S-Ketamine Pretreatment Alleviates Anxiety-Like Behaviors and Mechanical Allodynia and Blocks the Pro-inflammatory Response in Striatum and Periaqueductal Gray From a Post-traumatic Stress Disorder Model

Abstract

This study aims to explore the regulatory effect of S-ketamine on the mechanical allodynia, anxiety-like behaviors and microglia activation in adult male rats exposed to an animal model of post-traumatic stress disorder (PTSD). The rat PTSD model was established by the exposure to single-prolonged stress (SPS), and 1 day later, rats were intraperitoneally injected with 5 mg/kg S-ketamine or normal saline, respectively. Paw withdrawal mechanical threshold was measured 2 days before, and 1, 3, 5, 7, 10, 14, 21 and 28 days after injection to assess mechanical allodynia in the SPS-exposed rats. For anxiety-like behaviors, the open field test and elevated plus maze test were performed at 7 and 14 days after S-ketamine treatment in the SPS-exposed rats, respectively. SPS-induced rats presented pronounced mechanical allodynia and anxiety-like behaviors, which were alleviated by S-ketamine treatment. After behavioral tests, rats were sacrificed for collecting the anterior cingulate cortex (ACC), prefrontal cortex (PFC), dorsal striatum, and periaqueductal gray (PAG). Protein levels of TNF-α, IL-1β, p-NF-κB, and NF-κB in brain regions were examined by Western blot. In addition, microglia activation in each brain region was determined by immunofluorescence staining of the microglia-specific biomarker Iba-1. Interestingly, pro-inflammatory cytokines were significantly upregulated in the dorsal striatum and PAG, rather than ACC and PFC. Activated microglia was observed in the dorsal striatum and PAG as well, and upregulated p-NF-κB was detected in the dorsal striatum. Inflammatory response, phosphorylation of NF-κB and microglia activation in certain brain regions were significantly alleviated by S-ketamine treatment. Collectively, S-ketamine is a promising drug in alleviating mechanical allodynia, anxiety-like behaviors, and pro-inflammatory responses in discrete brain regions in a model of PTSD.

Esketamine Inhibits Cocaine-Seeking Behaviour Subsequent to Various Abstinence Conditions in Rats

“…In fact, esketamine has shown antidepressant effects in preclinical research [ 8 , 9 ] and clinical trials [ 10 , 11 ], which may have had significant implications in reducing the risk of relapse to cocaine in rats in the present study. Additionally, a very recent paper by Yang et al (2022) demonstrated that esketamine alleviated anxiety-like behaviours in a rat model of post-traumatic stress disorder [ 12 ]. Similarly, in male rats submitted to a panicogenic challenge, esketamine caused the rapid-onset of anxiolytic-like effects [ 32 ].…”

“…Based on these observations, an intranasal delivery of esketamine (branded as Spravato ® ) was recently approved in the United States and Europe to treat treatment-resistant depression. Other findings indicate anxiolytic-like effects of esketamine [ 12 ].…”

Ketamine’s rapid antidepressant effects are mediated by Ca2+-permeable AMPA receptors

“…Both the open field test and tail suspension test have long been used to determine animals’ anxiety- and depression-like behaviors, respectively, in rodents ( Seibenhener and Wooten, 2015 ; Ueno et al, 2022 ). Specifically, the open field test has been widely used to measure the ketamine effects on anxiety-like behavior in rodents ( Guarraci et al, 2018 ; Pitsikas et al, 2019 ; Shin et al, 2019 ; Akillioglu and Karadepe, 2021 ; Yang et al, 2022 ; Acevedo et al, 2023 ). We thus measured locomotor activity and anxiety-like behavior using the open field test as carried out previously ( Shou et al, 2019 ).…”

Effect of General Anesthetic Agents on Microglia

“…Ketamine inhibited the LPS-induced increases in TNF-α, IL-1β, and nitrite in primary cultured microglia in a dose-dependent manner, which may be the result of inhibition of ERK1/2 phosphorylation [ 97 ]. In a rat model of post-traumatic stress disorder, esketamine reduced pro-inflammatory cytokines, NF-κB phosphorylation, and microglial activation in the dorsal striatum and periaqueductal gray [ 98 ]. In contrast to the above findings, ketamine also has pro-inflammatory effects.…”