NeuropharmacologyOct 30, 2025

Blocking TREK-1 channels may underlie hydroxynorketamine’s antidepressant-like effects

Psychedelic Science Weekly Brief ↗PubMed ↗DOI ↗

Updated Dec 29, 2025

Abstract

The ketamine metabolite (2R,6R)-HNK may provide rapid antidepressant effects by targeting TREK-1.

(2R,6R)-HNK could inhibit TREK-1 currents at concentrations effective for antidepressant action.
TREK-1 is found widely in the brain and is involved in controlling depressive-like behaviors.
Increased TREK-1 expression due to early-life stress may disrupt synaptic plasticity and neural circuit formation.
(2R,6R)-HNK appears to boost the activity of mPFC pyramidal neurons and increase key proteins related to synaptic plasticity.
The antidepressant effects of (2R,6R)-HNK were lost in mice lacking TREK-1 specifically in mPFC pyramidal neurons.

Simplified

The ketamine metabolite (2R,6R)-hydroxynorketamine [(2R,6R)-HNK] exhibits rapid antidepressant effects without the psychotomimetic or addictive side effects associated with ketamine, making it a promising therapeutic candidate. However, the precise molecular targets and mechanisms underlying its antidepressant actions remain controversial. In this study, we identified TREK-1, a two-pore domain potassium channel, as a key target of (2R,6R)-HNK. Electrophysiological experiments revealed that (2R,6R)-HNK selectively inhibits TREK-1 currents, with an ICclose to its effective antidepressant concentration. TREK-1 is widely expressed in the brain, and its activity in the mPFC has been implicated in regulating depressive-like behaviors. Early-life stress increases TREK-1 expression in the mPFC, impairing synaptic plasticity and neural circuit formation, which contributes to emotional disorders. Further investigations demonstrated that (2R,6R)-HNK enhances the firing frequency of mPFC pyramidal neurons and upregulates synaptic plasticity-related proteins, including CREB and PSD95. Crucially, the antidepressant effects of (2R,6R)-HNK were abolished in mice with pyramidal neuron-specific knockdown of TREK-1 in the mPFC, confirming the essential role of TREK-1 inhibition in mediating (2R,6R)-HNK's actions. Our findings establish TREK-1 as a critical target for (2R,6R)-HNK's rapid antidepressant effects, providing new insights into the mechanisms of depression treatment and the development of novel therapeutics. 50

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Blocking TREK-1 channels may underlie hydroxynorketamine’s antidepressant-like effects

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