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Ethanol withdrawal-induced depressive symptoms in animals and therapeutic potential of sigma1 receptor ligands

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Abstract

Clinical evidence has indicated a high degree of comorbidity of alcoholism and depression. Manifestation of the depression symptoms during abstinence increases the likelihood of relapse and indicates a worse prognosis in terms of treatment outcome. The depressive symptoms may be alcohol independent or alcohol induced. In this paper, only the ethanol-related depression is the focus of interest. In preclinical studies, some models of depressive-like symptoms induced by chronic alcohol treatment and withdrawal were proposed. In this minireview, the results concerning the depression-like behavior and some accompanying biochemical changes induced by prolonged ethanol exposure and its cessation in rats and mice were summarized. Moreover, the therapeutic potential of sigma1 receptor ligands for the treatment of depression disorder induced by ethanol abuse and withdrawal is discussed.

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References

  1. Alén F, Orio L, Gorriti MÁ, de Heras RG, Ramírez-López MT, Pozo MÁ, de Fonseca FR: Increased alcohol consumption in rats after subchronic antidepressant treatment. Int J Neuropsychopharmacol, 2013, 8, 1809–1818.

    Article  CAS  Google Scholar 

  2. Altar CA, Whitehead RE, Chen R, Wörtwein G, Madsen TM: Effects of electroconvulsive seizures and antide-pressant drugs on brain-derived neurotrophic factor protein in rat brain. Biol Psychiatry, 2003, 54, 703–709.

    Article  CAS  PubMed  Google Scholar 

  3. Brière FN, Rohde P, Seeley JR, Klein D, Lewinsohn PM: Comorbidity between major depression and alcohol use disorder from adolescence to adulthood. Compr Psychiatry, 2013, [Epub ahead of print].

  4. Briones TL, Woods J: Chronic binge-like alcohol consumption in adolescence causes depression-like symptoms possibly mediated by the effects of BDNF on neu-rogenesis. Neuroscience, 2013, 254, 324–334.

    Article  CAS  PubMed  Google Scholar 

  5. Caldwell KK, Sheema S, Paz RD, Samudio-Ruiz SL, Laughlin MH, Spence NE, Roehlk MJ et al.: evidence for reductions in the levels of brain-derived neurotrophic factor in a mouse model. Pharmacol Biochem Behav, 2008, 90, 614–624.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Duman RS, Heninger GR, Nestler EJ: A molecular and cellular theory of depression. Arch Gen Psychiatry, 1997, 54, 597–606.

    Article  CAS  PubMed  Google Scholar 

  7. Duman RS, Malberg J, Nakagawa S, D’Sa C: Neuronal plasticity and survival in mood disorders. Biol Psychiatry, 2000, 48, 732–739.

    Article  CAS  PubMed  Google Scholar 

  8. Duman RS, Malberg J, Thome J: Neural plasticity to stress and antidepressant treatment. Biol Psychiatry, 1999, 46, 1181–1191.

    Article  CAS  PubMed  Google Scholar 

  9. Duman RS, Monteggia LM: A neurotrophic model for stress-related mood disorders. Biol Psychiatry, 2006, 59, 1116–1127.

    CAS  PubMed  Google Scholar 

  10. Evans SM, Levin FR, Brooks DJ, Garawi F: A pilot double-blind treatment trial of memantine for alcohol dependence. Alcohol Clin Exp Res, 2007, 31, 775–782.

    Article  CAS  PubMed  Google Scholar 

  11. Fishback JA, Robson MJ, Xu YT, Matsumoto RR: Sigma receptors: potential targets for a new class of anti-depressant drug. Pharmacol Ther, 2010, 127, 271–282.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Fujimoto M, Hayashi T, Urfer R, Mita S, Su TP: Sigma-1 receptor chaperones regulate the secretion of brain-derived neurotrophic factor. Synapse, 2012, 66, 630–639.

    Article  CAS  PubMed  Google Scholar 

  13. Greenfield SF, Weiss RD, Muenz LR, Vagge LM, Kelly JF, Bello LR, Michael J: The effect of depression on return to drinking: a prospective study. Arch Gen Psychiatry, 1998, 55, 259–265.

    Article  CAS  PubMed  Google Scholar 

  14. Grigoriadis S, Robinson GE: Gender issues in depression. Ann Clin Psychiatry, 2007, 19, 247–255.

    Article  PubMed  Google Scholar 

  15. Hasin D, Liu X, Nunes E, McCloud S, Samet S, Endicott J: Effects of major depression on remission and relapse of substance dependence. Arch Gen Psychiatry, 2002, 59, 375–380.

    Article  PubMed  Google Scholar 

  16. Hayashi T, Maurice T, Su TP: Ca(2+) signaling via sigma(1)-receptors: novel regulatory mechanism affecting intracellular Ca(2+) concentration. J Pharmacol Exp Ther, 2000, 293, 788–798.

    CAS  PubMed  Google Scholar 

  17. Hayley S, Litteljohn D: Neuroplasticity and the next wave of antidepressant strategies. Front Cell Neurosci, 2013, 7, Article 218 (review).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Heinrichs SC, Menzaghi F, Pich EM, Baldwin HA, Rassnick S, Britton KT, Koob GF: Anti-stress action of a corticotropin-releasing factor antagonist on behavioral reactivity to stressors of varying type and intensity. Neu-ropsychopharmacology, 1994, 11, 179–186.

    Article  CAS  PubMed  Google Scholar 

  19. Jacobs BL, van Praag H, Gage FH: Adult brain neuro-genesis and psychiatry: a novel theory of depression. Mol Psychiatry, 2000, 5, 262–269.

    Article  CAS  PubMed  Google Scholar 

  20. Jansen KL, Dragunow M, Faull RL: Sigma receptors are highly concentrated in the rat pineal gland. Brain Res, 1990, 507, 158–160.

    Article  CAS  PubMed  Google Scholar 

  21. Johnson SA, Fournier NM, Kalynchuk LE: Effect of different doses of corticosterone on depression-like behavior and HPA axis responses to a novel stressor. Behav Brain Res, 2006, 168, 280–288.

    Article  CAS  PubMed  Google Scholar 

  22. Kos T, Legutko B, Danysz W, Samoriski G, Popik P: Enhancement of antidepressant-like effects but not brain-derived neurotrophic factor mRNA expression by the novel N-methyl-D-aspartate receptor antagonist nera-mexane in mice. J Pharmacol Exp Ther, 2006, 318, 1128–1136.

    Article  CAS  PubMed  Google Scholar 

  23. Lynskey MT: The comorbidity of alcohol dependence and affective disorders: treatment implications. Drug Alcohol Depend, 1998, 52, 201–209.

    Article  CAS  PubMed  Google Scholar 

  24. Malberg JE, Duman RS: Cell proliferation in adult hippocampus is decreased by inescapable stress: reversal by fluoxetine treatment. Neuropsychopharmacology, 2003, 28, 1562–1571.

    Article  CAS  PubMed  Google Scholar 

  25. Malberg JE, Eisch AJ, Nestler EJ, Duman RS: Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci, 2000, 20, 9104–9110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Maurice T, Casalino M, Lacroix M, Romieu P: Involvement of the sigma 1 receptor in the motivational effects of ethanol in mice. Pharmacol Biochem Behav, 2003 ,74, 869–876.

    Article  CAS  PubMed  Google Scholar 

  27. Muhonen LH, Lönnqvist J, Juva K, Alho H: Double-blind, randomized comparison of memantine and escitalopram for the treatment of major depressive disorder comorbid with alcohol dependence. J Clin Psychiatry, 2008, 69, 392–399.

    Article  CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Nikisch G, Mathé AA: CSF monoamine metabolites and neuropeptides in depressed patients before and after electroconvulsive therapy. Eur Psychiatry, 2008, 23, 356–359.

    Article  PubMed  Google Scholar 

  30. Ostacher MJ: Comorbid alcohol and substance abuse dependence in depression: impact on the outcome of anti-depressant treatment. Psychiatr Clin North Am, 2007, 30, 69–76.

    Article  PubMed  Google Scholar 

  31. Overstreet DH, Griebel G: Antidepressant-like effects of CRF1 receptor antagonist SSR125543 in an animal model of depression. Eur J Pharmacol, 2004, 497, 49–53.

    Article  CAS  PubMed  Google Scholar 

  32. Palmer TD, Takahashi J, Gage FH: The adult rat hippocampus contains primordial neural stem cells. Mol Cell Neurosci, 1997, 8, 389–404.

    Article  CAS  PubMed  Google Scholar 

  33. Pang TY, Renoir T, Du X, Lawrence AJ, Hannan AJ: Depression-related behaviours displayed by female C57BL/6J mice during abstinence from chronic ethanol consumption are rescued by wheel-running. Eur J Neurosci, 2013, 37, 1803–1810.

    Article  PubMed  Google Scholar 

  34. Paschos KA, Veletza S, Chatzaki E: Neuropeptide and sigma receptors as novel therapeutic targets for the phar-macotherapy of depression. CNS Drugs, 2009, 9, 755–772.

    Article  Google Scholar 

  35. Peeters M, Romieu P, Maurice T, Su TP, Maloteaux JM, Hermans E: Involvement of the sigma1 receptor in the modulation of dopaminergic transmission by amantadine. Eur J Neurosci, 2004, 19, 2212–2220.

    Article  PubMed  Google Scholar 

  36. Peskind ER, Potkin SG, Pomara N, Ott BR, Graham SM, Olin JT, McDonald S: Memantine treatment in mild to moderate Alzheimer disease: a 24-week randomized, controlled trial. Am J Geriatr Psychiatry, 2006, 14, 704–715.

    Article  PubMed  Google Scholar 

  37. Pettinati HM, Oslin DW, Kampman KM, Dundon WD, Xie H, Gallis TL, Dackis CA, O’Brien CP: A double-blind, placebo-controlled trial combining sertraline and naltrexone for treating co-occurring depression and alcohol dependence. Am J Psychiatry, 2010, 167, 668–675.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Płaźnik A, Tamborska E, Hauptmann M, Bidziński A, Kostowski W: Brain neurotransmitter systems mediating behavioral deficits produced by inescapable shock treatment in rats. Brain Res, 1988, 447, 122–132.

    Article  PubMed  Google Scholar 

  39. Redrobe JP, Dumont Y, Quirion R. Neuropeptide Y (NPY) and depression: from animal studies to the human condition. Life Sci, 2002, 71, 2921–2937.

    Article  CAS  PubMed  Google Scholar 

  40. Rice AC, Bullock MR, Shelton KL: Chronic ethanol consumption transiently reduces adult neural progenitor cell proliferation. Brain Res, 2004, 1011, 94–98.

    Article  CAS  PubMed  Google Scholar 

  41. Roberto M, Bajo M, Crawford E, Madamba SG, Siggins GR: Chronic ethanol exposure and protracted abstinence alter NMDA receptors in central amygdala. Neuropsy-chopharmacology, 2006, 31, 988–996.

    Article  CAS  PubMed  Google Scholar 

  42. Rogóż Z, Skuza G, Maj J, Danysz W: Synergistic effects of uncompetitive NMDA receptor antagonists and anti-depressant drugs in the forced swimming test in rats. Neuropharmacology, 2002, 42, 1024–1030.

    Article  PubMed  Google Scholar 

  43. Sabino V, Cottone P, Zhao Y, Iyer MR, Steardo L, Jr, Steardo L, Rice KC et al.: The sigma-receptor antagonist BD-1063 decreases ethanol intake and reinforcement in animal models of excessive drinking. Neuropsychophar-macology, 2009, 34, 1482–1493.

    Article  CAS  PubMed  Google Scholar 

  44. Sabino V, Cottone P, Zhao Y, Steardo L, Koob GF, Zorrilla EP: Selective reduction of alcohol drinking in Sardinian alcohol-preferring rats by a sigma-1 receptor antagonist. Psychopharmacology (Berl), 2009, 205, 327–335.

    Article  CAS  Google Scholar 

  45. Siuciak JA, Lewis DR, Wiegand SJ, Lindsay RM: Antidepressant-like effect of brain-derived neurotrophic factor (BDNF). Pharmacol Biochem Behav, 1997, 56, 131–137.

    Article  CAS  PubMed  Google Scholar 

  46. Skolnick P, Layer RT, Popik P, Nowak G, Paul IA, Trullas R: Adaptation of N-methyl-D-aspartate (NMDA) receptors following antidepressant treatment: implications for the pharmacotherapy of depression. Pharmacopsychiatry, 1996, 29, 23–26.

    Article  CAS  PubMed  Google Scholar 

  47. Skolnick P, Miller R, Young A, Boje K, Trullas R: Chronic treatment with 1-aminocyclopropanecarboxylic acid desensitizes behavioral responses to compounds acting at the N-methyl-D-aspartate receptor complex. Psychopharmacology (Berl), 1992, 107, 489–496.

    Article  CAS  Google Scholar 

  48. Skuza G: Pharmacology of sigma (a) receptor ligands from a behavioral perspective. Curr Pharm Des, 2012,18, 863–874.

    Article  CAS  PubMed  Google Scholar 

  49. Skuza G, Rogóz Z: The synergistic effect of selective sigma receptor agonists and uncompetitive NMDA receptor antagonists in the forced swim test in rats. J Physiol Pharmacol, 2006, 57, 217–229.

    CAS  PubMed  Google Scholar 

  50. Skuza G, Sadaj W, Kabzinski M: The impact of co-treatment with antidepressants and memantine on immobility time in the forced swim test and tail suspension test in mice: The role of sigma1 receptors. Pharmacol Rep, 2013, 65, Suppl, 83.

    Article  Google Scholar 

  51. Smith MA, Lynch WJ: Exercise as a potential treatment for drug abuse: evidence from preclinical studies. Front Psychiatry, 2012, 2, 82.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Stevenson JR, Schroeder JP, Nixon K, Besheer J, Crews FT, Hodge CW: Abstinence following alcohol drinking produces depression-like behavior and reduced hippo-campal neurogenesis in mice. Neuropsychopharmacology, 2009, 34, 1209–1222.

    Article  CAS  PubMed  Google Scholar 

  53. Stogner KA, Holmes PV: Neuropeptide-Y exerts antidepressant-like effects in the forced swim test in rats. Eur J Pharmacol, 2000, 387, R9–10.

    Article  CAS  PubMed  Google Scholar 

  54. Walker BM, Drimmer DA, Walker JL, Liu T, Mathé AA, Ehlers CL: Effects of prolonged ethanol vapor exposure on forced swim behavior, and neuropeptide Y and corticotropin-releasing factor levels in rat brains. Alcohol, 2010, 6, 487–493.

    Article  CAS  Google Scholar 

  55. Wang T, Huang XJ, Van KC, Went GT, Nguyen JT, Lyeth BG: Amantadine improves cognitive outcome and increases neuronal survival after fluid percussion traumatic brain injury in rats. J Neurotrauma, 2013. [Epub ahead of print].

  56. Wlaź P, Kasperek R, Wlaź A, Szumiło M, Wróbel A, Nowak G, Poleszak E: NMDA and AMPA receptors are involved in the antidepressant-like activity of tianeptine in the forced swim test in mice. Pharmacol Rep, 2011, 63, 1526–1532.

    Article  PubMed  Google Scholar 

  57. Yilmaz N, Demirdas A, Yilmaz M, Sutcu R, Kirbas A, Cure MC, Eren I: Effects of venlafaxine and escitalopram treatments on NMDA receptors in the rat depression model. J Membr Biol, 2011, 242, 145–151.

    Article  CAS  PubMed  Google Scholar 

  58. Zhou FC, Sari Y, Li TK, Goodlett C, Azmitia EC: Deviations in brain early serotonergic development as a result of fetal alcohol exposure. Neurotox Res, 2002, 4, 337–342.

    Article  CAS  PubMed  Google Scholar 

  59. Zhou FC, Sari Y, Powrozek TA: Fetal alcohol exposure reduces serotonin innervation and compromises development of the forebrain along the serotonergic pathway. Alcohol Clin Exp Res, 2005, 29, 141–149.

    Article  CAS  PubMed  Google Scholar 

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  1. Department of Pharmacology, Institute of Pharmacology, Polish Academy of Sciences, Smętna 12, PL 31-343, Kraków, Poland

    Grażyna Skuza

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  1. Grażyna Skuza
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Skuza, G. Ethanol withdrawal-induced depressive symptoms in animals and therapeutic potential of sigma1 receptor ligands. Pharmacol. Rep 65, 1681–1687 (2013). https://doi.org/10.1016/S1734-1140(13)71530-5

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