PMID- 34632008 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20211012 IS - 2352-2895 (Print) IS - 2352-2895 (Electronic) IS - 2352-2895 (Linking) VI - 15 DP - 2021 Nov TI - Longitudinal CSF proteome profiling in mice to uncover the acute and sustained mechanisms of action of rapid acting antidepressant (2R,6R)-hydroxynorketamine (HNK). PG - 100404 LID - 10.1016/j.ynstr.2021.100404 [doi] LID - 100404 AB - Delayed onset of antidepressant action is a shortcoming in depression treatment. Ketamine and its metabolite (2R,6R)-hydroxynorketamine (HNK) have emerged as promising rapid-acting antidepressants. However, their mechanism of action remains unknown. In this study, we first described the anxious and depression-prone inbred mouse strain, DBA/2J, as an animal model to assess the antidepressant-like effects of ketamine and HNK in vivo. To decode the molecular mechanisms mediating HNK's rapid antidepressant effects, a longitudinal cerebrospinal fluid (CSF) proteome profiling of its acute and sustained effects was conducted using an unbiased, hypothesis-free mass spectrometry-based proteomics approach. A total of 387 proteins were identified, with a major implication of significantly differentially expressed proteins in the glucocorticoid receptor (GR) signaling pathway, providing evidence for a link between HNK and regulation of the stress hormone system. Mechanistically, we identified HNK to repress GR-mediated transcription and reduce hormonal sensitivity of GR in vitro. In addition, mammalian target of rapamycin (mTOR) and brain-derived neurotrophic factor (BDNF) were predicted to be important upstream regulators of HNK treatment. Our results contribute to precise understanding of the temporal dynamics and molecular targets underlying HNK's rapid antidepressant-like effects, which can be used as a benchmark for improved treatment strategies for depression in future. CI - (c) 2021 The Authors. FAU - Herzog, David P AU - Herzog DP AD - Department of Psychiatry and Psychotherapy and Focus Program Translational Neurosciences, Johannes Gutenberg University Medical Center Mainz, Mainz, Germany. FAU - Perumal, Natarajan AU - Perumal N AD - Experimental and Translational Ophthalmology, Department of Ophthalmology, Johannes Gutenberg University Medical Center, Mainz, Germany. FAU - Manicam, Caroline AU - Manicam C AD - Experimental and Translational Ophthalmology, Department of Ophthalmology, Johannes Gutenberg University Medical Center, Mainz, Germany. FAU - Treccani, Giulia AU - Treccani G AD - Department of Psychiatry and Psychotherapy and Focus Program Translational Neurosciences, Johannes Gutenberg University Medical Center Mainz, Mainz, Germany. AD - Institute for Microscopic Anatomy and Neurobiology, Johannes Gutenberg University Medical Center, Mainz, Germany. AD - Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Risskov, Denmark. FAU - Nadig, Jens AU - Nadig J AD - Department of Psychiatry and Psychotherapy and Focus Program Translational Neurosciences, Johannes Gutenberg University Medical Center Mainz, Mainz, Germany. FAU - Rossmanith, Milena AU - Rossmanith M AD - Experimental and Translational Ophthalmology, Department of Ophthalmology, Johannes Gutenberg University Medical Center, Mainz, Germany. FAU - Engelmann, Jan AU - Engelmann J AD - Department of Psychiatry and Psychotherapy and Focus Program Translational Neurosciences, Johannes Gutenberg University Medical Center Mainz, Mainz, Germany. FAU - Jene, Tanja AU - Jene T AD - Department of Psychiatry and Psychotherapy and Focus Program Translational Neurosciences, Johannes Gutenberg University Medical Center Mainz, Mainz, Germany. FAU - Hasch, Annika AU - Hasch A AD - Department of Psychiatry and Psychotherapy and Focus Program Translational Neurosciences, Johannes Gutenberg University Medical Center Mainz, Mainz, Germany. FAU - van der Kooij, Michael A AU - van der Kooij MA AD - Department of Psychiatry and Psychotherapy and Focus Program Translational Neurosciences, Johannes Gutenberg University Medical Center Mainz, Mainz, Germany. AD - Leibniz Institute for Resilience Research, Mainz, Germany. FAU - Lieb, Klaus AU - Lieb K AD - Department of Psychiatry and Psychotherapy and Focus Program Translational Neurosciences, Johannes Gutenberg University Medical Center Mainz, Mainz, Germany. AD - Leibniz Institute for Resilience Research, Mainz, Germany. FAU - Gassen, Nils C AU - Gassen NC AD - Neurohomeostasis Research Group, Department of Psychiatry and Psychotherapy, University Medical Center Bonn, Bonn, Germany. FAU - Grus, Franz H AU - Grus FH AD - Experimental and Translational Ophthalmology, Department of Ophthalmology, Johannes Gutenberg University Medical Center, Mainz, Germany. FAU - Muller, Marianne B AU - Muller MB AD - Department of Psychiatry and Psychotherapy and Focus Program Translational Neurosciences, Johannes Gutenberg University Medical Center Mainz, Mainz, Germany. AD - Leibniz Institute for Resilience Research, Mainz, Germany. LA - eng PT - Journal Article DEP - 20210929 PL - United States TA - Neurobiol Stress JT - Neurobiology of stress JID - 101643409 PMC - PMC8488754 OTO - NOTNLM OT - (2R,6R)-Hydroxynorketamine OT - Antidepressant OT - CSF OT - Glucocorticoid receptor signaling OT - Ketamine OT - Proteomics COIS- Authors declare that they have no conflict of interest. EDAT- 2021/10/12 06:00 MHDA- 2021/10/12 06:01 PMCR- 2021/09/29 CRDT- 2021/10/11 06:11 PHST- 2021/07/16 00:00 [received] PHST- 2021/09/16 00:00 [revised] PHST- 2021/09/26 00:00 [accepted] PHST- 2021/10/11 06:11 [entrez] PHST- 2021/10/12 06:00 [pubmed] PHST- 2021/10/12 06:01 [medline] PHST- 2021/09/29 00:00 [pmc-release] AID - S2352-2895(21)00112-0 [pii] AID - 100404 [pii] AID - 10.1016/j.ynstr.2021.100404 [doi] PST - epublish SO - Neurobiol Stress. 2021 Sep 29;15:100404. doi: 10.1016/j.ynstr.2021.100404. eCollection 2021 Nov.