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Psychopharmacology

, Volume 236, Issue 11, pp 3183–3195 | Cite as

Vortioxetine reverses medial prefrontal cortex-mediated cognitive deficits in male rats induced by castration as a model of androgen deprivation therapy for prostate cancer

  • Alexandra M. Sharp
  • Suphada Lertphinyowong
  • Samantha S. Yee
  • Denisse Paredes
  • Jonathan Gelfond
  • Teresa L. Johnson-Pais
  • Robin J. Leach
  • Michael Liss
  • April L. Risinger
  • Anna C. Sullivan
  • Ian M. Thompson
  • David A. MorilakEmail author
Original Investigation
  • 262 Downloads

Abstract

Rationale

Androgen deprivation therapy (ADT) is an effective treatment for prostate cancer, but induces profound cognitive impairment. Little research has addressed mechanisms underlying these deficits or potential treatments. This is an unmet need to improve quality of life for prostate cancer survivors.

Objectives

We investigated mechanisms of cognitive impairment after ADT in rats and potential utility of the multimodal serotonin-targeting drug, vortioxetine, to improve the impairment, as vortioxetine has specific efficacy against cognitive impairment in depression.

Methods

Male Sprague-Dawley rats were surgically castrated. Vortioxetine (28 mg/kg/day) was administered in the diet. The attentional set-shifting test was used to assess medial prefrontal cortex (mPFC) executive function. Afferent-evoked field potentials were recorded in the mPFC of anesthetized rats after stimulating the ventral hippocampus (vHipp) or medial dorsal thalamus (MDT). Gene expression changes were assessed by microarray. Effects of vortioxetine on growth of prostate cancer cells were assessed in vitro.

Results

ADT impaired cognitive set shifting and attenuated responses evoked in the mPFC by the vHipp afferent, but not the MDT. Both the cognitive impairment and attenuated vHipp-evoked responses were reversed by chronic vortioxetine treatment. Preliminary investigation of gene expression in the mPFC indicates that factors involved in neuronal plasticity and synaptic transmission were down-regulated by castration and up-regulated by vortioxetine in castrated animals. Vortioxetine neither altered the growth of prostate cancer cells in vitro nor interfered with the antiproliferative effects of the androgen antagonist, enzalutamide.

Conclusions

These results suggest that vortioxetine may be useful in mitigating cognitive impairment associated with ADT for prostate cancer.

Keywords

Cognitive flexibility Antidepressant Androgen Medial prefrontal cortex Ventral hippocampus Medial dorsal thalamus Prostate cancer 

Abbreviations

ADT

Androgen deprivation therapy

AR

Androgen receptor

AST

Attentional set-shifting test

ED

Extra-dimensional

FDA

Food and Drug Administration

fMRI

Functional magnetic resonance imaging

Hipp

Hippocampus

vHipp

Ventral hippocampus

5-HT

5-Hydroxytryptamine

MDT

Medial dorsal thalamus

mPFC

Medial prefrontal cortex

SRB

Sulforhodamine B assay

VTX

Vortioxetine

Notes

Acknowledgments

The authors thank Dr. Sarah Bulin for assistance with the electrophysiological experiments.

Funding

This work was supported by research grant RP180055 from the Cancer Prevention and Research Institute of Texas; research grant R01 CA224672 from the National Cancer Institute, National Institutes of Health; the Quincy and Estine Lee Endowment Fund; and pilot funding provided by the Mays Cancer Center, UT Health San Antonio. Gene expression data were generated by the Mays Cancer Center Genomics Shared Resource Facility (P30 CA054174). In-kind support was provided by H. Lundbeck A/S, which generously provided the drug-containing chow and control chow.

Compliance with ethical standards

All research procedures were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of the University of Texas Health, San Antonio, and are compliant with the ethical standards of the National Institutes of Health as specified in the Guide for the Care and Use of Laboratory Animals.

Conflict of interest

Vortioxetine was provided by H. Lundbeck A/S, which had no input into the conduct of the study, analysis or interpretation of the data, and no role in the decision to publish or in the writing of the manuscript. Dr. Morilak receives research funding from Alkermes that has no relation to the present work. All other authors declare that they have no conflicts of interest.

References

  1. Bang-Anderson B et al (2011) Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder. J Med Chem 54:3206–3221CrossRefGoogle Scholar
  2. Becker D, Deller T, Vlachos A (2015) Tumor necrosis factor (TNF)-receptor 1 and 2 mediate homeostatic synaptic plasticity of denervated mouse dentate granule cells. Sci Rep 5:12726.  https://doi.org/10.1038/srep12726 CrossRefPubMedPubMedCentralGoogle Scholar
  3. Bondi CO, Rodriguez G, Gould GG, Frazer A, Morilak DA (2008) Chronic unpredictable stress induces a cognitive deficit and anxiety-like behavior in rats that is prevented by chronic antidepressant drug treatment. Neuropsychopharmacology 33:320–331.  https://doi.org/10.1038/sj.npp.1301410 CrossRefPubMedGoogle Scholar
  4. Bondi CO, Jett JD, Morilak DA (2010) Beneficial effects of desipramine on cognitive function of chronically stressed rats are mediated by alpha1-adrenergic receptors in medial prefrontal cortex. Prog Neuro-Psychopharmacol Biol Psychiatry 34:913–923.  https://doi.org/10.1016/j.pnpbp.2010.04.016 CrossRefGoogle Scholar
  5. Chao HH, Uchio E, Zhang S, Hu S, Bednarski SR, Luo X, Rose M, Concato J, Li CSR (2012) Effects of androgen deprivation on brain function in prostate cancer patients—a prospective observational cohort analysis. BMC Cancer 12:371CrossRefGoogle Scholar
  6. Chao HH, Hu S, Ide JS, Uchio E, Zhang S, Rose M, Concato J, Li CSR (2013) Effects of androgen deprivation on cerebral morphometry in prostate cancer patients—an exploratory study. PLoS One 8:e72032CrossRefGoogle Scholar
  7. Chen F, du Jardin KG, Waller JA, Sanchez C, Nyengaard JR, Wegener G (2016) Vortioxetine promotes early changes in dendritic morphology compared to fluoxetine in rat hippocampus. Eur Neuropsychopharmacol 26:234–245.  https://doi.org/10.1016/j.euroneuro.2015.12.018 CrossRefPubMedGoogle Scholar
  8. Cherrier MM, Aubin S, Higano CS (2009) Cognitive and mood changes in men undergoing intermittent combined androgen blockade for non-metastatic prostate cancer. Psychooncology 18:237–247.  https://doi.org/10.1002/pon.1401 CrossRefPubMedGoogle Scholar
  9. Correa SA, Eales KL (2012) The role of p38 MAPK and its substrates in neuronal plasticity and neurodegenerative disease. J Signal Transduction 2012:649079.  https://doi.org/10.1155/2012/649079 CrossRefGoogle Scholar
  10. Denis LJ, Griffiths K (2000) Endocrine treatment in prostate cancer. Semin Surg Oncol 18:52–74CrossRefGoogle Scholar
  11. du Jardin KG, Müller HK, Sanchez C, Wegener G, Elfving B (2016) A single dose of vortioxetine, but not ketamine or fluoxetine, increases plasticity-related gene expression in the rat frontal cortex. Eur J Pharmacol 786:29–35CrossRefGoogle Scholar
  12. Fucich EA, Paredes D, Morilak DA (2016) Therapeutic effects of extinction learning as a model of exposure therapy in rats. Neuropsychopharmacology 41:3092–3102.  https://doi.org/10.1038/npp.2016.127 CrossRefPubMedPubMedCentralGoogle Scholar
  13. Gilbert SM, Kuo YF, Shahinian VB (2011) Prevalent and incident use of androgen deprivation therapy among men with prostate cancer in the United States. Urol Oncol 29:647–653.  https://doi.org/10.1016/j.urolonc.2009.09.004 CrossRefPubMedGoogle Scholar
  14. Gonzalez BD, Jim HSL, Booth-Jones M, Small BJ, Sutton SK, Lin HY, Park JY, Spiess PE, Fishman MN, Jacobsen PB (2015) Course and predictors of cognitive function in patients with prostate cancer receiving androgen-deprivation therapy: a controlled comparison. J Clin Oncol 33:2021–2027CrossRefGoogle Scholar
  15. Green HJ, Pakenham KI, Headley BC, Yaxley J, Nicol DL, Mactaggart PN, Swanson C, Watson RB, Gardiner RA (2002) Altered cognitive function in men treated for prostate cancer with luteinizing hormone-releasing hormone analogues and cyproterone acetate: a randomized controlled trial. BJU Int 90:427–432CrossRefGoogle Scholar
  16. Gupta D, Salmane C, Slovin S, Steingart RM (2017) Cardiovascular complications of androgen deprivation therapy for prostate cancer. Curr Treat Options Cardiovasc Med 19:61.  https://doi.org/10.1007/s11936-017-0563-1 CrossRefPubMedGoogle Scholar
  17. Hajszan T, MacLusky NJ, Johansen JA, Jordan CL, Leranth C (2007) Effects of androgens and estradiol on spine synapse formation in the prefrontal cortex of normal and testicular feminization mutant male rats. Endocrinology 148:1963–1967.  https://doi.org/10.1210/en.2006-1626 CrossRefPubMedPubMedCentralGoogle Scholar
  18. Hajszan T, MacLusky NJ, Leranth C (2008) Role of androgens and the androgen receptor in remodeling of spine synapses in limbic brain areas. Horm Behav 53:638–646CrossRefGoogle Scholar
  19. Hawley WR, Grissom EM, Martin RC, Halmos MB, Bart CL, Dohanich GP (2013) Testosterone modulates spatial recognition memory in male rats. Horm Behav 63:559–565.  https://doi.org/10.1016/j.yhbeh.2013.02.007 CrossRefPubMedGoogle Scholar
  20. Jamadar RJ, Winters MJ, Maki PM (2012) Cognitive changes associated with ADT: a review of the literature. Asian J Androl 14:232–238.  https://doi.org/10.1038/aja.2011.107 CrossRefPubMedPubMedCentralGoogle Scholar
  21. Jenkins VA, Bloomfield DJ, Shilling VM, Edginton TL (2005) Does neoadjuvant hormone therapy for early prostate cancer affect cognition? Results from a pilot study. BJU Int 96:48–53.  https://doi.org/10.1111/j.1464-410X.2005.05565.x CrossRefPubMedGoogle Scholar
  22. Jett JD, Morilak DA (2013) Too much of a good thing: blocking noradrenergic facilitation in medial prefrontal cortex prevents the detrimental effects of chronic stress on cognition. Neuropsychopharmacology 38:585–595.  https://doi.org/10.1038/npp.2012.216 CrossRefPubMedGoogle Scholar
  23. Jett JD, Boley AM, Girotti M, Shah A, Lodge DJ, Morilak DA (2015) Antidepressant-like cognitive and behavioral effects of acute ketamine administration associated with plasticity in the ventral hippocampus to medial prefrontal cortex pathway. Psychopharmacology 232:3123–3133.  https://doi.org/10.1007/s00213-015-3957-3 CrossRefPubMedPubMedCentralGoogle Scholar
  24. Jett JD, Bulin SE, Hatherall LC, McCartney CM, Morilak DA (2017) Deficits in cognitive flexibility induced by chronic unpredictable stress are associated with impaired glutamate neurotransmission in the rat medial prefrontal cortex. Neuroscience 346:284–297.  https://doi.org/10.1016/j.neuroscience.2017.01.017 CrossRefPubMedPubMedCentralGoogle Scholar
  25. Katona C, Hansen T, Olsen CK (2012) A randomized, double-blind, placebo-controlled, duloxetine-referenced, fixed-dose study comparing the efficacy and safety of Lu AA21004 in elderly patients with major depressive disorder. Int Clin Psychopharmacol 27:215–223CrossRefGoogle Scholar
  26. Kerr JE, Allore RJ, Beck SG, Handa RJ (1995) Distribution and hormonal regulation of androgen receptor (AR) and AR messenger ribonucleic acid in the rat hippocampus. Endocrinology 136:3213–3221.  https://doi.org/10.1210/endo.136.8.7628354 CrossRefPubMedGoogle Scholar
  27. Kugathasan P et al. (2017) In vivo and in vitro effects of vortioxetine on molecules associated with neuroplasticity J Psychopharmacol 31:365-376CrossRefGoogle Scholar
  28. Lapiz MDS, Morilak DA (2006) Noradrenergic modulation of cognitive function in rat medial prefrontal cortex as measured by attentional set shifting capability. Neuroscience 137:1039–1049.  https://doi.org/10.1016/j.neuroscience.2005.09.031 CrossRefPubMedGoogle Scholar
  29. Leranth C, Petnehazy O, MacLusky NJ (2003) Gonadal hormones affect spine synaptic density in the CA1 hippocampal subfield of male rats. J Neurosci 23:1588–1592CrossRefGoogle Scholar
  30. Li Y, Abdourahman A, Tamm JA, Pehrson AL, Sanchez C, Gulinello M (2015) Reversal of age-associated cognitive deficits is accompanied by increased plasticity-related gene expression after chronic antidepressant administration in middle-aged mice. Pharmacol Biochem Behav 135:70–82CrossRefGoogle Scholar
  31. Libert Y, Dubruille S, Borghgraef C, Etienne AM, Merckaert I, Paesmans M, Reynaert C, Roos M, Slachmuylder JL, Vandenbossche S, Bron D, Razavi D (2016) Vulnerabilities in older patients when cancer treatment is initiated: does a cognitive impairment impact the two-year survival? PLoS One 11:e0159734.  https://doi.org/10.1371/journal.pone.0159734 CrossRefPubMedPubMedCentralGoogle Scholar
  32. MacLusky NJ, Hajszan T, Prange-Kiel J, Leranth C (2006) Androgen modulation of hippocampal synaptic plasticity. Neuroscience 138:957–965CrossRefGoogle Scholar
  33. Mahableshwarkar AR, Zajecka J, Jacobson W, Chen Y, Keefe RSE (2015) A randomized, placebo-controlled, active-reference, double-blind, flexible-dose study of the efficacy of vortioxetine on cognitive function in major depressive disorder. Neuropsychopharmacology 40:2025–2037CrossRefGoogle Scholar
  34. McIntyre RS, Lophaven S, Olsen CK (2014) A randomized, double-blind, placebo-controlled study of vortioxetine on cognitive function in depressed adults. Int J Neuropsychopharmacol 17:1557–1567CrossRefGoogle Scholar
  35. McIntyre RS, Harrison J, Loft H, Jacobson W, Olsen CK (2016) The effects of vortioxetine on cognitive function in patients with major depressive disorder: a meta-analysis of three randomized controlled trials. Int J Neuropsychopharmacol 19:1–9CrossRefGoogle Scholar
  36. Nead KT, Gaskin G, Chester C, Swisher-McClure S, Dudley JT, Leeper NJ, Shah NH (2016) Androgen deprivation therapy and future Alzheimer’s disease risk. J Clin Oncol 34:566–571.  https://doi.org/10.1200/jco.2015.63.6266 CrossRefPubMedGoogle Scholar
  37. Nead KT, Gaskin G, Chester C, Swisher-McClure S, Leeper NJ, Shah NH (2017) Association between androgen deprivation therapy and risk of dementia. JAMA oncology 3:49–55.  https://doi.org/10.1001/jamaoncol.2016.3662 CrossRefPubMedGoogle Scholar
  38. Nelson CJ, Lee JS, Gamboa MC, Roth AJ (2008) Cognitive effects of hormone therapy in men with prostate cancer. Cancer 113:1097–1106CrossRefGoogle Scholar
  39. Pirl WF, Siegel GI, Goode MJ, Smith MR (2002) Depression in men receiving androgen deprivation therapy for prostate cancer: a pilot study. Psycho-oncology 11:518–523CrossRefGoogle Scholar
  40. Ritchie ME, Phipson B, Wu D, Hu Y, Law CW, Shi W, Smyth GK (2015) limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res 43:e47CrossRefGoogle Scholar
  41. Russell N, Grossmann M (2018) Management of bone and metabolic effects of androgen deprivation therapy urologic oncology doi: https://doi.org/10.1016/j.urolonc.2018.10.007
  42. Sanchez C, Asin KE, Artigas F (2015) Vortioxetine, a novel antidepressant with multimodal activity: review of preclinical and clinical data. Pharmacol Ther 145:43–57.  https://doi.org/10.1016/j.pharmthera.2014.07.001 CrossRefPubMedGoogle Scholar
  43. Sharp AM et al. (2017) Vortioxetine reverses cognitive impairment induced by castration as a model of androgen deprivation therapy for prostate cancer in male rats Neuroscience Meeting Planner Washington, D C: Society for Neuroscience Program No. 520.03Google Scholar
  44. Siddiqui EJ, Shabbir M, Mikhailidis DP, Thompson CS, Mumtaz FH (2006) The role of serotonin (5-hydroxytryptamine1A and 1B) receptors in prostate cancer cell proliferation. J Urol 176:1648–1653.  https://doi.org/10.1016/j.juro.2006.06.087 CrossRefPubMedGoogle Scholar
  45. Siegel RL, Miller KD, Jemal A (2018) Cancer statistics, 2018 CA Cancer J Clin 68:7–30 doi: https://doi.org/10.3322/caac.21442 Google Scholar
  46. Simerly RB, Chang C, Muramatsu M, Swanson LW (1990) Distribution of androgen and estrogen receptor mRNA-containing cells in the rat brain: an in situ hybridization study. J Comp Neurol 294:76–95.  https://doi.org/10.1002/cne.902940107 CrossRefPubMedGoogle Scholar
  47. Skehan P, Storeng R, Scudiero D, Monks A, McMahon J, Vistica D, Warren JT, Bokesch H, Kenney S, Boyd MR (1990) New colorimetric cytotoxicity assay for anticancer-drug screening. J Natl Cancer Inst 82:1107–1112CrossRefGoogle Scholar
  48. Wallace A, Pehrson AL, Sánchez C, Morilak DA (2014) Vortioxetine restores reversal learning impaired by 5-HT depletion or chronic intermittent cold stress in rats. Int J Neuropsychopharmacol 17:1695–1706.  https://doi.org/10.1017/S1461145714000571 CrossRefPubMedPubMedCentralGoogle Scholar
  49. Waller JA, Tamm JA, Abdourahman A, Pehrson AL, Li Y, Cajina M, Sanchez C (2017) Chronic vortioxetine treatment in rodents modulates gene expression of neurodevelopmental and plasticity markers. Eur Neuropsychopharmacol 27:192–203CrossRefGoogle Scholar
  50. Watts S, Leydon G, Birch B, Prescott P, Lai L, Eardley S, Lewith G (2014) Depression and anxiety in prostate cancer: a systematic review and meta-analysis of prevalence rates. BMJ Open 4:e003901CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Alexandra M. Sharp
    • 1
    • 2
  • Suphada Lertphinyowong
    • 1
    • 2
  • Samantha S. Yee
    • 1
  • Denisse Paredes
    • 1
    • 2
  • Jonathan Gelfond
    • 3
  • Teresa L. Johnson-Pais
    • 4
    • 5
  • Robin J. Leach
    • 4
    • 6
    • 5
  • Michael Liss
    • 4
    • 5
    • 7
  • April L. Risinger
    • 1
    • 5
  • Anna C. Sullivan
    • 8
    • 2
    • 9
  • Ian M. Thompson
    • 4
    • 10
  • David A. Morilak
    • 1
    • 2
    • 5
    • 7
    Email author
  1. 1.Department of PharmacologyUniversity of Texas Health Science CenterSan AntonioUSA
  2. 2.Center for Biomedical NeuroscienceUniversity of Texas Health Science CenterSan AntonioUSA
  3. 3.Department of Epidemiology and BiostatisticsUniversity of Texas Health Science CenterSan AntonioUSA
  4. 4.Department of UrologyUniversity of Texas Health Science CenterSan AntonioUSA
  5. 5.Mays Cancer CenterUniversity of Texas Health Science CenterSan AntonioUSA
  6. 6.Department of Cell Systems & AnatomyUniversity of Texas Health Science CenterSan AntonioUSA
  7. 7.South Texas Veterans Health Care ServiceSan AntonioUSA
  8. 8.Department of NeurologyUniversity of Texas Health Science CenterSan AntonioUSA
  9. 9.Glenn Biggs Institute for Alzheimer’s & Neurodegenerative DiseasesUniversity of Texas Health Science CenterSan AntonioUSA
  10. 10.CHRISTUS Santa Rosa HospitalSan AntonioUSA

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