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Ketamine and its metabolite, (2R,6R)-HNK, restore hippocampal LTP and long-term spatial memory in the Wistar-Kyoto rat model of depression

L. Aleksandrova, Y. Wang, A. Phillips

Molecular Brain June 16, 2020 DOI: 10.1186/s13041-020-00627-z (opens in new tab)

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AI-extracted from the abstract
Characteristics Preclinical study Peer reviewed
Population Wistar-Kyoto (WKY) rats and Wistar control rats
Interventions Ketamine (2R 6R)-HNK
Dose 5 mg/kg, ip
Duration 3.5 hours and 24 hours post-injection for LTP; pre-treatment before behavioral tests
Topics Depression Esketamine Ketamine
Citations 87
Key points Ketamine and its metabolite (2R,6R)-HNK rescue impaired hippocampal long-term potentiation and spatial memory deficits in WKY rats, but only ketamine has rapid effects on stress coping behavior in the forced swim test.

Abstract

Accumulating evidence implicates dysregulation of hippocampal synaptic plasticity in the pathophysiology of depression. However, the effects of ketamine on synaptic plasticity and their contribution to its mechanism of action as an antidepressant, are still unclear. We investigated ketamine’s effects on in vivo dorsal hippocampal (dHPC) synaptic plasticity and their role in mediating aspects of antidepressant activity in the Wistar-Kyoto (WKY) model of depression. dHPC long-term potentiation (LTP) was significantly impaired in WKY rats compared to Wistar controls. Importantly, a single low dose (5 mg/kg, ip) of ketamine or its metabolite, (2R,6R)-HNK, rescued the LTP deficit in WKY rats at 3.5 h but not 30 min following injection, with residual effects at 24 h, indicating a delayed, sustained facilitatory effect on dHPC synaptic plasticity. Consistent with the observed dHPC LTP deficit, WKY rats exhibited impaired hippocampal-dependent long-term spatial memory as measured by the novel object location recognition test (NOLRT), which was effectively restored by pre-treatment with both ketamine or (2R,6R)-HNK. In contrast, in WKYs, which display abnormal stress coping, ketamine, but not (2R,6R)-HNK, had rapid and sustained effects in the forced swim test (FST), a commonly used preclinical screen for antidepressant-like activity. The differential effects of (2R,6R)-HNK observed here reveal a dissociation between drug effects on FST immobility and dHPC synaptic plasticity. Therefore, in the WKY rat model, restoring dHPC LTP was not correlated with ketamine’s effects in FST, but importantly, may have contributed to the reversal of hippocampal-dependent cognitive deficits, which are critical features of clinical depression. Our findings support the theory that ketamine may reverse the stress-induced loss of connectivity in key neural circuits by engaging synaptic plasticity processes to “reset the system”.

Comparable studies

Other preclinical and animal studies on ketamine for depression, most cited first.

Study Year Design Participants
Psychedelics, but Not Ketamine, Produce Persistent Antidepressant-like Effects in a Rodent Experimental System for the Study of Depression Rats 2020 Preclinical study
A Single Subanesthetic Dose of Ketamine Relieves Depression-like Behaviors Induced by Neuropathic Pain in Rats Rats with spared nerve injury (neuropathic pain model), sham-operated rats, and control... 2011 Animal experimental study
Comparison of (R)-ketamine and lanicemine on depression-like phenotype and abnormal composition of gut microbiota in a social defeat stress model Susceptible mice after chronic social defeat stress 2017 Preclinical animal study
Comparison of R-ketamine and rapastinel antidepressant effects in the social defeat stress model of depression Susceptible mice in the social defeat stress model 2016 Animal experimental study
Effect of Ketamine on LTP and NMDAR EPSC in Hippocampus of the Chronic Social Defeat Stress Mice Model of Depression Male C57BL/6J mice 2018 Controlled laboratory experiment

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