The delayed onset of antidepressant action is a major shortcoming in depression treatment. Ketamine, an N-methyl-D-aspartate (NMDA)-receptor antagonist and, more recently, its metabolite (2R,6R)-hydroxynorketamine (HNK) have emerged as promising rapid-acting antidepressants. Still, knowledge about their mechanism of action remains fragmentary. In the present study, we first confirmed the antidepressant-responsive mouse strain DBA/2J to be a suitable strain sensitive to the effects of both ketamine and HNK. To decode the molecular pathways mediating HNKs rapid antidepressant effects, we took advantage of an in vivo approach enabling longitudinal proteome profiling of acute and sustained antidepressant-like effects of (2R,6R)-hydroxynorketamine (HNK) in cerebrospinal fluid (CSF) of conscious DBA/2J mice. Serial CSF samples were investigated using an unbiased, hypothesis-free mass spectrometry-based approach. We identified a total of 387 proteins in murine CSF, among them were several protein targets involved in the glucocorticoid receptor signaling pathway; thus revealing an intriguing mechanistic link between HNKs antidepressant mechanism of action and regulation of the stress hormone system. In addition, mTOR and BDNF were predicted to be important upstream regulators of HNK treatment. Our data substantially contribute to a more precise understanding of the temporal dynamics and molecular targets underlying HNKs rapid antidepressant-like effects, and can be used as a proteomic database supporting the development of improved treatment strategies for depression in the future.
bioRxiv Subject Collection: Neuroscience