Neurochemical Research

, Volume 43, Issue 9, pp 1756–1765 | Cite as

Effects of rTMS on Hippocampal Endocannabinoids and Depressive-like Behaviors in Adolescent Rats

  • Guoxiang Fang
  • Ying WangEmail author
Original Paper


Depression is a common mental disorder in adolescents, with a prevalence rate of 5.6%. Current anti-depressive options for adolescents are limited: psychological intervention and conventional antidepressants have low efficacy, a delayed onset of action and increased possibility of suicidal risk. Repetitive transcranial magnetic stimulation (rTMS) as an effective and noninvasive physical therapy for adult depression has been investigated in recent years. However, whether it also produces similar effects on juvenile depression and the underlying mechanism are not clearly understood. In this study, chronic unpredictable mild stress (CMS) was applied to 3-week-old male Sprague Dawley rats for 21 days. Then rTMS was performed for seven consecutive days, and the anti-depressive effects were evaluated by behavioral tests including the sucrose preference test (SPT), the forced swimming test (FST), and the novelty suppressed feeding test (NSF). Expression of hippocampal cannabinoid type I receptor (CB1R), 2-arachidonoylglycerol (2-AG) and relative synthetase and degradative enzymes-diacylglycerol lipase (DAGL) and monoacylglycerol lipase (MAGL) were also investigated. The behavioral parameters were also observed after the administration of the selective CB1 receptor antagonist AM251. The results showed that CMS induced a significant decrease in sucrose preference, a significant increase of immobility time in the FST, and an increased latency to feed in the NSF. In addition, reduced hippocampal CB1 receptor, 2-AG level and increased MAGL protein expression level were also observed in CMS rats. Meanwhile, rTMS treatment upregulated 2-AG level in the hippocampus and ameliorated depressive-like behaviors. The anti-depressive effect of rTMS was attenuated by AM251, a specific CB1R antagonist that was administered 30 min before the onset of rTMS by either intraperitoneal administration or hippocampal microinjection. These results indicate that rTMS can be used as an antidepressive therapy for juvenile depression at least partly mediated by increasing hippocampal 2-AG and CB1 receptor expression levels.


Repetitive transcranial magnetic stimulation (rTMS) Juvenile depression Endocannabinoid Hippocampus 



Repetitive transcranial magnetic stimulation


Chronic unpredictable mild stress


Sucrose preference test


Forced swimming test


Novelty suppressed feeding test


Cannabinoid type I receptor




Monoacylglycerol lipase


Diacylglycerol lipase



We thank Dr. Sun XL for language assistance. This project was supported by grant from the National Natural Science Foundation of China (NSFC) to Y. Wang (Grant No. 81671343).


NSFC had no role in the design and conduct of the study; in the collection, management, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.

Compliance with Ethical Standards

Conflict of interest

There are no conflicts of interest relevant to this study.


  1. 1.
    Smith K (2014) Mental health: a world of depression. Nature 515(7526):180–181. CrossRefGoogle Scholar
  2. 2.
    Jane Costello E, Erkanli A, Angold A (2006) Is there an epidemic of child or adolescent depression? J Child Psychol Psychiatry Allied Discip 47(12):1263–1271. CrossRefGoogle Scholar
  3. 3.
    Hopkins K, Crosland P, Elliott N, Bewley S, Clinical Guidelines Update Committee B (2015) Diagnosis and management of depression in children and young people: summary of updated NICE guidance. BMJ 350:h824. CrossRefPubMedGoogle Scholar
  4. 4.
    Thapar A, Collishaw S, Pine DS, Thapar AK (2012) Depression in adolescence. Lancet 379(9820):1056–1067. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Hazell P (2002) Depression in children and adolescents. Clin Evid 7:307–313Google Scholar
  6. 6.
    Malhi GS, Bassett D, Boyce P, Bryant R, Fitzgerald PB, Fritz K, Hopwood M, Lyndon B, Mulder R, Murray G, Porter R, Singh AB (2015) Royal Australian and New Zealand College of Psychiatrists clinical practice guidelines for mood disorders. Aust N Z J Psychiatry 49(12):1087–1206. CrossRefPubMedGoogle Scholar
  7. 7.
    Nutt DJ, Sharpe M (2008) Uncritical positive regard? Issues in the efficacy and safety of psychotherapy. J Psychopharmacol 22(1):3–6. CrossRefPubMedGoogle Scholar
  8. 8.
    Linden M, Schermuly-Haupt ML (2014) Definition, assessment and rate of psychotherapy side effects. World Psychiatry 13(3):306–309. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Bachmann CJ, Aagaard L, Burcu M, Glaeske G, Kalverdijk LJ, Petersen I, Schuiling-Veninga CC, Wijlaars L, Zito JM, Hoffmann F (2016) Trends and patterns of antidepressant use in children and adolescents from five western countries, 2005–2012. Eur Neuropsychopharmacol 26(3):411–419. CrossRefPubMedGoogle Scholar
  10. 10.
    Cipriani A, Zhou X, Del Giovane C, Hetrick SE, Qin B, Whittington C, Coghill D, Zhang Y, Hazell P, Leucht S, Cuijpers P, Pu J, Cohen D, Ravindran AV, Liu Y, Michael KD, Yang L, Liu L, Xie P (2016) Comparative efficacy and tolerability of antidepressants for major depressive disorder in children and adolescents: a network meta-analysis. Lancet 388(10047):881–890. CrossRefPubMedGoogle Scholar
  11. 11.
    Daskalakis ZJ, Levinson AJ, Fitzgerald PB (2008) Repetitive transcranial magnetic stimulation for major depressive disorder: a review. Can J Psychiatry Revue Canadienne de Psychiatrie 53(9):555–566. CrossRefPubMedGoogle Scholar
  12. 12.
    Bestmann S (2008) The physiological basis of transcranial magnetic stimulation. Trends Cognit Sci 12(3):81–83. CrossRefGoogle Scholar
  13. 13.
    Kennedy SH, Giacobbe P (2007) Treatment resistant depression–advances in somatic therapies. Ann Clin Psychiatry 19(4):279–287. CrossRefPubMedGoogle Scholar
  14. 14.
    Rajapakse T, Kirton A (2013) Non-invasive brain stimulation in children: applications and future directions. Transl Neurosci. PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Spear LP (2000) The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev 24(4):417–463CrossRefPubMedGoogle Scholar
  16. 16.
    Lee TT, Gorzalka BB (2012) Timing is everything: evidence for a role of corticolimbic endocannabinoids in modulating hypothalamic-pituitary-adrenal axis activity across developmental periods. Neuroscience 204:17–30. CrossRefPubMedGoogle Scholar
  17. 17.
    Gorzalka BB, Hill MN (2011) Putative role of endocannabinoid signaling in the etiology of depression and actions of antidepressants. Prog Neuro-Psychopharmacol Biol Psychiatry 35(7):1575–1585. CrossRefGoogle Scholar
  18. 18.
    Reich CG, Mihalik GR, Iskander AN, Seckler JC, Weiss MS (2013) Adolescent chronic mild stress alters hippocampal CB1 receptor-mediated excitatory neurotransmission and plasticity. Neuroscience 253:444–454. CrossRefPubMedGoogle Scholar
  19. 19.
    Hill MN, Patel S (2013) Translational evidence for the involvement of the endocannabinoid system in stress-related psychiatric illnesses. Biol Mood Anxiety Disord 3(1):19. CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Hillard CJ, Liu QS (2014) Endocannabinoid signaling in the etiology and treatment of major depressive illness. Curr Pharm Des 20(23):3795–3811CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Wang H, Xue Y, Chen Y, Zhang R, Wang H, Zhang Y, Gan J, Zhang L, Tan Q (2013) Efficacy of repetitive transcranial magnetic stimulation in the prevention of relapse of depression: study protocol for a randomized controlled trial. Trials 14:338. CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Wang HN, Wang L, Zhang RG, Chen YC, Liu L, Gao F, Nie H, Hou WG, Peng ZW, Tan Q (2014) Anti-depressive mechanism of repetitive transcranial magnetic stimulation in rat: the role of the endocannabinoid system. J Psychiatr Res 51:79–87. CrossRefPubMedGoogle Scholar
  23. 23.
    Wang Y, Gu N, Duan T, Kesner P, Blaskovits F, Liu J, Lu Y, Tong L, Gao F, Harris C, Mackie K, Li J, Tan Q, Hill MN, Yuan Z, Zhang X (2017) Monoacylglycerol lipase inhibitors produce pro- or antidepressant responses via hippocampal CA1 GABAergic synapses. Mol Psychiatry 22(2):215–226. CrossRefPubMedGoogle Scholar
  24. 24.
    Lenz M, Galanis C, Muller-Dahlhaus F, Opitz A, Wierenga CJ, Szabo G, Ziemann U, Deller T, Funke K, Vlachos A (2016) Repetitive magnetic stimulation induces plasticity of inhibitory synapses. Nat Commun 7:10020. CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Wang Y, Yang F, Liu YF, Gao F, Jiang W (2011) Acetylsalicylic acid as an augmentation agent in fluoxetine treatment resistant depressive rats. Neurosci Lett 499(2):74–79. CrossRefPubMedGoogle Scholar
  26. 26.
    Feng SF, Shi TY, Fan Y, Wang WN, Chen YC, Tan QR (2012) Long-lasting effects of chronic rTMS to treat chronic rodent model of depression. Behav Brain Res 232(1):245–251. CrossRefPubMedGoogle Scholar
  27. 27.
    Esser SK, Huber R, Massimini M, Peterson MJ, Ferrarelli F, Tononi G (2006) A direct demonstration of cortical LTP in humans: a combined TMS/EEG study. Brain Res Bull 69(1):86–94. CrossRefPubMedGoogle Scholar
  28. 28.
    Wang Q, Peng Y, Chen S, Gou X, Hu B, Du J, Lu Y, Xiong L (2009) Pretreatment with electroacupuncture induces rapid tolerance to focal cerebral ischemia through regulation of endocannabinoid system. Stroke 40(6):2157–2164. CrossRefPubMedGoogle Scholar
  29. 29.
    Atsak P, Hauer D, Campolongo P, Schelling G, McGaugh JL, Roozendaal B (2012) Glucocorticoids interact with the hippocampal endocannabinoid system in impairing retrieval of contextual fear memory. Proc Natl Acad Sci USA 109(9):3504–3509. CrossRefPubMedGoogle Scholar
  30. 30.
    Wang Y, Cui XL, Liu YF, Gao F, Wei D, Li XW, Wang HN, Tan QR, Jiang W (2011) LPS inhibits the effects of fluoxetine on depression-like behavior and hippocampal neurogenesis in rats. Prog Neuro-Psychopharmacol Biol Psychiatry 35(8):1831–1835. CrossRefGoogle Scholar
  31. 31.
    Vogeser M, Hauer D, Christina Azad S, Huber E, Storr M, Schelling G (2006) Release of anandamide from blood cells. Clin Chem Lab Med 44(4):488–491. CrossRefPubMedGoogle Scholar
  32. 32.
    Vogeser M, Schelling G (2007) Pitfalls in measuring the endocannabinoid 2-arachidonoyl glycerol in biological samples. Clin Chem Lab Med 45(8):1023–1025. CrossRefPubMedGoogle Scholar
  33. 33.
    Charney DA, Palacios-Boix J, Negrete JC, Dobkin PL, Gill KJ (2005) Association between concurrent depression and anxiety and six-month outcome of addiction treatment. Psychiatr Serv 56(8):927–933. CrossRefPubMedGoogle Scholar
  34. 34.
    Kim DR, Pesiridou A, O’Reardon JP (2009) Transcranial magnetic stimulation in the treatment of psychiatric disorders. Curr Psychiatry Rep 11(6):447–452CrossRefPubMedGoogle Scholar
  35. 35.
    Poleszczyk A (2015) Transcranial magnetic stimulation in treatment of various psychiatric disorders—review of the most prominent studies and the latest news. Psychiatria polska 49(4):779–789. CrossRefPubMedGoogle Scholar
  36. 36.
    Benadhira R, Saba G, Samaan A, Dumortier G, Lipski H, Gastal D, Kalalou K, Verdon CM, Januel D (2005) Transcranial magnetic stimulation for refractory depression. Am J Psychiatry 162(1):193. CrossRefPubMedGoogle Scholar
  37. 37.
    Gaynes BN, Lloyd SW, Lux L, Gartlehner G, Hansen RA, Brode S, Jonas DE, Swinson Evans T, Viswanathan M, Lohr KN (2014) Repetitive transcranial magnetic stimulation for treatment-resistant depression: a systematic review and meta-analysis. J Clin Psychiatry 75(5):477–489. quiz 489.CrossRefPubMedGoogle Scholar
  38. 38.
    Leite CE, Mocelin CA, Petersen GO, Leal MB, Thiesen FV (2009) Rimonabant: an antagonist drug of the endocannabinoid system for the treatment of obesity. Pharmacol Rep PR 61(2):217–224CrossRefPubMedGoogle Scholar
  39. 39.
    Wang Y, Zhang X (2017) FAAH inhibition produces antidepressant-like efforts of mice to acute stress via synaptic long-term depression. Behav Brain Res 324:138–145. CrossRefPubMedGoogle Scholar
  40. 40.
    Zhong P, Wang W, Pan B, Liu X, Zhang Z, Long JZ, Zhang HT, Cravatt BF, Liu QS (2014) Monoacylglycerol lipase inhibition blocks chronic stress-induced depressive-like behaviors via activation of mTOR signaling. Neuropsychopharmacology 39(7):1763–1776. CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Shearman LP, Rosko KM, Fleischer R, Wang J, Xu S, Tong XS, Rocha BA (2003) Antidepressant-like and anorectic effects of the cannabinoid CB1 receptor inverse agonist AM251 in mice. Behav Pharmacol 14(8):573–582. CrossRefPubMedGoogle Scholar
  42. 42.
    Hill MN, McLaughlin RJ, Bingham B, Shrestha L, Lee TT, Gray JM, Hillard CJ, Gorzalka BB, Viau V (2010) Endogenous cannabinoid signaling is essential for stress adaptation. Proc Natl Acad Sci USA 107(20):9406–9411. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of EmergencyXi’an NO.3 hospital (The Affiliated Hospital of Northwest University)Xi’anChina
  2. 2.Department of Psychiatry, Xijing HospitalFourth Military Medical UniversityXi’anChina

Personalised recommendations