Elsevier

Neurochemistry International

Volume 110, November 2017, Pages 91-100
Neurochemistry International

Treadmill exercise alleviated prenatal buprenorphine exposure-induced depression in rats

https://doi.org/10.1016/j.neuint.2017.09.012Get rights and content

Highlights

  • Prenatal buprenorphine exposure induces depression-like behavior in weanlings.

  • Treadmill exercise improves depression-like phenotypes.

  • Treadmill exercise increases expression of neurotrophins and neurotransmitters.

  • Treadmill exercise decreases oxidative stress and inflammation.

Abstract

Mounting evidence suggests that physical exercise shows health benefits in a range of diseases, including psychiatric disorders. Perinatal opioid exposure produces neurobehavioral abnormality, which includes depression symptoms, in patients and their offspring following chronic use of buprenorphine, a mixed agonist/antagonist with a high affinity to opioid receptors, for pain control. Previously, we demonstrated that prenatal buprenorphine exposure in pregnant Sprague-Dawley rats starting from gestation day 7 and lasting for 14 days caused the development of depression-like phenotypes in pups at postnatal day 21. Using the same prenatal buprenorphine exposure model, we further demonstrated that a 4-week course of moderate treadmill exercise conducted on pups starting from postnatal day 22 improved depression-like neurobehaviors. Prenatal buprenorphine exposure-induced neurobehavioral changes were accompanied by reductions of neuronal survival, neural stem cell-associated genes, plasma level of brain-derived neurotrophic factor (BDNF) and serotonin, phosphorylated tropomyosin-related kinase receptor type B (TrkB), phosphorylated extracellular signal-regulated kinase (ERK), PKA activity, phosphorylated cAMP response element-binding protein (CREB), and CREB DNA binding activity, as well as elevation of repressor element-1 silencing transcription factor (REST), oxidative stress, and inflammatory responses. Those changes in parameters of plasma and brain were improved by treadmill exercise. In conclusion, the findings of the current study suggest that a non-pharmacological option, i.e., moderate treadmill exercise, alleviated the development of depression-like neurobehaviors by resolving the oxidative and inflammatory burden as well as by enhancing neurochemical and neuroendocrine signaling.

Introduction

Depression is a chronic mood disorder with a heterogeneous etiology. Social isolation, chronic stress, diseases, drug abuse, obesity, and menopause are risk factors in patients suffering from depression (Barichello et al., 2010, Hauser et al., 2011, Hong et al., 2015, Lee et al., 2015, Liu et al., 2012, Lu et al., 2014, Park et al., 2017, Roh et al., 2016). Genetic predisposition and dysregulation of neurotransmitter and neurohormonal pathways have been implicated in the pathogenesis of depression. Moreover, increasing evidence also highlights the pathogenic roles of inflammation, oxidative stress, and impaired neurogenesis in the development and progression of depression (Chung et al., 2013, Hariri and Holmes, 2006, Kim and Leem, 2014, Liu et al., 2013, Otsuka et al., 2016, Wang et al., 2016, Xu et al., 2006). Since the risk factors and pathogenic mechanisms of depression are multifactorial, a better understanding of its molecular and biochemical basis may be of practical value in the prevention and treatment of depression.

Clinically, tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors are therapeutic drugs that are routinely prescribed to patients with depression. However, adverse effects are the major concern with respect to their clinical application (Zhou et al., 2017). Nowadays, the use of physical exercise is increasingly becoming a non-pharmacological strategy for health promotion and as a therapeutic treatment, including psychotherapy. The beneficial effects of voluntary exercise have been reported in patients with depression and in rodent models of depression caused by glucocorticoid exposure, social isolation, chronic mild stress, stroke, obesity, and ovariectomy (Hong et al., 2015, Lee et al., 2015, Liu et al., 2012, Lu et al., 2014, Park et al., 2017, Roh et al., 2016). Experimental studies have further revealed that exercise has a role in neurogenesis, angiogenesis, apoptosis, inflammation, as well as oxidative stress, and exercise-induced expression of neurotrophins and neurochemicals was associated with substantially improved depressive symptoms (Boehme et al., 2011; Ferrira et al., 2011, Hong et al., 2015, Kiuchi et al., 2012, Lee et al., 2015, Liu et al., 2013, Lu et al., 2014, Moon et al., 2012, Shin et al., 2013, Speisman et al., 2013, Wang et al., 2016, Zhang et al., 2013).

Opioid-dependent patients often develop psychiatric disorders and depression is one such common complication with a poor prognosis (Rounsaville et al., 1982). Buprenorphine, a partial agonist of the μ-opioid receptor and an antagonist of the κ- and δ-opioid receptors, is prescribed as a maintenance therapy for opioid addicts (Alto and O'Connor, 2011). Although buprenorphine has been suggested to have an antidepressant-like effect, a wide range of clinical observations and rodent studies have demonstrated the reverse, i.e., the use of the drug was found to be closely associated with worse neurobehaviors, including depression-like phenotypes (Almatroudi et al., 2015, Blandthorn et al., 2011, Browne et al., 2015, Coyle et al., 2012, Jansson et al., 2011, Lund et al., 2013, Richards et al., 2017, Stein et al., 2015). These findings raise concerns about the potential adverse effects related to neurobehavioral development following buprenorphine treatment, particularly in pregnant mothers.

Our previous studies showed that prenatal buprenorphine exposure in pregnant rats caused a depression-like effect in weanlings (Hung et al., 2013, Wu et al., 2014). We also found treadmill exercise improved botulinum toxin-degenerated skeletal muscles (Tsai et al., 2012). The beneficial effects of treadmill exercise have been demonstrated in several types of disease models of depression (Hong et al., 2015, Kim and Leem, 2014, Lee et al., 2015, Otsuka et al., 2016, Roh et al., 2016, Wang et al., 2016), whereas, its effect on maternal depression has not been characterized. To extend the scope of relevant studies, we therefore undertook the present investigation to examine the effects of treadmill exercise on prenatal buprenorphine exposure-produced depression-like changes in rat weanlings and to identify the causative mediators involved.

Section snippets

Animals and buprenorphine treatment

The protocols of animal experiments in this study were reviewed and approved by the Animal Experimental Committee of Taichung Veterans General Hospital. The pregnant Sprague-Dawley rats (200–250 g) (40 rats in total) were housed in a regular animal facility with a 12-hour light-dark cycle and free access to food and water ad libitum. On day 7 of gestation, these pregnant rats (20 rats per group) started to receive daily (9:00 a.m.) single intraperitoneal injection of buprenorphine (0 and

Treadmill exercise improved prenatal buprenorphine exposure-induced depression-like neurobehaviors

On postnatal day 21, pups born to mothers receiving 1 mg/kg/day buprenorphine showed a slight decrease in body weight (Fig. 2A). However, data of the travel distance (Fig. 2B) and moving time (Fig. 2C) in open field test revealed that prenatal buprenorphine exposure did not cause significant alterations in locomotor activity. As with our previous reports (Hung et al., 2013, Wu et al., 2014), pups born to dams that were exposed to buprenorphine starting from gestation day 7 and lasting for 14

Discussion

Depression is a heterogeneous psychiatric disorder with multiple pathogenic mechanisms. The etiology of depression is further complicated by disturbances of the hypothalamic-pituitary-adrenal axis, neurochemicals, the neuroendocrine system, inflammation, oxidative stress, neurogenesis, and angiogenesis (Chung et al., 2013, Hariri and Holmes, 2006, Kim and Leem, 2014, Liu et al., 2013, Otsuka et al., 2016, Wang et al., 2016, Xu et al., 2006). Consistent with the results of our previous studies (

Conflicts of interest

The authors declare that there are no conflicts of interest.

Acknowledgements

This study was supported by grants from Taichung Veterans General Hospital (TCVGH-1007306C and TCVGH-1067309C) and the Yen Tjing Ling Medical Foundation (CI-98-10 and CI-103-19), Taiwan, Republic of China. The funders had no roles in the study design, data analysis, or preparation and submission of the manuscript. We are grateful to Dr. Cheng Fu-Chou (Department of Medical Research, Taichung Veterans General hospital) for his assistance with the treadmill apparatus.

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    Chih-Cheng Wu and Chih-Jen Hung contributed equally in this study.

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