Antidepressant-Like Effects of CX717, a Positive Allosteric Modulator of AMPA Receptors


Conventional antidepressant drugs elevate the availability of monoamine neurotransmitters. However, these pharmacological therapies have limited efficacy and a slow onset of action as main limitations. New glutamatergic drugs such as ketamine have shown promise as a rapid-acting antidepressant drugs although with adverse effects. The mechanism of action of ketamine is hypothesized to involve a dis-inhibition of cortical pyramidal neurons produced by an stimulation of AMPA receptors by glutamate. In this context, low-impact positive allosteric modulators of the AMPA receptors (a.k.a. ampakines) have been regarded as potential antidepressant drugs. Here, we have examined the behavioral, biochemical, and molecular effects of a low-impact ampakine, CX717. Our results show that CX717 has a rapid (30 min) but short-lasting (up to 24 h) antidepressant-like effect in the forced swim test. Intra-cortical infusion of CX717 increases the efflux of noradrenaline, dopamine, and serotonin, but not glutamate. However, systemic CX717 does not alter these neurotransmitters. CX717 also produced a rapid (up to 1 h) increase of brain-derived neurotrophic factor (BDNF) and a more sustained (up to 6 h) increase of p11. Overall, CX717 appears to possess a rapid but not sustained antidepressant action possibly caused by rapid increases of BDNF and p11.

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  1. 1.

    Dingledine R, Borges K, Bowie D, Traynelis SF (1999) The glutamate receptor ion channels. Pharmacol Rev 51:7–61

    CAS  PubMed  Google Scholar 

  2. 2.

    Beneyto M, Kristiansen LV, Oni-Orisan A, McCullumsmith RE, Meador-Woodruff JH (2007) Abnormal glutamate receptor expression in the medial temporal lobe in schizophrenia and mood disorders. Neuropsychopharmacology 32:1888–1902

    CAS  PubMed  Google Scholar 

  3. 3.

    Duric V, Banasr M, Stockmeier CA, Simen AA, Newton SS, Overholser JC, Jurjus GJ, Dieter L et al (2013) Altered expression of synapse and glutamate related genes in post-mortem hippocampus of depressed subjects. Int J Neuropsychopharmacol 16:69–82

    CAS  PubMed  Google Scholar 

  4. 4.

    Wisden W, Seeburg PH, Monyer H (2000) AMPA, kainate and NMDA ionotropic glutamate receptor expression – an in situ hybridization atlas. In: Ottersen OP, Storm-Mathisen J (eds) Handbook of Chemical Neuroanatomy, Glutamate, vol 18. Elsevier, Amsterdam, pp. 99–143

    Google Scholar 

  5. 5.

    Beneyto M, Meador-Woodruff JH (2008) Lamina-specific abnormalities of NMDA receptor-associated postsynaptic protein transcripts in the prefrontal cortex in schizophrenia and bipolar disorder. Neuropsychopharmacology 33:2175–2186

    CAS  PubMed  Google Scholar 

  6. 6.

    Barbon A, Caracciolo L, Orlandi C, Musazzi L, Mallei A, La Via L, Bonini D, Mora C et al (2011) Chronic antidepressant treatments induce a time-dependent up-regulation of AMPA receptor subunit protein levels. Neurochem Int 59:896–905

    CAS  PubMed  Google Scholar 

  7. 7.

    Akinfiresoye L, Tizabi Y (2013) Antidepressant effects of AMPA and ketamine combination: role of hippocampal BDNF, synapsin, and mTOR. Psychopharmacology 230:291–298

    CAS  PubMed  Google Scholar 

  8. 8.

    Jiménez-Sánchez L, Castañé A, Pérez-Caballero L, Grifoll-Escoda M, López-Gil X, Campa L, Galofré M, Berrocoso E et al (2016) Activation of AMPA receptors mediates the antidepressant action of deep brain stimulation of the infralimbic prefrontal cortex. Cereb Cortex 26:2778–2789

    PubMed  Google Scholar 

  9. 9.

    Maeng S, Zarate CA Jr, Du J, Schloesser RJ, McCammon J, Chen G, Manji HK (2008) Cellular mechanisms underlying the antidepressant effects of ketamine: Role of a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biol Psychiatry 63:349–352

    CAS  PubMed  Google Scholar 

  10. 10.

    Autry AE, Adachi M, Nosyreva E, Na ES, Los MF, Cheng PF, Kavalali ET, Monteggia LM (2011) NMDA receptor blockade at rest triggers rapid behavioural antidepressant responses. Nature 475:91–95

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Koike H, Iijima M, Chaki S (2011) Involvement of AMPA receptor in both the rapid and sustained antidepressant-like effects of ketamine in animal models of depression. Behav Brain Res 224:107–111

    CAS  PubMed  Google Scholar 

  12. 12.

    Melendez RI, Kalivas PW (2003) Metabotropic glutamate receptor regulation of extracellular glutamate levels in the prefrontal cortex. Ann NY Acad. Sci 1003:443–444

    PubMed  Google Scholar 

  13. 13.

    Xi ZX, Baker DA, Shen H, Carson DS, Kalivas PW (2002) Group II metabotropic glutamate receptors modulate extracellular glutamate in the nucleus accumbens. J Pharmacol Exp Ther 300:162–171

    CAS  PubMed  Google Scholar 

  14. 14.

    Karasawa J, Shimazaki T, Kawashima N, Chaki S (2005) AMPA receptor stimulation mediates the antidepressant-like effect of a group II metabotropic glutamate receptor antagonist. Brain Res 1042:92–98

    CAS  PubMed  Google Scholar 

  15. 15.

    Witkin JM, Monn JA, Schoepp DD, Li X, Overshiner C, Mitchell SN, Carter G, Johnson B et al (2016) The rapidly acting antidepressant ketamine and the mGlu2/3 receptor antagonist LY341495 rapidly engage dopaminergic mood circuits. J Pharmacol Exp Ther 358:71–82

    CAS  PubMed  Google Scholar 

  16. 16.

    Derkach VA, Oh MC, Guire ES, Soderling TR (2007) Regulatory mechanisms of AMPA receptors in synaptic plasticity. Nat Rev Neurosci 8:101–113

    CAS  PubMed  Google Scholar 

  17. 17.

    O'Neill MJ, Dix S (2007) AMPA receptor potentiators as cognitive enhancers. IDrugs 10:185–192

    CAS  PubMed  Google Scholar 

  18. 18.

    Hampson RE, España RA, Rogers GA, Porrino LJ, Deadwyler SA (2009) Mechanisms underlying cognitive enhancement and reversal of cognitive deficits in nonhuman primates by the ampakine CX717. Psychopharmacology 202:355–369

    CAS  PubMed  Google Scholar 

  19. 19.

    Kunugi A, Tanaka M, Suzuki A, Tajima Y, Suzuki N, Suzuki M, Nakamura S, Kuno H et al (2019) TAK-137, an AMPA-R potentiator with little agonistic effect, has a wide therapeutic window. Neuropsychopharmacology 44:961–970

    CAS  PubMed  Google Scholar 

  20. 20.

    Meldrum BS (1994) The role of glutamate in epilepsy and other CNS disorders. Neurology 44(Suppl 8):S14–S23

    CAS  PubMed  Google Scholar 

  21. 21.

    Lynch G (2006) Glutamate-based therapeutic approaches: ampakines. Curr Opin Pharmacol 6:82–88

    CAS  PubMed  Google Scholar 

  22. 22.

    Lapidus KA, Soleimani L, Murrough JW (2013) Novel glutamatergic drugs for the treatment of mood disorders. Neuropsychiatr Dis Treat 9:1101–1112

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Arai A, Guidotti A, Costa E, Lynch G (1996) Effect of the AMPA receptor modulator IDRA 21 on LTP in hippocampal slices. Neuroreport 7:2211–2215

    CAS  PubMed  Google Scholar 

  24. 24.

    Li X, Tizzano JP, Griffey K, Clay M, Lindstrom T, Skolnick P (2001) Antidepressant-like actions of an AMPA receptor potentiator (LY392098). Neuropharmacology 40:1028–1033

    CAS  PubMed  Google Scholar 

  25. 25.

    Knapp RJ, Goldenberg R, Shuck C, Cecil A, Watkins J, Miller C, Crites G, Malatynska E (2002) Antidepressant activity of memory-enhancing drugs in the reduction of submissive behavior model. Eur J Pharmacol 440:27–35

    CAS  PubMed  Google Scholar 

  26. 26.

    Alt A, Nisenbaum ES, Bleakman D, Witkin JM (2006) A role for AMPA receptors in mood disorders. Biochem Pharmacol 71:1273–1288

    CAS  PubMed  Google Scholar 

  27. 27.

    Boyle J, Stanley N, James LM, Wright N, Johnsen S, Arbon EL, Dijk DJ (2012) Acute sleep deprivation: the effects of the AMPAKINE compound CX717 on human cognitive performance, alertness and recovery sleep. J Psychopharmacol 26:1047–1057

    PubMed  Google Scholar 

  28. 28.

    Oertel BG, Felden L, Tran PV, Bradshaw MH, Angst MS, Schmidt H, Johnson S, Greer JJ et al (2010) Selective antagonism of opioid-induced ventilatory depression by an ampakine molecule in humans without loss of opioid analgesia. Clin Pharmacol Ther 87:204–211

    CAS  PubMed  Google Scholar 

  29. 29.

    Wesensten NJ, Reichardt RM, Balkin TJ (2007) Ampakine (CX717) effects on performance and alertness during simulated night shift work. Aviat Space Environ Med 78:937–943

    CAS  PubMed  Google Scholar 

  30. 30.

    Porrino LJ, Daunais JB, Rogers GA, Hampson RE, Deadwyler SA (2005) Facilitation of task performance and removal of the effects of sleep deprivation by an ampakine (CX717) in nonhuman primates. PLoS Biol 3:e299

    PubMed  PubMed Central  Google Scholar 

  31. 31.

    Andreasen JT, Gynther M, Rygaard A, Bøgelund T, Nielsen SD, Clausen RP, Mogensen J, Pickering DS (2013) Does increasing the ratio of AMPA-to-NMDA receptor mediated neurotransmission engender antidepressant action? Studies in the mouse forced swim and tail suspension tests. Neurosci Lett 546:6–10

    CAS  PubMed  Google Scholar 

  32. 32.

    Li X, Witkin JM, Need AB, Skolnick P (2003) Enhancement of antidepressant potency by a potentiator of AMPA receptors. Cell Mol Neurobiol 23:419–430

    CAS  PubMed  Google Scholar 

  33. 33.

    Ren J, Lenal F, Yang M, Ding X, Greer JJ (2013) Coadministration of the AMPAKINE CX717 with propofol reduces respiratory depression and fatal apneas. Anesthesiology 118:1437–1445

    CAS  PubMed  Google Scholar 

  34. 34.

    Ren J, Ding X, Greer JJ (2012) Respiratory depression in rats induced by alcohol and barbiturate and rescue by ampakine CX717. J Appl Physiol 113:1004–1011

    CAS  PubMed  PubMed Central  Google Scholar 

  35. 35.

    Cryan JF, Valentino RJ, Lucki I (2005) Assessing substrates underlying the behavioral effects of antidepressants using the modi?ed rat forced swimming test. Neurosci Biobehav Rev 29:547–569

    CAS  PubMed  Google Scholar 

  36. 36.

    Benveniste H, Diemer NH (1987) Cellular reactions to implantation of a microdialysis tube in the rat hippocampus. Acta Neuropathol 74:234–238

    CAS  PubMed  Google Scholar 

  37. 37.

    Benveniste H, Drejer J, Schousboe A, Diemer NH (1987) Regional cerebral glucose phosphorylation and blood flow after insertion of a microdialysis fiber through the dorsal hippocampus in the rat. J Neurochem 49:729–734

    CAS  PubMed  Google Scholar 

  38. 38.

    Detke MJ, Rickels M, Lucki I (1995) Active behaviors in the rat forced swimming test differentially produced by serotonergic and noradrenergic antidepressants. Psychopharmacology 121:66–72

    CAS  PubMed  Google Scholar 

  39. 39.

    Paxinos C, Watson D (2005) The rat brain in stereotaxic coordinates. Elsevier/Academic Press, Amsterdam

    Google Scholar 

  40. 40.

    Mayberg HS, Lozano AM, Voon V, McNeely HE, Seminowicz D, Hamani C, Schwalb JM, Kennedy SH (2005) Deep brain stimulation for treatment-resistant depression. Neuron 45:651–660

    CAS  PubMed  Google Scholar 

  41. 41.

    Arai AC, Xia YF, Rogers G, Lynch G, Kessler M (2002) Benzamide-type AMPA receptor modulators form two subfamilies with distinct modes of action. J Pharmacol Exp Ther 303:1075–1085

    CAS  PubMed  Google Scholar 

  42. 42.

    Mul JD, Zheng J, Goodyear LJ (2016) Validity assessment of 5 day repeated forced-swim stress to model human depression in young-adult C57BL/6J and BALB/cJ mice. eNeuro 29:3

    Google Scholar 

  43. 43.

    Mezadri TJ, Batista GM, Portes AC, Marino-Neto J, Lino-de-Oliveira C (2011) Repeated rat-forced swim test: reducing the number of animals to evaluate gradual effects of antidepressants. J Neurosci Methods 195:200–205

    CAS  PubMed  Google Scholar 

  44. 44.

    Gordillo-Salas M, Pilar-Cuéllar F, Auberson YP, Adell A (2018) Signaling pathways responsible for the rapid antidepressant-like effects of a GluN2A-preferring NMDA receptor antagonist. Transl Psychiatry 8:84

    PubMed  PubMed Central  Google Scholar 

  45. 45.

    Lucas G, Rymar VV, Du J, Mnie-Filali O, Bisgaard C, Manta S, Lambas-Senas L, Wiborg O et al (2007) Serotonin4 (5-HT4) receptor agonists are putative antidepressants with a rapid onset of action. Neuron 55:712–725

    CAS  PubMed  Google Scholar 

  46. 46.

    Ramboz S, Oosting R, Amara DA, Kung HF, Blier P, Mendelsohn M, Mann JJ, Brunner D et al (1998) Serotonin receptor 1A knockout: an animal model of anxiety-related disorder. Proc Natl Acad Sci USA 95:14476–14481

    CAS  PubMed  Google Scholar 

  47. 47.

    Richardson-Jones JW, Craige CP, Guiard BP, Stephen A, Metzger KL, Kung HF, Gardier AM, Dranovsky A et al (2010) 5-HT1A autoreceptor levels determine vulnerability to stress and response to antidepressants. Neuron 65:40–52

    CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Bortolozzi A, Castañé A, Semakova J, Santana N, Alvarado G, Cortés R, Ferrés-Coy A, Fernández G et al (2012) Selective siRNA-mediated suppression of 5-HT1A autoreceptors evokes strong anti-depressant-like effects. Mol Psychiatry 17:612–623

    CAS  PubMed  Google Scholar 

  49. 49.

    Jedema HP, Moghaddam B (1994) Glutamatergic control of dopamine release during stress in the rat prefrontal cortex. J Neurochem 63:785–788

    CAS  PubMed  Google Scholar 

  50. 50.

    Covington HE 3rd, Lobo MK, Maze I, Vialou V, Hyman JM, Zaman S, LaPlant Q, Mouzon E et al (2010) Antidepressant effect of optogenetic stimulation of the medial prefrontal cortex. J Neurosci 30:16082–16090

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Warden MR, Selimbeyoglu A, Mirzabekov JJ, Lo M, Thompson KR, Kim SY, Adhikari A, Tye KM et al (2012) A prefrontal cortex-brainstem neuronal projection that controls response to behavioural challenge. Nature 492:428–432

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Chaudhury D, Walsh JJ, Friedman AK, Juarez B, Ku SM, Koo JW, Ferguson D, Tsai HC et al (2013) Rapid regulation of depression-related behaviours by control of midbrain dopamine neurons. Nature 493:532–536

    CAS  PubMed  Google Scholar 

  53. 53.

    Lauterborn JC, Lynch G, Vanderklish P, Arai A, Gall CM (2000) Positive modulation of AMPA receptors increases neurotrophin expression by hippocampal and cortical neurons. J Neurosci 20:8–21

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Mackowiak M, O'Neill MJ, Hicks CA, Bleakman D, Skolnick P (2002) An AMPA receptor potentiator modulates hippocampal expression of BDNF: an in vivo study. Neuropharmacology 43:1–10

    CAS  PubMed  Google Scholar 

  55. 55.

    Radin DP, Johnson S, Purcell R, Lippa AS (2018) Effects of chronic systemic low-impact ampakine treatment on neurotrophin expression in rat brain. Biomed Pharmacother 105:540–544

    CAS  PubMed  Google Scholar 

  56. 56.

    Nibuya M, Morinobu S, Duman RS (1995) Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci 15:7539–7547

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Björkholm C, Monteggia LM (2016) BDNF - A key transducer of antidepressant effects. Neuropharmacology 102:72–79

    PubMed  Google Scholar 

  58. 58.

    Ramaker MJ, Dulawa SC (2017) Identifying fast-onset antidepressants using rodent models. Mol Psychiatry 22:656–665

    CAS  PubMed  Google Scholar 

  59. 59.

    Jourdi H, Hsu YT, Zhou M, Qin Q, Bi X, Baudry M (2009) Positive AMPA receptor modulation rapidly stimulates BDNF release and increases dendritic mRNA translation. J Neurosci 29:8688–8697

    CAS  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Nikonenko I, Boda B, Steen S, Knott G, Welker E, Muller D (2008) PSD-95 promotes synaptogenesis and multiinnervated spine formation through nitric oxide signaling. J Cell Biol 183:1115–1127

    CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Svenningsson P, Kim Y, Warner-Schmidt J, Oh YS, Greengard P (2013) p11 and its role in depression and therapeutic responses to antidepressants. Nat Rev Neurosci 14:673–680

    CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Warner-Schmidt JL, Schmidt EF, Marshall JJ, Rubin AJ, Arango-Lievano M, Kaplitt MG, Ibañez-Tallon I, Heintz N et al (2012) Cholinergic interneurons in the nucleus accumbens regulate depression-like behavior. Proc Natl Acad Sci USA 109:11360–11365

    CAS  PubMed  Google Scholar 

  63. 63.

    Svenningsson P, Chergui K, Rachleff I, Flajolet M, Zhang X, El Yacoubi M, Vaugeois JM, Nomikos GG et al (2006) Alterations in 5-HT1B receptor function by p11 in depression-like states. Science 311:77–80

    CAS  PubMed  Google Scholar 

  64. 64.

    Warner-Schmidt JL, Chen EY, Zhang X, Marshall JJ, Morozov A, Svenningsson P, Greengard P (2010) A role for p11 in the antidepressant action of brain-derived neurotrophic factor. Biol Psychiatry 68:528–535

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    ®2015 Allen Institute for Brain Science. Allen Brain Atlas API. Available from:

  66. 66.

    Schmidt EF, Warner-Schmidt JL, Otopalik BG, Pickett SB, Greengard P, Heintz N (2012) Identification of the cortical neurons that mediate antidepressant responses. Cell 149:1152–1163

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Freudenberg F, Celikel T, Reif A (2015) The role of a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in depression: central mediators of pathophysiology and antidepressant activity? Neurosci Biobehav Rev 52:193–206

    CAS  PubMed  Google Scholar 

  68. 68.

    Martínez-Turrillas R, Del Río J, Frechilla D (2005) Sequential changes in BDNF mRNA expression and synaptic levels of AMPA receptor subunits in rat hippocampus after chronic antidepressant treatment. Neuropharmacology 49:1178–1188

    PubMed  Google Scholar 

  69. 69.

    Li N, Lee B, Liu RJ, Banasr M, Dwyer JM, Iwata M, Li XY, Aghajanian G et al (2010) mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science 329:959–964

    CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Duman RS, Shinohara R, Fogaça MV, Hare B (2019) Neurobiology of rapid-acting antidepressants: convergent effects on GluA1-synaptic function. Mol Psychiatry 24:1816–1832

    PubMed  PubMed Central  Google Scholar 

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We thank RespireRX Pharmaceuticals for the generous gift of CX717.


This work was supported by the Instituto de Salud Carlos III, Subdirección General de Evaluación y Fomento de la Investigación (FIS Grant PI16/00217) that was co-funded by the European Regional Development Fund (‘A way to build Europe’). Funding from the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III is also acknowledged. The funding agencies had no role in the design and conduct of the study, collection, management, analyses, and interpretation of the data; and preparation, review, or approval of the manuscript and the decision to submit it for publication. MG-S and RP-A were recipients of contracts from the Sistema Nacional de Garantía Juvenil co-funded by the European Social Fund..

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Correspondence to Albert Adell.

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Gordillo-Salas, M., Pascual-Antón, R., Ren, J. et al. Antidepressant-Like Effects of CX717, a Positive Allosteric Modulator of AMPA Receptors. Mol Neurobiol 57, 3498–3507 (2020).

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  • Ampakine
  • Antidepressant
  • Prefrontal cortex
  • BDNF
  • p11