Yıl 2017, Cilt 11, Sayı 3, Sayfalar 115 - 120 2017-12-15

Single dose ketamine injection affects activation of cells in the nucleus accumbens of prenatally stressed rats

Elif Polat Çorumlu [1] , Osman Özcan Aydın [2] , Emel Ulupınar [3]

95 88

Objectives: The nucleus accumbens (NAc) has recently been implicated in the pathophysiology of depression. In animals displaying depressive-like behavior following chronic stress exposure, glutamatergic transmission increases in the NAc. NMDA receptor antagonist ketamine act as an antidepressant, especially in treatment-resistant cases. In this study, we aimed to investigate the effects of single-dose ketamine application in the activation of cells in the NAc of prenatally stressed rats.


Methods: Sprague-Dawley dams were exposed to immobilization stress during the last week of pregnancy for 3 hours. Male offspring were divided into four groups at postnatal day 40. Prenatal stress and control groups received either a single dose of ketamine (10 mg/kg, i.p.) or same doses of saline injections. Immediate gene activation was stimulated by forced swim for 6 minutes and assessed by c-Fos immunohistochemistry. The total number of activated cells in the core and shell subregions was estimated by optical fractionator method.


Results: The total number of activated cells in the shell subregion significantly decreased in prenatally stressed rats. Ketamine administration reversed their activation level similar to those of control group. Although activation of cells did not change in the core region following prenatal stress, ketamine treatment enhanced the activation of cells in this region both control and prenatally stressed animals.


Conclusion: These results suggest that prenatal stress influences the activation of NAc in a subdivision specific manner, but ketamine treatment could act on both core and shell regions by affecting glutamatergic limbic information that flows from shell to core subregion of the NAc.
c-Fos; ketamine; nucleus accumbens; prenatal stress; stereology
  • 1. Fumagalli F, Molteni R, Racagni G, Riva MA. Stress during development: impact on neuroplasticity and relevance to psychopathology. Prog Neurobiol 2007;81:197–217. 2. Weinstock M. The long-term behavioural consequences of prenatal stress. Neurosci Biobehav Rev 2008;32:1073–86. 3. Said N, Lakehayli S, El Khachibi M, El Ouahli M, Nadifi S, Hakkou F, Tazi A. Prenatal stress induces vulnerability to nicotine addiction and alters D2 receptors’ expression in the nucleus accumbens in adult rats. Neuroscience 2015;304:279–85. 4. Zhu X, Li T, Peng S, Ma X, Chen X, Zhang X. Maternal deprivation-caused behavioral abnormalities in adult rats relate to a nonmethylation-regulated D2 receptor levels in the nucleus accumbens. Behav Brain Res 2010;209:281–8. 5. Cai Q, Zhu Z, Li H, Fan X, Jia N, Bai Z, Song L, Li X, Liu J. Prenatal stress on the kinetic properties of Ca2+ and K+ channels in offspring hippocampal CA3 pyramidal neurons. Life Sci 2007;80:681–9. 6. Ulupinar E, Yucel F, Ortug G. The effects of prenatal stress on the Purkinje cell neurogenesis. Neurotoxicol Teratol 2006;28:86–94. 7. Weinstock M. Prenatal stressors in rodents: effects on behavior. Neurobiol Stress 2016;6:3–13. 8. Kofman O. The role of prenatal stress in the etiology of developmental behavioural disorders. Neurosci Biobehav Rev 2002;26:457–70. 9. Kawamura T, Chen J, Takahashi T, Ichitani Y, Nakahara D. Prenatal stress suppresses cell proliferation in the early developing brain. Neuroreport 2006;17:1515–8. 10. McClure WO, Ishtoyan A, Lyon M. Very mild stress of pregnant rats reduces volume and cell number in nucleus accumbens of adult offspring: some parallels to schizophrenia. Brain Res Dev Brain Res 2004;149:21–8. 11. Shirayama Y, Chaki S. Neurochemistry of the nucleus accumbens and its relevance to depression and antidepressant action in rodents. Curr Neuropharmacol 2006;4:277–91. 12. Baier CJ, Katunar MR, Adrover E, Pallarés ME, Antonelli MC. Gestational restraint stress and the developing dopaminergic system: an overview. Neurotox Res 2012;22:16–32. 13. Salgado S, Kaplitt MG. The nucleus accumbens: a comprehensive review. Stereotact Funct Neurosurg 2015;93:75–93. 14. Meredith GE, Pennartz CM, Groenewegen HJ. The cellular framework for chemical signalling in the nucleus accumbens. Prog Brain Res 1993;99:3–24. 15. Pennartz CM, Dolleman-Van der Weel MJ, Kitai ST, Lopes da Silva FH. Presynaptic dopamine D1 receptors attenuate excitatory and inhibitory limbic inputs to the shell region of the rat nucleus accumbens studied in vitro. J Neurophysiol 1992;67:1325–34. 16. Zahm DS, Brog JS. On the significance of subterritories in the “accumbens” part of the rat ventral striatum. Neuroscience 1992;50:751–67. 17. Deutch AY, Lee MC, Iadarola MJ. Regionally specific effects of atypical antipsychotic drugs on striatal Fos expression: the nucleus accumbens shell as a locus of antipsychotic action. Mol Cell Neurosci 1992;3:332–41. 18. Vialou V, Robison AJ, Laplant QC, Covington HE 3rd, Dietz DM, Ohnishi YN, Mouzon E, Rush AJ 3rd, Watts EL, Wallace DL, Iñiguez SD, Ohnishi YH, Steiner MA, Warren BL, Krishnan V, Bolaños CA, Neve RL, Ghose S, Berton O, Tamminga CA, Nestler EJ. DeltaFosB in brain reward circuits mediates resilience to stress and antidepressant responses. Nat Neurosci 2010;13:745–52. 19. Lim BK, Huang KW, Grueter BA, Rothwell PE, Malenka RC. Anhedonia requires MC4R-mediated synaptic adaptations in nucleus accumbens. Nature 2012;487:183–9. 20. Bagot RC, Parise EM, Peña CJ, Zhang HX, Maze I, Chaudhury D, Persaud B, Cachope R, Bolaños-Guzmán CA, Cheer JF, Deisseroth K, Han MH, Nestler EJ. Ventral hippocampal afferents to the nucleus accumbens regulate susceptibility to depression. Nat Commun 2015;6:7062. 21. Browne CA, Lucki I. Antidepressant effects of ketamine: mechanisms underlying fast-acting novel antidepressants. Front Pharmacol 2013;4:161. 22. Duman RS, Li N, Liu RJ, Duric V, Aghajanian G. Signaling pathways underlying the rapid antidepressant actions of ketamine. Neuropharmacology 2012;62:35–41. 23. Wu R, Zhang H, Xue W, Zou Z, Lu C, Xia B, Wang W, Chen G. Transgenerational impairment of hippocampal Akt-mTOR signaling and behavioral deficits in the offspring of mice that experience postpartum depression-like illness. Prog Neuropsychopharmacol Biol Psychiatry 224. Kokkinou M, Ashok AH, Howes OD. The effects of ketamine on dopaminergic function: meta-analysis and review of the implications for neuropsychiatric disorders. Mol Psychiatry 2017. 25. Masuzawa M, Nakao S, Miyamoto E, Yamada M, Murao K, Nishi K, Shingu K. Pentobarbital inhibits ketamine-induced dopamine release in the rat nucleus accumbens: a microdialysis study. Anesth Analg 2003;96:148–52. 26. Polat Çorumlu E, Aydın OÖ, Gülhan Aydın E, Ulupınar E. Effects of single-dose ketamine infusion on behavioral parameters and neuronal activation in the medial prefrontal cortex of juvenile rats exposed to prenatal stress. Anatomy 2015;9:142–50. 27. Paxinos G, Watson C. The rat brain in stereotaxic coordinates. 2nd ed., San Diego (CA): Academic Press; 1986. 28. Peleg-Raibstein D, Feldon J. Effects of dorsal and ventral hippocampal NMDA stimulation on nucleus accumbens core and shell dopamine release. Neuropharmacology 2006;51:947–57. 29. Robinson TE, Kolb B. Structural plasticity associated with exposure to drugs of abuse. Neuropharmacology 2004;47:33–46. 30. Russo SJ, Dietz DM, Dumitriu D, Morrison JH, Malenka RC, Nestler EJ. The addicted synapse: mechanisms of synaptic and structural plasticity in nucleus accumbens. Trends Neurosci 2010;33:267–76. 31. Schmidt HD, Pierce RC. Cocaine-induced neuroadaptations in glutamate transmission: potential therapeutic targets for craving and addiction. Ann N Y Acad Sci 2010;1187:35–75. 32. Solinas M, Thiriet N, El Rawas R, Lardeux V, Jaber M. Environmental enrichment during early stages of life reduces the behavioral, neurochemical, and molecular effects of cocaine. Neuropsychopharmacology 2009;34:1102–11. 33. Bremner JD, Narayan M, Anderson ER, Staib LH, Miller HL, Charney DS. Hippocampal volume reduction in major depression. Am J Psychiatry 2000;157:115–8. 34. Hannestad J, Taylor WD, McQuoid DR, Payne ME, Krishnan KR, Steffens DC, Macfall JR. White matter lesion volumes and caudate volumes in late-life depression. Int J Geriatr Psychiatry 2006;21:1193–8. 35. Russo SJ, Nestler EJ. The brain reward circuitry in mood disorders. Nat Rev Neurosci 2013;14:609–25. 36. Krishnan KR, McDonald WM, Escalona PR, Doraiswamy PM, Na C, Husain MM, Figiel GS, Boyko OB, Ellinwood EH, Nemeroff CB. Magnetic resonance imaging of the caudate nuclei in depression. Preliminary observations. Arch Gen Psychiatry 1992;49:553–7. 37. Abdallah CG, Jackowski A, Salas R, Gupta S, Sato JR, Mao X, Coplan JD, Shungu DC, Mathew SJ. The nucleus accumbens and ketamine treatment in major depressive disorder. 2017;42:1739–46. 38. Drevets WC, Videen TO, Price JL, Preskorn SH, Carmichael ST, Raichle ME. A functional anatomical study of unipolar depression. J Neurosci 1992;12:3628–41.017;73:11–8. 39. Kawamura T, Chen J, Takahashi T, Ichitani Y, Nakahara D. Prenatal stress suppresses cell proliferation in the early developing brain. Neuroreport 2006;17:1515–8. 40. McClure WO, Ishtoyan A, Lyon M. Very mild stress of pregnant rats reduces volume and cell number in nucleus accumbens of adult offspring: some parallels to schizophrenia. Brain Res Dev Brain Res 2004;149:21–8. 41. Walsh JJ, Friedman AK, Sun H, Heller EA, Ku SM, Juarez B, Burnham VL, Mazei-Robison MS, Ferguson D, Golden SA, Koo JW, Chaudhury D, Christoffel DJ, Pomeranz L, Friedman JM, Russo SJ, Nestler EJ, Han MH. Stress and CRF gate neural activation of BDNF in the mesolimbic reward pathway. Nat Neurosci 2014;17:27–9. 42. Witkin JM, Monn JA, Schoepp DD, Li X, Overshiner C, Mitchell SN, Carter G, Johnson B, Rasmussen K, Rorick-Kehn LM. The rapidly acting antidepressant ketamine and the mGlu2/3 receptor antagonist LY341495 rapidly engage dopaminergic mood circuits. J Pharmacol Exp Ther 2016;358:71–82. 43. Schroeder FA, Penta KL, Matevossian A, Jones SR, Konradi C, Tapper AR, Akbarian S. Drug-induced activation of dopamine D(1) receptor signaling and inhibition of class I/II histone deacetylase induce chromatin remodeling in reward circuitry and modulate cocaine-related behaviors. Neuropsychopharmacology 2008;33:2981–92. 44. Réus GZ, Abelaira HM, dos Santos MA, Carlessi AS, Tomaz DB, Neotti MV, Liranço JL, Gubert C, Barth M, Kapczinski F, Quevedo J. Ketamine and imipramine in the nucleus accumbens regulate histone deacetylation induced by maternal deprivation and are critical for associated behaviors. Behav Brain Res 2013;256:451–6. 45. Svensson TH. Dysfunctional brain dopamine systems induced by psychotomimetic NMDA-receptor antagonists and the effects of antipsychotic drugs. Brain Res Brain Res Rev 2000;31:320–9. 46. Peleg-Raibstein D, Feldon J. Effects of dorsal and ventral hippocampal NMDA stimulation on nucleus accumbens core and shell dopamine release. Neuropharmacology 2006;57:947–57. 47. Marcus MM, Mathé JM, Nomikos GG, Svensson TH. Effects of competitive and non-competitive NMDA receptor antagonists on dopamine output in the shell and core subdivisions of the nucleus accumbens. Neuropharmacology 2001;40:482–90. 48. Pouvreau T, Tagliabue E, Usun Y, Eybrard S, Meyer F, Louilot A. Neonatal prefrontal inactivation results in reversed dopaminergic responses in the shell subregion of the nucleus accumbens to NMDA antagonists. ACS Chem Neurosci 2016;7:964–71. 49. Irifune M, Fukuda T, Nomoto M, Sato T, Kamata Y, Nishikawa T, Mietani W, Yokoyama K, Sugiyama K, Kawahara M. Effects of ketamine on dopamine metabolism during anesthesia in discrete brain regions in mice: comparison with the effects during the recovery and subanesthetic phases. Brain Res 1997;763:281–4.
Konular Sağlık Bilimleri
Dergi Bölümü Original Articles
Yazarlar

Yazar: Elif Polat Çorumlu
Ülke: Turkey


Yazar: Osman Özcan Aydın
Ülke: Turkey


Yazar: Emel Ulupınar
Ülke: Turkey


Bibtex @araştırma makalesi { anatomy385505, journal = {Anatomy}, issn = {1307-8798}, eissn = {1308-8459}, address = {Türk Anatomi ve Klinik Anatomi Derneği}, year = {2017}, volume = {11}, pages = {115 - 120}, doi = {}, title = {Single dose ketamine injection affects activation of cells in the nucleus accumbens of prenatally stressed rats}, key = {cite}, author = {Özcan Aydın, Osman and Ulupınar, Emel and Polat Çorumlu, Elif} }
APA Polat Çorumlu, E , Özcan Aydın, O , Ulupınar, E . (2017). Single dose ketamine injection affects activation of cells in the nucleus accumbens of prenatally stressed rats. Anatomy, 11 (3), 115-120. Retrieved from http://dergipark.gov.tr/anatomy/issue/34659/385505
MLA Polat Çorumlu, E , Özcan Aydın, O , Ulupınar, E . "Single dose ketamine injection affects activation of cells in the nucleus accumbens of prenatally stressed rats". Anatomy 11 (2017): 115-120 <http://dergipark.gov.tr/anatomy/issue/34659/385505>
Chicago Polat Çorumlu, E , Özcan Aydın, O , Ulupınar, E . "Single dose ketamine injection affects activation of cells in the nucleus accumbens of prenatally stressed rats". Anatomy 11 (2017): 115-120
RIS TY - JOUR T1 - Single dose ketamine injection affects activation of cells in the nucleus accumbens of prenatally stressed rats AU - Elif Polat Çorumlu , Osman Özcan Aydın , Emel Ulupınar Y1 - 2017 PY - 2017 N1 - DO - T2 - Anatomy JF - Journal JO - JOR SP - 115 EP - 120 VL - 11 IS - 3 SN - 1307-8798-1308-8459 M3 - UR - Y2 - 2017 ER -
EndNote %0 Anatomy Single dose ketamine injection affects activation of cells in the nucleus accumbens of prenatally stressed rats %A Elif Polat Çorumlu , Osman Özcan Aydın , Emel Ulupınar %T Single dose ketamine injection affects activation of cells in the nucleus accumbens of prenatally stressed rats %D 2017 %J Anatomy %P 1307-8798-1308-8459 %V 11 %N 3 %R %U