Skip to main content
SpringerLink
Log in

Antidepressants that inhibit both serotonin and norepinephrine reuptake impair long-term potentiation in hippocampus

  • Original Investigation
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

Rationale

Monoamine reuptake inhibitors can stimulate expression of brain-derived neurotrophic factor (BDNF) and alter long-term potentiation (LTP), a widely used model for the synaptic mechanisms that underlie memory formation. BDNF expression is upregulated during LTP, and BDNF in turn positively modulates LTP. Previously, we found that treatment with venlafaxine, a serotonin and norepinephrine reuptake inhibitor (SNRI), but not citalopram, a selective serotonin reuptake inhibitor (SSRI), reduced LTP in hippocampal area CA1 without changing hippocampal BDNF protein expression.

Objectives

We tested the hypothesis that combined serotonin and norepinephrine reuptake inhibition is necessary for LTP impairment, and we reexamined the potential role of BDNF by testing for region-specific changes in areas CA1, CA3, and dentate gyrus. We also tested whether early events in the LTP signaling pathway were altered to impair LTP.

Methods

Animals were treated for 21 days with venlafaxine, imipramine, fluoxetine, or maprotiline. In vitro hippocampal slices were used for electrophysiological measurements. Protein expression was measured by enzyme-linked immunosorbent assay (ELISA) and Western blotting.

Results

LTP was impaired only following treatment with combined serotonin and norepinephrine reuptake inhibitors (venlafaxine, imipramine) but not with selective serotonin (fluoxetine) or norepinephrine (maprotiline) reuptake inhibitors. BDNF protein expression was not altered by venlafaxine or imipramine treatment, nor were postsynaptic depolarization during LTP inducing stimulation or synaptic membrane NMDA receptor subunit expression affected.

Conclusions

LTP is impaired by chronic treatment with antidepressant that inhibit both serotonin and norepinephrine reuptake; this impairment results from changes that are downstream of postsynaptic depolarization and calcium influx.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Altar CA, Whitehead RE, Chen R et al (2003) Effects of electroconvulsive seizures and antidepressant drugs on brain-derived neurotrophic factor protein in rat brain. Biol Psychiatry 54:703–709

    Article  CAS  PubMed  Google Scholar 

  • Anwyl R, Walshe J, Rowan M (1987) Electroconvulsive treatment reduces long-term potentiation in rat hippocampus. Brain Res 435:377–379

    Article  CAS  PubMed  Google Scholar 

  • Aydemir O, Deveci A, Taneli F (2005) The effect of chronic antidepressant treatment on serum brain-derived neurotrophic factor levels in depressed patients: a preliminary study. Prog Neuropsychopharmacol Biol Psychiatry 29:261–265. doi:10.1016/j.pnpbp.2004.11.009

    Article  CAS  PubMed  Google Scholar 

  • Balu DT, Hoshaw BA, Malberg JE et al (2008) Differential regulation of central BDNF protein levels by antidepressant and non-antidepressant drug treatments. Brain Res 1211:37–43. doi:10.1016/j.brainres.2008.03.023

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Barbiero VS, Giambelli R, Musazzi L et al (2007) Chronic antidepressants induce redistribution and differential activation of alphaCaM kinase II between presynaptic compartments. Neuropsychopharmacology 32:2511–2519. doi:10.1038/sj.npp.1301378

    Article  CAS  PubMed  Google Scholar 

  • Bath KG, Jing DQ, Dincheva I et al (2012) BDNF Val66Met impairs fluoxetine-induced enhancement of adult hippocampus plasticity. Neuropsychopharmacology 37:1297–1304. doi:10.1038/npp.2011.318

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bliss TV, Collingridge GL (1993) A synaptic model of memory: long-term potentiation in the hippocampus. Nature 361:31–39. doi:10.1038/361031a0

    Article  CAS  PubMed  Google Scholar 

  • Blundon JA, Zakharenko SS (2008) Dissecting the components of long-term potentiation. Neuroscientist 14:598–608. doi:10.1177/1073858408320643

    Article  PubMed Central  PubMed  Google Scholar 

  • Calabrese F, Molteni R, Racagni G, Riva MA (2009) Neuronal plasticity: a link between stress and mood disorders. Psychoneuroendocrinology 34(Suppl 1):S208–S216. doi:10.1016/j.psyneuen.2009.05.014

    Article  CAS  PubMed  Google Scholar 

  • Campbell IG, Guinan MJ, Horowitz JM (2002) Sleep deprivation impairs long-term potentiation in rat hippocampal slices. J Neurophysiol 88:1073–1076

    CAS  PubMed  Google Scholar 

  • Castrén E, Rantamäki T (2010) Role of brain-derived neurotrophic factor in the aetiology of depression: implications for pharmacological treatment. CNS Drugs 24:1–7. doi:10.2165/11530010-000000000-00000

    Article  PubMed  Google Scholar 

  • Castrén E, Pitkänen M, Sirviö J et al (1993) The induction of LTP increases BDNF and NGF mRNA but decreases NT-3 mRNA in the dentate gyrus. Neuroreport 4:895–898

    Article  PubMed  Google Scholar 

  • Castrén E, Võikar V, Rantamäki T (2007) Role of neurotrophic factors in depression. Curr Opin Pharmacol 7:18–21. doi:10.1016/j.coph.2006.08.009

    Article  PubMed  Google Scholar 

  • Cooke JD, Grover LM, Spangler PR (2009) Venlafaxine treatment stimulates expression of brain-derived neurotrophic factor protein in frontal cortex and inhibits long-term potentiation in hippocampus. Neuroscience 162:1411–1419. doi:10.1016/j.neuroscience.2009.05.037

    Article  CAS  PubMed  Google Scholar 

  • Davis CJ, Harding JW, Wright JW (2003) REM sleep deprivation-induced deficits in the latency-to-peak induction and maintenance of long-term potentiation within the CA1 region of the hippocampus. Brain Res 973:293–297

    Article  CAS  PubMed  Google Scholar 

  • De Foubert G, Carney SL, Robinson CS et al (2004) Fluoxetine-induced change in rat brain expression of brain-derived neurotrophic factor varies depending on length of treatment. Neuroscience 128:597–604. doi:10.1016/j.neuroscience.2004.06.054

    Article  PubMed  Google Scholar 

  • Deisseroth K, Bito H, Tsien RW (1996) Signaling from synapse to nucleus: postsynaptic CREB phosphorylation during multiple forms of hippocampal synaptic plasticity. Neuron 16:89–101

    Article  CAS  PubMed  Google Scholar 

  • Del Cerro S, Jung M, Lynch G (1992) Benzodiazepines block long-term potentiation in slices of hippocampus and piriform cortex. Neuroscience 49:1–6

    Article  PubMed  Google Scholar 

  • Desmond NL, Colbert CM, Zhang DX, Levy WB (1991) NMDA receptor antagonists block the induction of long-term depression in the hippocampal dentate gyrus of the anesthetized rat. Brain Res 552:93–98

    Article  CAS  PubMed  Google Scholar 

  • Duman RS, Monteggia LM (2006) A neurotrophic model for stress-related mood disorders. Biol Psychiatry 59:1116–1127. doi:10.1016/j.biopsych.2006.02.013

    Article  CAS  PubMed  Google Scholar 

  • Eitan R, Lerer B (2006) Nonpharmacological, somatic treatments of depression: electroconvulsive therapy and novel brain stimulation modalities. Dialogues Clin Neurosci 8:241–258

    PubMed Central  PubMed  Google Scholar 

  • Figurov A, Pozzo-Miller LD, Olafsson P et al (1996) Regulation of synaptic responses to high-frequency stimulation and LTP by neurotrophins in the hippocampus. Nature 381:706–709. doi:10.1038/381706a0

    Article  CAS  PubMed  Google Scholar 

  • Gonul AS, Akdeniz F, Taneli F et al (2005) Effect of treatment on serum brain-derived neurotrophic factor levels in depressed patients. Eur Arch Psychiatry Clin Neurosci 255:381–386. doi:10.1007/s00406-005-0578-6

    Article  PubMed  Google Scholar 

  • Greenberg ME, Xu B, Lu B, Hempstead BL (2009) New insights in the biology of BDNF synthesis and release: implications in CNS function. J Neurosci 29:12764–12767. doi:10.1523/JNEUROSCI.3566-09.2009

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Grey KB, Burrell BD (2011) Seasonal variation of long-term potentiation at a central synapse in the medicinal leech. J Exp Biol 214:2534–2539. doi:10.1242/jeb.057224

    Article  PubMed Central  PubMed  Google Scholar 

  • Grover LM, Yan C (1999) Blockade of GABAA receptors facilitates induction of NMDA receptor-independent long-term potentiation. J Neurophysiol 81:2814–2822

    CAS  PubMed  Google Scholar 

  • Grover LM, Kim E, Cooke JD, Holmes WR (2009) LTP in hippocampal area CA1 is induced by burst stimulation over a broad frequency range centered around delta. Learn Mem 16:69–81. doi:10.1101/lm.1179109

    Article  PubMed Central  PubMed  Google Scholar 

  • Hashimoto K (2011) The role of glutamate on the action of antidepressants. Prog Neuropsychopharmacol Biol Psychiatry 35:1558–1568. doi:10.1016/j.pnpbp.2010.06.013

    Article  CAS  PubMed  Google Scholar 

  • Herron CE, Lester RA, Coan EJ, Collingridge GL (1986) Frequency-dependent involvement of NMDA receptors in the hippocampus: a novel synaptic mechanism. Nature 322:265–268. doi:10.1038/322265a0

    Article  CAS  PubMed  Google Scholar 

  • Higashima M, Kinoshita H, Koshino Y (1998) Differences in the effects of zolpidem and diazepam on recurrent inhibition and long-term potentiation in rat hippocampal slices. Neurosci Lett 245:77–80

    Article  CAS  PubMed  Google Scholar 

  • Karege F, Perret G, Bondolfi G et al (2002) Decreased serum brain-derived neurotrophic factor levels in major depressed patients. Psychiatry Res 109:143–148

    Article  CAS  PubMed  Google Scholar 

  • Kasahara J, Fukunaga K, Miyamoto E (2001) Activation of calcium/calmodulin-dependent protein kinase IV in long term potentiation in the rat hippocampal CA1 region. J Biol Chem 276:24044–24050. doi:10.1074/jbc.M100247200

    Article  CAS  PubMed  Google Scholar 

  • Kim EY, Mahmoud GS, Grover LM (2005) REM sleep deprivation inhibits LTP in vivo in area CA1 of rat hippocampus. Neurosci Lett 388:163–167. doi:10.1016/j.neulet.2005.06.057

    Article  CAS  PubMed  Google Scholar 

  • Kim E, Grover LM, Bertolotti D, Green TL (2010) Growth hormone rescues hippocampal synaptic function after sleep deprivation. Am J Physiol Regul Integr Comp Physiol 298:R1588–R1596. doi:10.1152/ajpregu.00580.2009

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Klein R, Conway D, Parada LF, Barbacid M (1990) The trkB tyrosine protein kinase gene codes for a second neurogenic receptor that lacks the catalytic kinase domain. Cell 61:647–656

    Article  CAS  PubMed  Google Scholar 

  • Kojima T, Matsumoto M, Togashi H et al (2003) Fluvoxamine suppresses the long-term potentiation in the hippocampal CA1 field of anesthetized rats: an effect mediated via 5-HT1A receptors. Brain Res 959:165–168

    Article  CAS  PubMed  Google Scholar 

  • Larson J, Wong D, Lynch G (1986) Patterned stimulation at the theta frequency is optimal for the induction of hippocampal long-term potentiation. Brain Res 368:347–350

    Article  CAS  PubMed  Google Scholar 

  • Linington A, Harris B (1988) Fifty years of electroconvulsive therapy. BMJ 297:1354–1355

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lu YF, Kandel ER, Hawkins RD (1999) Nitric oxide signaling contributes to late-phase LTP and CREB phosphorylation in the hippocampus. J Neurosci 19:10250–10261

    CAS  PubMed  Google Scholar 

  • Malenka RC, Bear MF (2004) LTP and LTD: an embarrassment of riches. Neuron 44:5–21. doi:10.1016/j.neuron.2004.09.012

    Article  CAS  PubMed  Google Scholar 

  • Maren S, Baudry M, Thompson RF (1991) Differential effects of ketamine and MK-801 on the induction of long-term potentiation. Neuroreport 2:239–242

    Article  CAS  PubMed  Google Scholar 

  • Massicotte G, Bernard J, Ohayon M (1993) Chronic effects of trimipramine, an antidepressant, on hippocampal synaptic plasticity. Behav Neural Biol 59:100–106

    Article  CAS  PubMed  Google Scholar 

  • Middlemas DS, Lindberg RA, Hunter T (1991) trkB, a neural receptor protein-tyrosine kinase: evidence for a full-length and two truncated receptors. Mol Cell Biol 11:143–153

    CAS  PubMed Central  PubMed  Google Scholar 

  • Minichiello L (2009) TrkB signalling pathways in LTP and learning. Nat Rev Neurosci 10:850–860. doi:10.1038/nrn2738

    Article  CAS  PubMed  Google Scholar 

  • Mnie-Filali O, El Mansari M, Espana A et al (2006) Allosteric modulation of the effects of the 5-HT reuptake inhibitor escitalopram on the rat hippocampal synaptic plasticity. Neurosci Lett 395:23–27. doi:10.1016/j.neulet.2005.10.044

    Article  CAS  PubMed  Google Scholar 

  • 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  Google Scholar 

  • Nibuya M, Nestler EJ, Duman RS (1996) Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus. J Neurosci 16:2365–2372

    CAS  PubMed  Google Scholar 

  • Ohashi S, Matsumoto M, Otani H et al (2002) Changes in synaptic plasticity in the rat hippocampo-medial prefrontal cortex pathway induced by repeated treatments with fluvoxamine. Brain Res 949:131–138

    Article  CAS  PubMed  Google Scholar 

  • Ohashi S, Togashi H, Matsumoto M et al (2003) Changes in synaptic properties in cortical-limbic communications induced by repeated treatments with fluvoxamine in rats. J Pharmacol Sci 92:100–107

    Article  CAS  PubMed  Google Scholar 

  • Pang PT, Teng HK, Zaitsev E et al (2004) Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science 306:487–491. doi:10.1126/science.1100135

    Article  CAS  PubMed  Google Scholar 

  • Patterson SL, Grover LM, Schwartzkroin PA, Bothwell M (1992) Neurotrophin expression in rat hippocampal slices: a stimulus paradigm inducing LTP in CA1 evokes increases in BDNF and NT-3 mRNAs. Neuron 9:1081–1088

    Article  CAS  PubMed  Google Scholar 

  • Patterson SL, Abel T, Deuel TA et al (1996) Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice. Neuron 16:1137–1145

    Article  CAS  PubMed  Google Scholar 

  • Poo MM (2001) Neurotrophins as synaptic modulators. Nat Rev Neurosci 2:24–32. doi:10.1038/35049004

    Article  CAS  PubMed  Google Scholar 

  • Randrup A, Braestrup C (1977) Uptake inhibition of biogenic amines by newer antidepressant drugs: relevance to the dopamine hypothesis of depression. Psychopharmacology (Berlin) 53:309–314

    Article  CAS  Google Scholar 

  • Reichardt LF (2006) Neurotrophin-regulated signalling pathways. Philos Trans R Soc Lond B Biol Sci 361:1545–1564

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Reynolds IJ, Miller RJ (1988) Tricyclic antidepressants block N-methyl-d-aspartate receptors: similarities to the action of zinc. Br J Pharmacol 95:95–102

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Roy A, Bhanji S (1976) Sleep deprivation treatment in depression: a review. Postgrad Med J 52:50–52

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Rubio FJ, Ampuero E, Sandoval R et al (2013) Long-term fluoxetine treatment induces input-specific LTP and LTD impairment and structural plasticity in the CA1 hippocampal subfield. Front Cell Neurosci 7:66. doi:10.3389/fncel.2013.00066

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Russo-Neustadt AA, Beard RC, Huang YM, Cotman CW (2000) Physical activity and antidepressant treatment potentiate the expression of specific brain-derived neurotrophic factor transcripts in the rat hippocampus. Neuroscience 101:305–312

    Article  CAS  PubMed  Google Scholar 

  • Schildkraut JJ (1965) The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am J Psychiatry 122:509–522

    CAS  PubMed  Google Scholar 

  • Schwaninger M, Schöfl C, Blume R et al (1995) Inhibition by antidepressant drugs of cyclic AMP response element-binding protein/cyclic AMP response element-directed gene transcription. Mol Pharmacol 47:1112–1118

    CAS  PubMed  Google Scholar 

  • Sernagor E, Kuhn D, Vyklicky L Jr, Mayer ML (1989) Open channel block of NMDA receptor responses evoked by tricyclic antidepressants. Neuron 2:1221–1227

    Article  CAS  PubMed  Google Scholar 

  • Shimizu E, Hashimoto K, Okamura N et al (2003) Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants. Biol Psychiatry 54:70–75

    Article  CAS  PubMed  Google Scholar 

  • Silva AJ, Stevens CF, Tonegawa S, Wang Y (1992) Deficient hippocampal long-term potentiation in alpha-calcium-calmodulin kinase II mutant mice. Science 257:201–206

    Article  CAS  PubMed  Google Scholar 

  • Skolnick P, Popik P, Trullas R (2009) Glutamate-based antidepressants: 20 years on. Trends Pharmacol Sci 30:563–569. doi:10.1016/j.tips.2009.09.002

    Article  CAS  PubMed  Google Scholar 

  • Stewart CA, Reid IC (2000) Repeated ECS and fluoxetine administration have equivalent effects on hippocampal synaptic plasticity. Psychopharmacology (Berlin) 148:217–223

    Article  CAS  Google Scholar 

  • Tachibana K, Matsumoto M, Togashi H et al (2004) Milnacipran, a serotonin and noradrenaline reuptake inhibitor, suppresses long-term potentiation in the rat hippocampal CA1 field via 5-HT1A receptors and alpha 1-adrenoceptors. Neurosci Lett 357:91–94. doi:10.1016/j.neulet.2003.11.016

    Article  CAS  PubMed  Google Scholar 

  • Tachibana K, Matsumoto M, Koseki H et al (2006) Electrophysiological and neurochemical characterization of the effect of repeated treatment with milnacipran on the rat serotonergic and noradrenergic systems. J Psychopharmacol (Oxford) 20:562–569. doi:10.1177/0269881106059694

    Article  CAS  Google Scholar 

  • Tardito D, Perez J, Tiraboschi E et al (2006) Signaling pathways regulating gene expression, neuroplasticity, and neurotrophic mechanisms in the action of antidepressants: a critical overview. Pharmacol Rev 58:115–134. doi:10.1124/pr.58.1.7

    Article  CAS  PubMed  Google Scholar 

  • Thome J, Sakai N, Shin K et al (2000) cAMP response element-mediated gene transcription is upregulated by chronic antidepressant treatment. J Neurosci 20:4030–4036

    CAS  PubMed  Google Scholar 

  • Tiraboschi E, Giambelli R, D’Urso G et al (2004a) Antidepressants activate CaMKII in neuron cell body by Thr286 phosphorylation. Neuroreport 15:2393–2396

    Article  CAS  PubMed  Google Scholar 

  • Tiraboschi E, Tardito D, Kasahara J et al (2004b) Selective phosphorylation of nuclear CREB by fluoxetine is linked to activation of CaM kinase IV and MAP kinase cascades. Neuropsychopharmacology 29:1831–1840. doi:10.1038/sj.npp.1300488

    Article  CAS  PubMed  Google Scholar 

  • Trepel C, Racine RJ (1999) Blockade and disruption of neocortical long-term potentiation following electroconvulsive shock in the adult, freely moving rat. Cereb Cortex 9:300–305

    Article  CAS  PubMed  Google Scholar 

  • Walton JC, Chen Z, Weil ZM, Pyter LM, Travers JB, Nelson RJ (2011) Photoperiod-mediated impairment of long-term potentiation and learning and memory in male white-footed mice. Neurosci 175:127–132. doi:10.1016/j.neuroscience.2010.12.004

    Article  CAS  Google Scholar 

  • Wang J-W, David DJ, Monckton JE et al (2008) Chronic fluoxetine stimulates maturation and synaptic plasticity of adult-born hippocampal granule cells. J Neurosci 28:1374–1384. doi:10.1523/JNEUROSCI.3632-07.2008

    Article  CAS  PubMed  Google Scholar 

  • Watanabe Y, Saito H, Abe K (1993) Tricyclic antidepressants block NMDA receptor-mediated synaptic responses and induction of long-term potentiation in rat hippocampal slices. Neuropharmacology 32:479–486

    Article  CAS  PubMed  Google Scholar 

  • Wigström H, Gustafsson B (1983) Facilitated induction of hippocampal long-lasting potentiation during blockade of inhibition. Nature 301:603–604

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by NIH grants P20RR016477 and P20GM103434 to the West Virginia INBRE. All animal procedures were approved by the Marshall University Institutional Animal Care and Use Committee and comply with the US Public Health Service policy on humane care and use of laboratory animals.

Conflict of interest

None of the authors declare a conflict of interest.

Author information

Authors and Affiliations

  1. Department of Pharmacology, Physiology and Toxicology, Joan C. Edwards School of Medicine, Marshall University, Robert C. Byrd Biotechnology Science Center, One John Marshall Drive, Huntington, WV, 25755, USA

    Jennifer D. Cooke, Hannah M. Cavender, Hope K. Lima & Lawrence M. Grover

Authors
  1. Jennifer D. Cooke
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hannah M. Cavender
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hope K. Lima
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lawrence M. Grover
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Lawrence M. Grover.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cooke, J.D., Cavender, H.M., Lima, H.K. et al. Antidepressants that inhibit both serotonin and norepinephrine reuptake impair long-term potentiation in hippocampus. Psychopharmacology 231, 4429–4441 (2014). https://doi.org/10.1007/s00213-014-3587-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00213-014-3587-1

Keywords

Search

Navigation