Elsevier

Behavioural Brain Research

Volume 316, 1 January 2017, Pages 152-159
Behavioural Brain Research

Research report
Differential regulation of GluA1 expression by ketamine and memantine

https://doi.org/10.1016/j.bbr.2016.09.002Get rights and content

Highlights

  • Memantine potentiates Schaffer collateral-CA1 excitatory synaptic transmission in hippocampal area CA1.

  • Administration of memantine or ketamine enhances GluA1 S845 phosphorylation, but only ketamine elevates the expression of GluA1.

  • Memantine-induced potentiation of SC-CA1 synaptic phosphorylation and GluA1 phosphorylation are not occluded by GAGA receptor blockade.

  • Ketamine but not memantine enhances the phosphorylation of mTOR, in a time course parallel to the elevation of GluA1 expression.

  • Neither ketamine or memantine reduces the phosphorylation of eEF2; instead, ketamine enhances eEF2 phosphorylation 30 min following administration.

Abstract

Evidence from preclinical and clinical studies shows that ketamine, a noncompetitive NMDA receptor antagonist, exerts rapid and sustained antidepressant responses. However, ketamine’s psychotomimetic side effects and abuse liability limit the clinical use of the compound. Interestingly, memantine, another NMDA receptor channel blocker, processes no defined antidepressant property but is much safer and clinical tolerated. Understanding why ketamine but not memantine exhibits rapid antidepressant responses is important to elucidate the cellular signaling underlying the fast antidepressant actions of ketamine and to design a new safer generation of fast-acting antidepressants. Here we show that ketamine but memantine caused a rapid and sustained antidepressant-like responses in forced swim test (FST). Both drugs enhanced GluA1 S845 phosphorylation and potentiated Schaffer collateral-CA1 synaptic transmission. However, ketamine but not memantine elevated the expression of GluA1. Incubating acutely prepared hippocampal slices with ketamine but not memantine enhanced mTOR phosphorylation in a time course parallel to the time course of GluA1 elevation. Our results suggest that distinct properties in regulation of mTOR phosphorylation and synaptic protein expression may underlie the differential effectiveness of ketamine and memantine in their antidepressant responses.

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.

Section snippets

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

References (39)

  • A.E. Autry et al.

    NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses

    Nature

    (2011)
  • T.G. Banke et al.

    Control of GluR1 AMPA receptor function by cAMP-dependent protein kinase

    J. Neurosc.

    (2000)
  • R.H. Belmaker et al.

    Major depressive disorder

    N. Engl. J. Med.

    (2008)
  • C.A. Browne et al.

    Antidepressant effects of ketamine: mechanisms underlying fast-acting novel antidepressants

    Front. Pharmacol.

    (2013)
  • X. Cai et al.

    Local potentiation of excitatory synapses by serotonin and its alteration in rodent models of depression

    Nat. Neurosci.

    (2013)
  • H.S. Chen et al.

    Pharmacological implications of two distinct mechanisms of interaction of memantine with N-methyl-d-aspartate-gated channels

    J. Pharmacol. Exp. Ther.

    (2005)
  • S.G. Cull-Candy et al.

    Role of distinct NMDA receptor subtypes at central synapses

    Sci. STKE: Signal Transduction Knowl. Environ.

    (2004)
  • V. Derkach et al.

    Ca2+/calmodulin-kinase II enhances channel conductance of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate type glutamate receptors

    Proc. Natl. Acad. Sci. U. S. A.

    (1999)
  • R. Dingledine et al.

    The glutamate receptor ion channels

    Pharmacol. Rev.

    (1999)
  • Cited by (40)

    • Contribution of DNA methyltransferases to spared nerve injury induced depression partially through epigenetically repressing Bdnf in hippocampus: Reversal by ketamine

      2021, Pharmacology Biochemistry and Behavior
      Citation 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).

    View all citing articles on Scopus
    View full text