Single subanesthesia dose of ketamine enhances GluR1 Ser845 phosphorylation in prefrontal cortex
Mingfa Huang, Ke Zhang, Xiang Cai
Study at a glance
AI-extracted from the abstract| Characteristics | Animal experimental study |
|---|---|
| Population | Male and female Sprague-Dawley rats weighing 200-350 g |
| Interventions | Ketamine PKA inhibitor H89 |
| Dose | single subanesthesia dose of ketamine (0.520 mg/kg stated for clinical trials; dose for rats not specified) |
| Measures | Forced swim test immobility time, GluR1 expression, GluR1 Ser845 phosphorylation |
| Topics | Esketamine Ketamine |
| Key findings | A single subanesthetic dose of ketamine reduced immobility in the rat forced swim test and increased GluR1 expression and Ser845 phosphorylation in the prefrontal cortex. The PKA inhibitor H89, given intracerebroventricularly, eliminated the rapid antidepressant-like behavioral effect, leading the authors to propose that PKA activation and GluR1 Ser845 phosphorylation are critical for ketamine's fast antidepressant action. |
Abstract
The mechanisms underlying the rapid-acting antidepressant effects of ketamine have not been fully identified. In current study, we observed that a single subanesthesia dose of ketamine strongly decreased the immobility time of Sprague–Dawley rats in forced swim test. Ketamine injection significantly increased GluR1 expression and GluR1 Ser845 phosphorylation in prefrontal cortex. Intracerebroventricular injection of PKA inhibitor H89 completely eliminated the fast antidepressant-like responses of ketamine in force swim test. Our results suggest that activation of PKA and phosphorylation of GluR1 Ser845 are critical for fast antidepressant action of ketamine. Introduction Major depressive disorder (MDD) is a serious public health problem with a lifetime prevalence of 17% in the United States [1]. Despite the high incidence of MDD and its socioeconomic impact, the etiology of MDD remains largely unknown. Existing treatments for MDD usually take weeks to months to achieve their antidepressant effects, and a significant number of patients do not have adequate improvement even after months of treatment. In addition, increased risk of suicide is a major public health concern during the first month of standard antidepressant therapy. Thus, improved therapeutics that exert antidepressant effects within hours or several days of administration are urgently needed. Recent clinical trials show that a single subanesthesia dose (0.520 mg/kg) of ketamine, a noncompetitive ionotropic glutamatergic NMDA receptor antagonist, produces rapid antidepressant responses in patients suffering from MDD [2]. Treatment-resistant, depressed patients reported alleviation of core symptoms of major depression within hours of a single dose of intravenously infused ketamine, with effects lasting up to 2 weeks [3]. Subsequent studies reported significant efficacy of ketamine in reducing suicidal ideation in individuals exhibiting treatment-resistant depression [4]. The discovery of ketamine’s rapid-acting antidepressant effect has been exciting. However, the psychotomimetic properties and abuse potential of ketamine necessitate caution in promoting this compound as a general treatment for depression. Understanding the underlying mechanism of action of ketamine linked to behavioral improvement is of significant importance for developing novel, safe and fast-acting antidepressants. Materials and methods Animals Male and female Sprague–Dawley rats weighing 200–350 g were used for all behavioral experiments (purchased from Guangdong Animal Experiment Center, Guangzhou, Guangdong, China). Animals were maintained on a 12-h light/dark cycle in a temperatureand humidity-controlled facility with ad libitum access to food and water. All experiments were in accordance with US National Institutes of Health guidelines and approved by the Guangzhou Medical University Institutional Animal Care and Use Committee. Forced swim test In the pretest session, rats were placed into a Plexiglas cylinder (65-cm-height, 30-cm-diameter) filled to a height of 45 cm water (22°C to 24 °C) for 15 min. Water was changed between subjects and rats were dried by paper towel after swim. After ketamine or saline injection for different period of time, the test session were performed twenty four hours later. The test session was 15 min for each subject and was recorded by a video camera positioned on the side of the cylinder. However, only the first 5 min of test session was analyzed and scored by an observer blind to group assignment. A decrease in immobility time is suggestive of an antidepressant-like response. Acute prefrontal brain slices preparation These methods are described in detail in our previous publications [5,6]. Rats were killed by decapitation after sedation with. Prefrontal cortices (PFC) were isolated and sectioned into 400-μm-thick slices in ice-cold ACSF ( in mM: 124 NaCl, 3 KCl, 1.25 NaH2PO4, 1.5 MgCl2, 2.5 CaCl2, 26 NaHCO3, and 10 glucose, bubbled with 95% O2/5% CO2) using a Leica VT 1200S vibratome (Leica Microsystems Inc., Bannockburn, IL, USA). The slices were maintained at room Correspondence to: Xiang Cai, The Institute of Neuroscience, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, P.R. China, and Department of Physiology, Southern Illinois University School of Medicine, Carbondale, IL, USA, E-mail: cai001@siu.edu
Comparable studies
Other preclinical and animal studies on ketamine, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| mTOR-Dependent Synapse Formation Underlies the Rapid Antidepressant Effects of NMDA Antagonists Rats | 2010 | Observational study | |
| Activation of Glutamatergic Neurotransmission by Ketamine: A Novel Step in the Pathway from NMDA Receptor Blockade to Dopaminergic and Cognitive Disruptions Associated with the Prefrontal Cortex Conscious rats | 1997 | Dose-response study with microdialysis and behavioral testing | |
| NMDAR inhibition-independent antidepressant actions of ketamine metabolites Mice | 2016 | Preclinical study | |
| The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N‐methyl‐aspartate Spinal neurons in decerebrate or pentobarbitone-anaesthetized cats and rats | 1983 | Experimental study | |
| R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects Mice | 2015 | Experimental study |