Research reportDifferential regulation of GluA1 expression by ketamine and memantine
Introduction
Major depressive disorder (MDD) is a serious public health problem with a lifetime prevalence about 16% worldwide [4], [13], [34]. 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 attempts is a concern during the first month of standard antidepressant therapy [23]. Thus, improved therapeutics that show rapid and uniform efficacy and better safety are urgently needed.
Emerging evidence from clinic trails demonstrate that a single dose of ketamine, a noncompetitive ionotropic glutamatergic NMDA receptor antagonist, produced rapid antidepressant responses in patients suffering from MDD [25]. Depressed, treatment-resistant patients reported alleviation of core symptoms of major depression within hours of a single dose of intravenously infused ketamine, with effects lasting up to 1 week or even longer [39], [15], [17]. Subsequent studies reported that ketamine significantly reduced suicidal ideality in individuals with treatment-resistant depression [1]. The discovery of ketamine’s rapid-acting effect opens up a potentially promising new approach to treating depression. However, the psychotomimetic properties and abuse potential limit ketamine to be promoted as a general treatment for depression [5]. Understanding the underlying mechanism responsible for ketamine’s beneficial behavioral effects may be the key to developing novel, safe, and fast-acting antidepressants.
Memantine, another noncompetitive NMDAR antagonist, has memory-improvement action and is a widely prescribed treatment for Alzheimer's disease. Memantine is a well-tolerated drug and lacks the psychotomimetic side effect at therapeutic doses. However, the antidepressant action of memantine is elusive and controversial [31], [24]. In clinical trials, chronic memantine administration did not elicit consistent antidepressant response in depressed patients compared with patients received placebo [22], [20]. Understanding why ketamine, but not memantine, generates fast antidepressant responses may help us identify the critical molecular events that mediate the antidepressant actions of ketamine and design new generation of fast and safe antidepressant.
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Animals and drug treatments
Sprague-Dawley (SD) rats were purchased from Harlan Laboratories (Indianapolis, IN, USA). Rats were kept on a 12/12-h light/dark cycle and allowed ad libitum access to food and water. Both male and female rats used for tissue preparation or behavioral tests in this study were eight- to fourteen-week old. Memantine hydrochloride (Sigma) and ketamine hydrochloride (Henry Schein) were dissolved (or diluted) in saline. Rats received ketamine or memantine injection (i.p.) at the time indicated in
Results
To detect the differential antidepressant actions of ketamine and memantine, SD rats pretreated with ketamine or memantine were subjected to forced swim test (FST), a standard antidepressant-predictive task. Comparing to saline-treated animals (i.p), a single dose of ketamine (10 mg/ kg, i.p.) significantly reduced the immobility time of animals in 5 min forced swim test. The action of ketamine appeared as early as 30 min and lasted at least for 4 h following injection. However, memantine only
Discussion
In the current study, we have demonstrated that a single dose of ketamine caused a rapid and sustained reduction of immobility in FST, whereas memantine only induced a transient decrease of immobility time in the test. This result is consistent with previous observations by others [13] and reveals a differential effectiveness of memantine and ketamine in antidepressant responses. To unveil the mechanisms accounting for the behavioral discrepancy between ketamine and memantine, our following
Conflict of interests
These authors declare no competing financial interest.
Acknowledgments
We thank Dr. Gregory Rose for valuable comments on the manuscript. This study was supported by NIMH R01 (086828), SIU School of Medicine startup funds, the National Natural Science Foundation of China (81271488, 81671339), the Pearl River Scholar Program by Guangdong Province, the Science and Technology Program of Guangzhou (2014Y2-00096), the Foundation for High-level Talents in Higher Education of Guangdong (310109-012), the Research Project for Colleges and Universities in Guangzhou (12A002S
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2021, Pharmacology Biochemistry and BehaviorCitation Excerpt :After then, the incision was sutured. The drug dose and route of administration were based on previously published papers that are considered sufficient to study the neurobiology of depression (Zhang et al., 2017; Nugent et al., 2015). RG108 is a novel nonnucleoside small-molecule DNMT inhibitors (DNMTi) that blocks the active site of the enzyme with low cytotoxicity and genotoxicity compared to five other DNMTi (5-aza-CR, 5-162 azaCdR, zebularine, procaine and epigallocatechin-3-gallate) (Park and Poo, 2013).