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

Abstract

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.

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Abbreviations

rTMS:

Repetitive transcranial magnetic stimulation

CMS:

Chronic unpredictable mild stress

SPT:

Sucrose preference test

FST:

Forced swimming test

NSF:

Novelty suppressed feeding test

CB1R:

Cannabinoid type I receptor

2-AG:

2-arachidonoylglycerol

MAGL:

Monoacylglycerol lipase

DAGL:

Diacylglycerol lipase

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Acknowledgements

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).

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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.

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Correspondence to Ying Wang.

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Fang, G., Wang, Y. Effects of rTMS on Hippocampal Endocannabinoids and Depressive-like Behaviors in Adolescent Rats. Neurochem Res 43, 1756–1765 (2018). https://doi.org/10.1007/s11064-018-2591-y

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  • DOI: https://doi.org/10.1007/s11064-018-2591-y

Keywords

  • Repetitive transcranial magnetic stimulation (rTMS)
  • Juvenile depression
  • Endocannabinoid
  • Hippocampus