Elsevier

Brain Research

Volume 1660, 1 April 2017, Pages 58-66
Brain Research

Research report
Inhibition of the NMDA and AMPA receptor channels by antidepressants and antipsychotics

https://doi.org/10.1016/j.brainres.2017.01.028Get rights and content

Highlights

  • Fluoxetine and desipramine inhibit calcium-permeable AMPARs.

  • Antidepressants and antipsychotics inhibit NMDARs by different mechanisms.

  • NMDAR block by antidepressants may contribute to their analgesic effects.

Abstract

It is known that some antidepressants and antipsychotics directly inhibit NMDA-type ionotropic glutamate receptors. In this study we systematically studied action of seven drugs (Fluoxetine, Citalopram, Desipramine, Amitriptyline, Atomoxetine, Chlorpromazine, and Clozapine) on NMDA receptors and Ca2+-permeable and -impermeable AMPA receptors in rat brain neurons by whole-cell patch-clamp technique. Except for weak effect of fluoxetine, all drugs were virtually inactive against Ca2+-impermeable AMPA receptors. Fluoxetine and desipramine significantly inhibited Ca2+-permeable AMPA receptors (IC50 = 43 ± 7 and 105 ± 12 µM, respectively). Desipramine, atomoxetine and chlorpromazine inhibited NMDA receptors in clinically relevant low micromolar concentrations, while citalopram had only weak effect. All tested medicines have been clustered into two groups by their action on NMDA receptors: desipramine, amitriptyline, chlorpromazine, and atomoxetine display voltage- and magnesium-dependent open channel blocking mechanism. Action of fluoxetine and clozapine was found to be voltage- and magnesium-independent. All voltage-dependent compounds could be trapped in closed NMDA receptor channels. Possible contribution of NMDA receptor inhibition by certain antidepressants and antipsychotics to their analgesic effects in neuropathic pain is discussed.

Introduction

The most important classes of antidepressants are selective serotonin reuptake inhibitors (SSRI), serotonin-norepinephrine reuptake inhibitors (SNRI), tricyclic antidepressants (TCA), tetracyclic antidepressants (TeCA) and monoamine oxidase inhibitors (MAOI). Many antidepressants show analgesic activities both in animal models and in humans. Therefore in modern medicine they are used not only for treatment of depression and anxiety but also for chronic pain and neuropathic pain and itch management (Mika et al., 2013, Yosipovitch and Bernhard, 2013). Some antidepressants are used off-label for treatment of several other conditions including premenstrual symptoms, bulimia nervosa and insomnia (Imai et al., 2015, McElroy et al., 2012, Becker, 2005).

Besides their primary targets different antidepressants and antipsychotics affect other molecules, including a number of receptor types involved in chronic pain and itch processing: adrenergic (Cottingham et al., 2014) and opioid (Onali et al., 2010) receptors, voltage-gated sodium (Lenkey et al., 2006, Theriault et al., 2015), potassium (Punke and Friederich, 2007, Choi and Hahn, 2012) and calcium channels (Zahradnik et al., 2008, Wu et al., 2012). It is worth to mention particularly that antidepressants directly affect glutamatergic system (Tohda et al., 1995, Szasz et al., 2007).

Glutamate is the major excitatory neurotransmitter in the brain. Its rapid postsynaptic actions are mediated by ionotropic glutamate receptors, including the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and NMDA subtypes. The changes in glutamatergic system are directly involved in the pathophysiology of depression (Thompson et al., 2015, Freudenberg et al., 2015). NMDA receptor antagonists, especially ketamine, exhibit antidepressant-like effects in humans (Berman et al., 2000, Zarate et al., 2006), though the exact mechanism and proteins involved are still under debate (Dutta et al., 2015, Zanos et al., 2016, Zhang et al., 2016). Thus it is not surprising that NMDA receptors are among the targets of antidepressants. Indeed, desipramine and fluoxetine inhibit NMDA receptors (Kiss et al., 2012, Tohda et al., 1995) but the mechanisms are different (Szasz et al., 2007, Kiss et al., 2012). Fluoxetine is a selective inhibitor of GluN2B-containing NMDARs, its action is voltage–independent. In contrast, action of desipramine is voltage-dependent and it blocks both GluN1/GluN2A and GluN1/GluN2B subtypes with similar activity. Chlorpromazine inhibits NMDA receptor but the mechanism is not resolved (Zarnowska and Mozrzymas, 2001). Atomoxetine was shown to block NMDA receptor channel in voltage- and use-dependent manner with low micromolar IC50 value (Ludolph et al., 2010). Until recently AMPA receptors were not considered as targets for antidepressants and antipsychotics. However we have shown that fluoxetine blocks calcium-permeable AMPA receptors in a voltage-dependent manner by an unusual mechanism (Barygin et al., 2015). Inhibitory action of desipramine on AMPA receptors of hippocampal neurons was also recently discovered (Koncz et al., 2014).

Although published data attract attention to the glutamate receptors as targets of antidepressants, the results are scattered and do not allow to conclude about possible role of anti-glutamate action in the pharmacological profile of the drugs. Even if some data about activities are available, the mechanisms of action remain not completely understood. Details of mechanisms of action are of critical importance for channel ligands. For instance, inhibitory activity of competitive antagonists decreases when concentration of agonist increases, and thus they are less useful in preventing excitotoxicity due to excess of glutamate in pathological conditions. Also, in some cases the most active compounds are not the most therapeutically effective and well tolerated. That is especially true for antagonists of ionotropic glutamate receptors because of their ubiquitous expression. For example the underlying reasons for favorable clinical profile of memantine – NMDA receptor antagonist approved to treatment of Alzheimer’s disease – reside in the details of its mechanisms of action such as rather fast kinetics and partial trapping (Chen and Lipton, 2006).

In the present work we performed systematic electrophysiological analysis of action of the set of seven compounds (Table 1). The tested medicines belong to various structural classes and have different mechanisms of basic action. According to general classification amitriptyline and desipramine are TCA, citalopram and fluoxetine are SSRI, atomoxetine is SNRI; chlorpromazine is neuroleptic, and clozapine – atypical antipsychotic. The aim of the present study was not simple estimation of activities but included analysis of use- and voltage-dependence as well as influence of magnesium, which modulates NMDA receptor channels and interaction with organic blockers (Kotermanski and Johnson, 2009, Nikolaev et al., 2012).

Section snippets

Characterization of NMDA receptor channel block

For comparison with the previous studies we initially estimated the IC50 values of the NMDA receptor channel block at −80 mV membrane voltage. Drugs were applied simultaneously with the selective NMDA receptor agonist – NMDA (100 µM). The percentages of the steady-state current inhibition by different drug concentrations were obtained. Finally, we approximated the concentration-inhibition dependencies by Hill equation. The results are presented in the Table 1 and in Fig. 1. Desipramine,

Discussion

In the present work, we studied the direct interaction of some antidepressants with native ionotropic glutamate receptors in neurons of rat brain. Low anti-AMPA activity of most of the compounds studied proves that this type of receptor does not contribute to the pharmacological profile of antidepressants, although some activity of fluoxetine and desipramine deserves further analysis. In contrast, the drugs studied demonstrated large variations in anti-NMDA activity. Atomoxetine, desipramine

Experimental procedures

All experimental procedures were approved by Animal Care and Use Committee of the Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences. Outbred male Wistar rats of 13–18 days old and 25–35 g were obtained from local (IEPHB) facility. Maximum efforts were made to minimize the number of animals used and to minimize discomfort.

Rats were anesthetised with urethane and then decapitated. Brains were removed quickly and cooled to 2–4 °C. Transverse hippocampal

Acknowledgements

The study was supported by RFBR grants 13-04-00724 and 12-04-00454, and by a President of Russia grant MK-4651.2011.4.

References (59)

  • F. Freudenberg et al.

    The role of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in depression: central mediators of pathophysiology and antidepressant activity?

    Neurosci. Biobehav. Rev.

    (2015)
  • V. Hajhashemi et al.

    Antinociceptive effects of venlafaxine in a rat model of peripheral neuropathy: role of alpha2-adrenergic receptors

    Eur. J. Pharmacol.

    (2014)
  • J.W. Johnson et al.

    Recent insights into the mode of action of memantine and ketamine

    Curr. Opin. Pharmacol.

    (2015)
  • J.P. Kiss et al.

    GluN2B-containing NMDA receptors as possible targets for the neuroprotective and antidepressant effects of fluoxetine

    Neurochem. Int.

    (2012)
  • I. Koncz et al.

    The tricyclic antidepressant desipramine inhibited the neurotoxic, kainate-induced [Ca(2+)]i increases in CA1 pyramidal cells in acute hippocampal slices

    Brain Res. Bull.

    (2014)
  • J. Mika et al.

    Neuronal and immunological basis of action of antidepressants in chronic pain - clinical and experimental studies

    Pharmacol. Rep.

    (2013)
  • M.V. Nikolaev et al.

    Influence of external magnesium ions on the NMDA receptor channel block by different types of organic cations

    Neuropharmacology

    (2012)
  • M.C. Rowbotham et al.

    Treatment response in antidepressant-naive postherpetic neuralgia patients: double-blind, randomized trial

    J. Pain

    (2005)
  • B.K. Szasz et al.

    Direct inhibitory effect of fluoxetine on N-methyl-D-aspartate receptors in the central nervous system

    Biol. Psychiatry

    (2007)
  • A. Tefferi et al.

    Selective serotonin reuptake inhibitors are effective in the treatment of polycythemia vera-associated pruritus

    Blood

    (2002)
  • O. Theriault et al.

    Differential modulation of Nav1.7 and Nav1.8 channels by antidepressant drugs

    Eur. J. Pharmacol.

    (2015)
  • S.M. Thompson et al.

    An excitatory synapse hypothesis of depression

    Trends Neurosci.

    (2015)
  • M. Tohda et al.

    Inhibitory effects of antidepressants on NMDA-induced currents in Xenopus oocytes injected with rat brain RNA

    Neurochem. Int.

    (1995)
  • V.S. Vorobjev

    Vibrodissociation of sliced mammalian nervous tissue

    J. Neurosci. Methods

    (1991)
  • W. Wu et al.

    Amitriptyline modulates calcium currents and intracellular calcium concentration in mouse trigeminal ganglion neurons

    Neurosci. Lett.

    (2012)
  • E.D. Zarnowska et al.

    Differential effects of chlorpromazine on ionotropic glutamate receptors in cultured rat hippocampal neurons

    Neurosci. Lett.

    (2001)
  • R. Baron et al.

    Peripheral input and its importance for central sensitization

    Ann. Neurol.

    (2013)
  • O.I. Barygin et al.

    Non-classical mechanism of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor channel block by fluoxetine

    Eur. J. Neurosci.

    (2015)
  • E.P. Calandre et al.

    The role of antipsychotics in the management of fibromyalgia

    CNS Drugs

    (2012)
  • Cited by (48)

    • Drug repositioning: Using psychotropic drugs for the treatment of glioma

      2022, Cancer Letters
      Citation Excerpt :

      Chlorpromazine exerts potent anticholinergic, antidopaminergic, antihistaminergic, and anti-adrenergic effects by acting on target receptors expressed by neurons [11]. In addition, chlorpromazine inhibits N-methyl-d-aspartate (NMDA) receptors in a voltage- and magnesium-dependent manner in rat brain neurons [7]. Chlorpromazine has antiproliferative effects through different mechanisms in various tumor cells.

    View all citing articles on Scopus
    1

    Pavlov State Medical University, Saint-Petersburg, Russia.

    View full text