyl-D-aspartate receptor antagonist in healthy, opioid-naive subjects: results of two phase 1 studies. J Clin Psychopharmacol. 2019;39:226–37.
pubmed: 30939592
Callahan RJ, Au JD, Paul M, Liu C, Yost CS. Functional inhibition by methadone of N-methyl-D-aspartate receptors expressed in Xenopus oocytes: stereospecific and subunit effects. Anesth Analg. 2004;98:653–9.
pubmed: 14980914
Kristensen K, Christensen CB, Christrup LL. Themu1, mu2, delta, kappa opioid receptor binding profiles of methadone stereoisomers and morphine. Life Sci. 1995;56:PL45–50.
pubmed: 7823756
Gorman AL, Elliott KJ, Inturrisi CE. The d- and l-isomers of methadone bind to the non-competitive site on the N-methyl-D-aspartate (NMDA) receptor in rat forebrain and spinal cord. Neurosci Lett. 1997;223:5–8.
pubmed: 9058409
Matsui A, Williams JT. Activation of micro-opioid receptors and block of Kir3 potassium channels and NMDA receptor conductance by L- and D-methadone in rat locus coeruleus. Br J Pharm. 2010;161:1403–13.
Chizh BA, Schlutz H, Scheede M, Englberger W. The N-methyl-D-aspartate antagonistic and opioid components of d-methadone antinociception in the rat spinal cord. Neurosci Lett. 2000;296:117–20.
pubmed: 11108995
Hanania T, Manfredi PL, Inturrisi C,Vitolo OV. The N-methyl-D-aspartate receptor antagonist d-methadone acutely improves depressive-like behavior in the forced swim test performance of rats. Exp Clin Psychopharmacol, 2019. https://doi.org/10.1037/pha0000310 . [Epub ahead of print].
Franklin TC, Wohleb ES, Zhang Y, Fogaca M, Hare B, Duman RS. Persistent increase in microglial RAGE contributes to chronic stress-induced priming of depressive-like behavior. Biol Psychiatry. 2018;83:50–60.
pubmed: 28882317
Malkesman O, Scattoni ML, Paredes D, Tragon T, Pearson B, Shaltiel G, et al. The female urine sniffing test: a novel approach for assessing reward-seeking behavior in rodents. Biol Psychiatry. 2010;67:864–71.
pubmed: 20034613
Liu RJ, Duman C, Kato T, Hare B, Lopresto D, Bang E, et al. GLYX-13 produces rapid antidepressant responses with key synaptic and behavioral effects distinct from ketamine. Neuropsychopharmacology. 2017;42:1231–42.
pubmed: 27634355
Rodriguez A, Ehlenberger DB, Dickstein DL, Hof PR, Wearne SL. Automated three-dimensional detection and shape classification of dendritic spines from fluorescence microscopy images. PLoS ONE. 2008;3:e1997.
pubmed: 18431482
pmcid: 2292261
Garcia LS, Comim CM, Valvassori SS, Reus GZ, Barbosa LM, Andreazza AC, et al. Acute administration of ketamine induces antidepressant-like effects in the forced swimming test and increases BDNF levels in the rat hippocampus. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32:140–4.
pubmed: 17884272
Willner P. The chronic mild stress (CMS) model of depression: History, evaluation and usage. Neurobiol Stress. 2017;6:78–93.
pubmed: 28229111
Willner P, Towell A, Sampson D, Sophokleous S, Muscat R. Reduction of sucrose preference by chronic unpredictable mild stress, and its restoration by a tricyclic antidepressant. Psychopharmacol (Berl). 1987;93:358–64.
Dwyer JM, Lepack AE, Duman RS. mTOR activation is required for the antidepressant effects of mGluR(2)/(3) blockade. Int J Neuropsychopharmacol. 2012;15:429–34.
pubmed: 22114864
Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF, et al. NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature. 2011;475:91–5.
pubmed: 21677641
pmcid: 3172695
Carreno FR, Donegan JJ, Boley AM, Shah A, DeGuzman M, Frazer A, et al. Activation of a ventral hippocampus-medial prefrontal cortex pathway is both necessary and sufficient for an antidepressant response to ketamine. Mol Psychiatry. 2016;21:1298–308.
pubmed: 26619811
Liu CY, Jiang XX, Zhu YH, Wei DN. Metabotropic glutamate receptor 5 antagonist 2-methyl-6-(phenylethynyl)pyridine produces antidepressant effects in rats: role of brain-derived neurotrophic factor. Neuroscience. 2012;223:219–24.
pubmed: 22890078
Liu RJ, Ota KT, Dutheil S, Duman RS, Aghajanian GK. Ketamine strengthens CRF-activated amygdala inputs to basal dendrites in mPFC layer V pyramidal cells in the prelimbic but not infralimbic subregion, a key suppressor of stress responses. Neuropsychopharmacology. 2015;40:2066–75.
pubmed: 25759300
pmcid: 4613616
Zhou W, Wang N, Yang C, Li XM, Zhou ZQ, Yang JJ. Ketamine-induced antidepressant effects are associated with AMPA receptors-mediated upregulation of mTOR and BDNF in rat hippocampus and prefrontal cortex. Eur Psychiatry. 2014;29:419–23.
pubmed: 24321772
Kato T, Fogaca MV, Deyama S, Li XY, Fukumoto K, Duman RS. BDNF release and signaling are required for the antidepressant actions of GLYX-13. Mol Psychiatry. 2018;23:2007–17.
pubmed: 29203848
Fukumoto K, Fogaca MV, Liu RJ, Duman C, Kato T, Li XY, et al. Activity-dependent brain-derived neurotrophic factor signaling is required for the antidepressant actions of (2R,6R)-hydroxynorketamine. Proc Natl Acad Sci USA. 2019;116:297–302.
pubmed: 30559184
Ghosal S, Bang E, Yue W, Hare BD, Lepack AE, Girgenti MJ, et al. Activity-dependent brain-derived neurotrophic factor release is required for the rapid antidepressant actions of scopolamine. Biol Psychiatry. 2018;83:29–37.
pubmed: 28751069
Muller HK, Wegener G, Liebenberg N, Zarate CA Jr., Popoli M, Elfving B. Ketamine regulates the presynaptic release machinery in the hippocampus. J Psychiatr Res. 2013;47:892–9.
pubmed: 23548331
pmcid: 3678963
Zhang K, Yamaki VN, Wei Z, Zheng Y, Cai X. Differential regulation of GluA1 expression by ketamine and memantine. Behav Brain Res. 2017;316:152–9.
pubmed: 27599619
MacQueen GM, Yucel K, Taylor VH, Macdonald K, Joffe R. Posterior hippocampal volumes are associated with remission rates in patients with major depressive disorder. Biol Psychiatry. 2008;64:880–3.
pubmed: 18722590
Savitz J, Drevets WC. Bipolar and major depressive disorder: neuroimaging the developmental-degenerative divide. Neurosci Biobehav Rev. 2009;33:699–771.
pubmed: 19428491
pmcid: 2858318
Fogaça MV, Campos AC, Coelho LD, Duman RS, Guimaraes FS. The anxiolytic effects of cannabidiol in chronically stressed mice are mediated by the endocannabinoid system: role of neurogenesis and dendritic remodeling. Neuropharmacology. 2018;135:22–33.
pubmed: 29510186
Cook SC, Wellman CL. Chronic stress alters dendritic morphology in rat medial prefrontal cortex. J Neurobiol. 2004;60:236–48.
pubmed: 15266654
Moda-Sava RN, Murdock MH, Parekh PK, Fetcho RN, Huang BS, Huynh TN, et al. Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation. Science. 2019;364:pii: eaat8078.
Wang JS, Ruan Y, Taylor RM, Donovan JL, Markowitz JS, DeVane CL. Brain penetration of methadone (R)- and (S)-enantiomers is greatly increased by P-glycoprotein deficiency in the blood-brain barrier of Abcb1a gene knockout mice. Psychopharmacol (Berl). 2004;173:132–8.
De Martin S VO, Bernstein G, Alimonti A, Traversa S, Inturrisi EC, Manfredi PL. The NMDAR antagonist dextromethadone increases plasma BDNF levels in healthy volunteers undergoing a 14-day in-patient phase 1 study. American College of Neuropsychopharmacology 2018 Annual Meeting, Miami, FL; 2018.