(2R,6R)-hydroxynorketamine rescues chronic stress-induced depression-like behavior through its actions in the midbrain periaqueductal gray.
Dylan Chou, Hsien-Yu Peng, Tzer-Bin Lin, Cheng-Yuan Lai, Ming-Chun Hsieh, Yang-Cheng Wen, An-Sheng Lee, Hsueh-Hsiao Wang, Po-Sheng Yang, Gin-Den Chen, Yu-Cheng Ho
Neuropharmacology September 1, 2018 DOI: 10.1016/j.neuropharm.2018.06.033 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Preclinical animal study Peer reviewed |
|---|---|
| Population | Male and female Sprague-Dawley rats |
| Interventions | (2R 6R)-hydroxynorketamine (2R 6R-HNK) CNQX |
| Duration | Up to 21 days |
| Measures | forced swim tests, sucrose preference tests, whole-cell patch-clamp electrophysiological recordings, Western blotting |
| Topics | Depression Ketamine |
| Keywords | Ampa receptor Chronic stress Electrophysiology Periaqueductal gray |
| Key points | A single systemic administration of (2R,6R)-HNK rapidly rescued chronic stress-induced depression-like behavior in rats and persisted for up to 21 days. The authors propose this antidepressant effect is mediated through enhancement of AMPA receptor-mediated glutamatergic transmission in the ventrolateral periaqueductal gray, as the effect was prevented by intra-vlPAG microinjection of the AMPA receptor antagonist CNQX. |
Abstract
It has been widely reported that ketamine rescues chronic stress-induced depression-like behavior, but the underlying cellular mechanisms of the rapid antidepressant actions of ketamine remain largely unclear. Both male and female Sprague-Dawley rats were used and received modified learned helplessness paradigm to induce depression-like behavior. Depression-like behavior was assayed and manipulated using forced swim tests, sucrose preference tests and pharmacological microinjection. We conducted whole-cell patch-clamp electrophysiological recordings in the midbrain ventrolateral periaqueductal gray (vlPAG) neurons. Surface and cytosolic glutamate receptor 1 (GluR1) α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor expression were analyzed using Western blotting. Phosphorylated GluR1 expression was quantified using Western blotting analysis. The results showed that a single systemic administration of a ketamine metabolite (2R,6R)-hydroxynorketamine (2R,6R-HNK) rapidly rescued chronic stress-induced depression-like behavior and persisted for up to 21 days. Consistently, the chronic stress-induced diminished glutamatergic transmission and surface GluR1 expression in the vlPAG were also reversed by a single systemic injection of (2R,6R)-HNK. Furthermore, bath application of (2R,6R)-HNK increased the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs) in the vlPAG. Further evidence for the antidepressant action of (2R,6R)-HNK is provided by the finding that microinjection of (2R,6R)-HNK into the vlPAG exhibited a rapid-acting and long-lasting antidepressant effect. This antidepressant effect of (2R,6R)-HNK was prevented by the intra-vlPAG microinjection of AMPA receptor antagonist CNQX. Together, the current results provide evidence that (2R,6R)-HNK rescues chronic stress-induced depression-like behavior with rapid-acting and long-lasting antidepressant effects through enhancement of AMPA receptor-mediated transmission in the vlPAG.
Comparable studies
Other preclinical and animal studies on ketamine for depression, most cited first.
Citations in the library
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- Antidepressant-relevant concentrations of the ketamine metabolite (2R,6R)-hydroxynorketamine do not block NMDA receptor function Proceedings of the National Academy of Sciences February 22, 2019
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