Electroacupuncture regulate hypothalamic–pituitary–adrenal axis and enhance hippocampal serotonin system in a rat model of depression

doi:10.1016/j.neulet.2016.01.004

Neuroscience Letters

Volume 615, 26 February 2016, Pages 66-71

https://doi.org/10.1016/j.neulet.2016.01.004 Get rights and content

Highlights

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In the current study, we used forced swimming test and open-field test to determine whether electroacupuncture (EA) affects chronic unpredictable mild stress (CUMS)-induced depression-like behavior. Further, we discussed the impacts of EA treatment on the regulation of hypothalamic–pituitary–adrenal (HPA) axis and hippocampal serotonin (5-hydroxytryptamine, 5-HT) system. Our results show that EA treatment could ameliorate CUMS-induced behavioral symptoms, stabilize the HPA axis and increase hippocampal 5-HT/5-HT1AR. The data provides preliminary evidence that EA could relieve behavioral symptoms by modulating HPA axis and enhancing hippocampal serotonin system in CUMS rats.
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This finding supports the clinical use of EA in treatment of depression disorder and may initiate a discussion on the involvement of HPA axis and hippocampal serotonin system in anti-depressive effect of EA.

Abstract

Hypothalamic–pituitary–adrenal (HPA) axis has been implicated in the pathogenesis of depression. Dysfunction of the hippocampal serotonin (5-hydroxytryptamine, 5-HT) system has been shown to be a key factor in depression. There is growing evidence that electro-acupuncture (EA) has antidepressant-like effect. However, the effect of EA on HPA axis and hippocampal serotonin system remains unknown. In our study, we investigated the antidepressant-like effect and mechanism of EA for depression rat models. Depression in rats was induced by chronic unpredictable mild stress (CUMS). EA treatment was administered once daily to CUMS rats for 14 days. The acupoints (ST36, bilateral and CV4) were selected. Untreated CUMS rats and normal rats were used as controls. Behavioral tests including forced swim test and open-field test were performed to evaluate the antidepressant effects of EA treatment. Hypothalamic corticotropin-releasing hormone (CRH) mRNA, plasma adrenocorticotropic hormone (ACTH) and corticosterone (CORT) were estimated as indices of HPA axis activity. Enzyme linked immunosorbent assay (ELISA) was performed to determine the concentrations of 5-HT in the hippocampus. Real-time PCR(RT-PCR)and Western blot were respectively used to detect the mRNA and protein levels of 5-hydroxytryptamine 1A receptor (5-HT1AR) in the hippocampus. Our results showed that EA treatment reversed the behavioral deficiency induced by CUMS in rats. EA treatment decreased CRH mRNA expression in the hypothalamic, and ACTH and CORT level in plasma, and markedly increased 5-HT concentration, 5-HT1AR (mRNA and protein) expression in the hippocampus. These results indicated that EA treatment could act on depression by modulating HPA axis and enhancing hippocampal 5-HT/5-HT1AR in CUMS Rats.

Introduction

Major depression disorder (MDD) is a recurrent and debilitating mental disorder with a lifetime prevalence of up to 20% in the general population, among the highest for psychiatric disorders [1]. Currently, the therapy (eg., antidepressants and cognitive behavioral therapy), which is directed toward relieving symptoms, often causes limited success and deleterious side effects [2]. Thus, seeking an alternative therapy for MDD is an urgent issue which is needed to be addressed.

Acupuncture is a major therapy that has been used in China for thousands of years to treat various psychiatric conditions and is still frequently used to treat MDD in the present clinical practice [3], [4], [5]. Electro-acupuncture (EA) is a modification of acupuncture in which the needles inserted are attached with electrodes to deliver a pulsed electrical current. A growing number of studies have demonstrated that acupuncture or EA treatment could alleviate depressive symptoms with very few side effects [6], [7], [8]. However, some researchers believe that there is a lack of sufficient evidence for supporting a beneficial effect from them. Therefore, using a well characterized rat model of depression, clarifying the possible effects of acupuncture treatment in depression and revealing its underlying mechanisms may be of clinical benefit.

The pathophysiological mechanism underlying depression is still unclear, and theories vary widely in scope and perspective. More recent theoretical focus has largely been on biological factors, including a wealth of information supporting stress as a causal factor in depression, largely concerning chronic stress-related hypothalamic–pituitary–adrenal (HPA) axis dysregulation. The HPA axis is considered to be the final common pathway in the stress response and the symptoms of depression [9], [10], [11]. It has been indicated in the previous studies that EA relieved the excessive excitation of HPA function induced by stress stimulation [12], [13]. From this, we can ask: what role does the HPA axis play in the anti-depression effect of EA in CUMS rats?

At the neurochemical level, the most widely accepted hypothesis concerns the depletion of serotonin (5-hydroxytryptamine, 5-HT) in the brains of depressed patients [14], [15]. Selective serotonin reuptake inhibitors account for about 60–80% of the market share of antidepressants [16]. Serotonin acts via seven different classes of serotonergic receptors with at least 21 subtypes. Of these, 5-HT1A receptor (5-HT1AR) is mostly expressed in the mammalian brain, and especially expressed in the hippocampus [17]. Altered regulation of the serotonin-1A (5-HT1A) receptor gene is implicated in major depression and mood disorders [18]. Neuroimaging evidence has shown 5-HT1AR play an important role in neuropsychiatric disorders such as depression [19]. It has been reported 5-HT1AR partial agonists is useful and beneficial in the treatment of depressive disorders through increased hippocampal neurogenesis [20]. 5-HT is long known as a potent regulator of adult hippocampal neurogenesis [21], [22], [23]. The hippocampus also could regulate HPA axis function [24]. Therefore, we believe that hippocampal 5-HT/5-HT1AR may be crucial for the anti-depressive effect of EA.

In the current study, we used forced swimming test and open-field test to determine whether EA affects CUMS-induced depression-like behavior. Further, we discussed the impacts of EA treatment on the regulation of HPA axis and hippocampal 5-HT/5-HT1AR.

Section snippets

Animals

All protocols were approved by the Committee on the Use of Human and Animal Subjects in Teaching and Research, Fudan University. All efforts were made to minimize the number of animals used and their suffering. Male Sprague-Dawley rats (180 ± 20 g body weight), SPF class, were supplied by the Experiment Animal Center, School of Pharmacy, Fudan University. All rats were housed at a constant temperature and a humidity environment with free access to food and water. After one week of adaptation, the

EA improved behavioral symptoms of CUMS rats

The FST results are shown in Fig. 1A. The CUMS rats showed a significant increase in the immobile time compared to the normal rat (P < 0.01), while the immobile time was notably shorter in EA group than in CUMS group (P < 0.01), suggesting that EA may decrease immobile time of FST in depressed rat. The number of horizontal locomotion and rearing from OFT are shown in Fig. 1B and C. Analysis showed that the number of horizontal locomotion and rearing significantly decreased in CUMS rats as compared

Discussion

The present study aimed at exploring the therapeutic mechanisms underlying anti-depressive effect of EA using a CUMS-treated rat model. Here, we demonstrated that EA treatment could act on depression by modulating HPA axis and enhancing hippocampal 5-HT system in CUMS Rats.

CUMS model, which mimics socioenvironmental stressors in everyday life, is one of the most extensively used animal models of depression [25]. OFT reflects the excitability of the central nervous system in the rat model of

Author’s contributions

Jing-jing Le and Tao Yi contributed equally to this work. Jing-cheng Dong and Jing-jing Le designed the study. Tao Yi, Li Qi, Ji Li and Jing-jing Le implemented the experiments. Lei Shao analyzed the data. Tao Yi and Jing-jing Le wrote and revised the manuscript. Jing-cheng Dong supervised the whole research and edited the manuscript.

Conflicts of interest

We declare that there are no competing interests.

Acknowledgments

The study was funded by the National Natural Science Foundation (Nos. 81303034 and 81303031), China Postdoctoral Science Foundation (No. KLF501004) and Development Project of shanghai Peak Disciplines-Integrated Chinese and Western Medicine (2015).

References (42)

C. Wang et al.
Attribution retraining group therapy for outpatients with major depression disorder, generalized anxiety disorder, and obsessive-compulsive disorder: a pilot study
J. Biomed. Res.
(2011)
S.J. Wang et al.
Acupoint specificity on acupuncture regulation of hypothalamic–pituitary–adrenal cortex axis function
BMC Complement. Altern. Med.
(2015)
D. Hoyer et al.
Molecular, pharmacological and functional diversity of 5-HT receptors
Pharmacol. Biochem. Behav.
(2002)
M. Czesak et al.
Increased serotonin-1A (5-HT1A) autoreceptor expression and reduced raphe serotonin levels in deformed epidermal autoregulatory factor-1 (Deaf-1) gene knock-out mice
J. Biol. Chem.
(2012)
I. Mahar et al.
Stress, serotonin, and hippocampal neurogenesis in relation to depression and antidepressant effects
Neurosci. Biobehav. Rev.
(2014)
M. Boyko et al.
Establishment of an animal model of depression contagion
Behav. Brain Res.
(2015)
D.D. Luo et al.
Involvement of hippocampal serotonin and neuropeptide Y in depression induced by chronic unpredicted mild stress
Brain Res. Bull.
(2008)
A. Holmes
Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease
Neurosci. Biobehav. Rev.
(2008)
W.C. Drevets et al.
Serotonin-1A receptor imaging in recurrent depression: replication and literature review
Nucl. Med. Biol.
(2007)
G.A. Ulett et al.
Electroacupuncture: mechanisms and clinical application
Biol. Psychiatry
(1998)

S.J. Wang et al.

Experimental study on acupuncture activating the gonadotropin-releasing hormone neurons in hypothalamus

J. Tradit. Chin. Med.

(2010)

J.N. Jureidini et al.

Efficacy and safety of antidepressants for children and adolescents

BMJ

(2004)

H. Macpherson et al.

Acupuncture for depression: patterns of diagnosis and treatment within a randomised controlled trial

Evid. Based Complement. Altern. Med.

(2013)

S. Schroer et al.

Acupuncture, or non-directive counselling versus usual care for the treatment of depression: a pilot study

Trials

(2009)

D.P. Sniezek et al.

Acupuncture for treating anxiety and depression in women: a clinical systematic review

Med. Acupunct.

(2013)

J.I. Youn et al.

Effects of electro-acupuncture therapy on post-stroke depression in patients with different degrees of motor function impairments: a pilot study

J. Phys. Ther. Sci.

(2013)

S.C. Man et al.

A pilot controlled trial of a combination of dense cranial electroacupuncture stimulation and body acupuncture for post-stroke depression

BMC Complement. Altern. Med.

(2014)

H. Sun et al.

Effects of electroacupuncture on depression and the production of glial cell line-derived neurotrophic factor compared with fluoxetine: a randomized controlled pilot study

J. Altern. Complement. Med.

(2013)

F.P. Varghese et al.

The hypothalamic–pituitary–adrenal axis in major depressive disorder: a brief primer for primary care physicians

Prim. Care Companion J. Clin. Psychiatry

(2001)

L.M. Thornton et al.

The pain, depression, and fatigue symptom cluster in advanced breast cancer: covariation with the hypothalamic–pituitary–adrenal axis and the sympathetic nervous system

Health Psychol.

(2010)

F. Chen et al.

Hypothalamic–pituitary–adrenal axis hyperactivity accounts for anxiety- and depression-like behaviors in rats perinatally exposed to bisphenol A

J. Biomed. Res.

(2015)

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Research paperElectroacupuncture regulate hypothalamic–pituitary–adrenal axis and enhance hippocampal serotonin system in a rat model of depression

Highlights

Abstract

Introduction

Section snippets

Animals

EA improved behavioral symptoms of CUMS rats

Discussion

Author’s contributions

Conflicts of interest

Acknowledgments

J. Biomed. Res.

BMC Complement. Altern. Med.

Pharmacol. Biochem. Behav.

J. Biol. Chem.

Neurosci. Biobehav. Rev.

Behav. Brain Res.

Brain Res. Bull.

Neurosci. Biobehav. Rev.

Nucl. Med. Biol.

Biol. Psychiatry

J. Tradit. Chin. Med.

Efficacy and safety of antidepressants for children and adolescents

BMJ

Acupuncture for depression: patterns of diagnosis and treatment within a randomised controlled trial

Evid. Based Complement. Altern. Med.

Acupuncture, or non-directive counselling versus usual care for the treatment of depression: a pilot study

Trials

Acupuncture for treating anxiety and depression in women: a clinical systematic review

Med. Acupunct.

Effects of electro-acupuncture therapy on post-stroke depression in patients with different degrees of motor function impairments: a pilot study

J. Phys. Ther. Sci.

A pilot controlled trial of a combination of dense cranial electroacupuncture stimulation and body acupuncture for post-stroke depression

BMC Complement. Altern. Med.

Effects of electroacupuncture on depression and the production of glial cell line-derived neurotrophic factor compared with fluoxetine: a randomized controlled pilot study

J. Altern. Complement. Med.

The hypothalamic–pituitary–adrenal axis in major depressive disorder: a brief primer for primary care physicians

Prim. Care Companion J. Clin. Psychiatry

The pain, depression, and fatigue symptom cluster in advanced breast cancer: covariation with the hypothalamic–pituitary–adrenal axis and the sympathetic nervous system

Health Psychol.

Hypothalamic–pituitary–adrenal axis hyperactivity accounts for anxiety- and depression-like behaviors in rats perinatally exposed to bisphenol A

J. Biomed. Res.

Research paper
Electroacupuncture regulate hypothalamic–pituitary–adrenal axis and enhance hippocampal serotonin system in a rat model of depression