Elsevier

Brain Research

Volume 1663, 15 May 2017, Pages 20-28
Brain Research

Research report
Low- and high-intensity treadmill exercise attenuates chronic morphine-induced anxiogenesis and memory impairment but not reductions in hippocampal BDNF in female rats

https://doi.org/10.1016/j.brainres.2017.02.024Get rights and content

Highlights

  • Chronic morphine impaired spatial memory and enhanced anxiety levels in female rats.

  • Chronic morphine reduced hippocampal BDNF.

  • Low and high intensity forced exercise improved behavioral deficits by morphine.

  • Low and high forced exercise did not reverse the reduced BDNF by morphine.

  • Forced exercise could alleviate disorders produced by chronic morphine in females.

Abstract

Previous studies from our laboratory have shown that treadmill exercise alleviates the deficits in cognitive functions and anxiety behaviors induced by chronic exposure to morphine in male rats. In this study, we investigated the effects of low and high intensities of treadmill exercise on spatial memory, anxiety-like behaviors, and biochemical changes in the hippocampus and serum of morphine-treated female rats. The adult virgin female rats were injected with bi-daily doses (10 mg/kg, at 12 h intervals) of morphine over a period of 10 days. Following these injections, the rats were exercised under low or high intensities for 30 min per session on five days a week for four weeks. After exercise training, object location memory, anxiety profile, hippocampal BDNF, and serum corticosterone and BDNF were examined. Morphine-treated animals exhibited increased anxiety levels, impaired object location memory, and reduced hippocampal BDNF. Exercise alleviated these impairing effects on anxiety profile and memory but not hippocampal BDNF. The high-intensity exercise even further reduced the hippocampal BDNF. Additionally, both exercise regimens in the morphine group and the high exercise in the saline group reduced serum BDNF. Finally, the high-intensity exercise enhanced corticosterone serum. These findings indicate that the negative cognitive and behavioral effects of chronic exposure to morphine could be relieved by forced exercise in female rats. However, the exercise intensity is an important factor to be considered during exercise training. Finally, the correlation between changes of brain and serum BDNF and cognitive functions following morphine exposure needs further research.

Introduction

Previous studies have shown that long-term exposure to opiates, including morphine, impairs cognitive functions in experimental animals and humans (Davis et al., 2002, Dougherty et al., 1996, Gu et al., 2007, Miladi Gorji et al., 2008, Robbins and Everitt, 1999, Spain and Newsom, 1991). A higher prevalence of mood disorders, such as anxiety and depression, has been clinically demonstrated among drug abusers, which may contribute to persistent use and relapse following abstinence (Davis et al., 2002, De Graaf et al., 2003). There is a growing body of knowledge about the beneficial effects of exercise on cognitive functions in humans and experimental animals (Kramer et al., 2006). Both voluntary running and forced exercise can improve learning and memory in rodents (Albeck et al., 2006, Van der Borght et al., 2007, van Praag et al., 1999, Wu et al., 2007). Exercise enhances the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus, a key brain structure in the medial temporal lobe which is essential for activity-dependent learning and memory (Neeper et al., 1996). BDNF, via a TrkB-dependent mechanism, mediates exercise-induced enhancement of learning, memory, and synaptic plasticity (Vaynman et al., 2004).

The effectiveness of exercise in drug addiction recovery and rehabilitation is demonstrated. For instance, we recently reported that concurrent access to a running wheel blocked the impairment of learning and memory induced by chronic exposure to morphine via the BDNF-TrkB mechanism in male rats (Miladi-Gorji et al., 2011). We also have demonstrated that treadmill and running wheel exercise regimens could blunt the deleterious effects of drugs of abuse after exposure to these substances or after long periods of abstinence (Mokhtari-Zaer et al., 2014). The forced exercise, particularly at high intensity, increases the secretion of glucocorticoids, such as cortisol or corticosterone (Soya et al., 2007). Elevated levels of glucocorticoids are known to inhibit neurogenesis in the hippocampus and disrupt hippocampal synaptic plasticity, resulting in impairment of learning and memory (McEwen, 1999). For example, high impact forced exercise with speeds up to 25 m/min leads to impairment of spatial learning and memory, while low impact forced exercise with speeds up to 12 m/min, which is well below those normally considered stressful (17–30 m/min), improves learning and memory in rodents (Kennard and Woodruff-Pak, 2012).

Recent studies have demonstrated sex -dependent differences in different phases of drug addiction (Lynch et al., 2002, Lynch, 2006). Females are more susceptible than males during transition periods of drug use that are characteristic of drug addiction and relapse. Females are also more sensitive than males to the reinforcing effects of stimulants. Female sex hormones, particularly estrogen, appear to contribute to the mechanisms of action underlying these sex differences (for review see (Roth et al., 2004)). Also, the influence of gender on the physiological effects of exercise is documented. For example, it has been reported that female rats with drug addiction often run longer distances in a running wheel than male rats in the same time frame (Peterson et al., 2014). Male rats showed a smaller reduction of serum corticosteroid binding globulin than female rats in a 10-day treadmill exercise regime (Brown et al., 2007). These sex-dependent effects of drug addiction and exercise may influence differentially the effectiveness of exercise on drug rehabilitation (Fattore et al., 2008).

So far, the therapeutic effects of physical exercise on drug addiction have been mainly focused on male animals, with few studies in females (see (Fattore et al., 2008) for review). In a recent study, we have demonstrated that voluntary exercise as well as the low-intensity treadmill exercise could ameliorate the cognitive and behavioral deficits after the chronic exposure to morphine or after long periods of abstinence in male rats (Mokhtari-Zaer et al., 2014), but these effects are not known in female rats. Thus, the aim of this study was to examine the effects of treadmill exercise with low or high intensity on cognitive, behavioral, and biochemical disorders induced following chronic exposure to morphine in female rats. Similar to our recent study (Mokhtari-Zaer et al., 2014), we applied the exercise regimen after a 10 -day period of morphine administration to examine whether exercise could blunt the deleterious effects of drugs of abuse after the exposure to these substances or after long periods of abstinence. The research is of potential relevance for the determination of the therapeutic effects of different intensities of exercise on drug rehabilitation in women.

Section snippets

Withdrawal signs

The overall Gellert–Holtzman scores were significantly higher in the morphine-treated female rats than the saline-treated female rats (t8 = 16.12, P = 0.0001). Among the graded signs, abdominal contractions (t8 = 4.33, P = 0.003) and weight loss (t8 = 4.32, P = 0.003) were significantly higher in the morphine group than the control one (Fig. 2).

Among the checked signs (Table 1), the number of rats per group with diarrhea (U = 0, P = 0.003), writhing (U = 0, P = 0.003), genital grooming (U = 5, P = 0.05), and ptosis (U =

Chronic exposure to morphine enhances anxious behaviors in female rats: effects of exercise

The present study showed that the administration of bi-daily doses (10 mg/kg, at 12 h intervals) of morphine over a period of 10 days induces dependency in female rats, similar to that seen in the previous findings in male rats (Miladi-Gorji et al., 2011, Mokhtari-Zaer et al., 2014). We found that the sedentary morphine-treated rats exhibited anxiogenic-like behaviors in the EPM task. They exhibited significantly less time in open arms and fewer open arms entries than control animals. However,

Animals

Adult virgin female Wistar rats (220 ± 10 g) were individually housed in cages (50 × 26 × 25 cm) in a 12 h light/dark cycle at 22–24 °C, with food and water ad libitum. The experimental protocol was approved by the Ethical Review Board of Semnan University of Medical Sciences (Iran). All experimental trials were conducted in agreement with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. All behavioral tests were performed between 8:00 am and 1:00 pm. Behavioral and

Conflict of interest statement

We attest that we have herein disclosed any and all financial or other relationships that could be construed as a conflict of interest and that all sources of financial support for this study have been disclosed.

Acknowledgments

This work was supported by grants from Cognitive Sciences and Technologies Council of Iran (91001448) and Semnan University of Medical Sciences (Semnan, Iran). In addition, Ms Shahrbanoo Ghodrati-Jaldbakhan carried out this work in partial project fulfillment of the requirements to obtain the Master of Science degree in Physiology.

References (60)

  • B. Greenwood et al.

    Voluntary freewheel running selectively modulates catecholamine content in peripheral tissue and c-Fos expression in the central sympathetic circuit following exposure to uncontrollable stress in rats

    Neuroscience

    (2003)
  • S.L. Handley

    5-Hydroxytryptamine pathways in anxiety and its treatment

    Pharmacol. Ther.

    (1995)
  • J.A. Kennard et al.

    A comparison of low-and high-impact forced exercise: effects of training paradigm on learning and memory

    Physiol. Behav.

    (2012)
  • H. Miladi-Gorji et al.

    Voluntary exercise ameliorates cognitive deficits in morphine dependent rats: the role of hippocampal brain-derived neurotrophic factor

    Neurobiol. Learn. Mem.

    (2011)
  • H. Miladi-Gorji et al.

    Anxiety profile in morphine-dependent and withdrawn rats: effect of voluntary exercise

    Physiol. Behav.

    (2012)
  • H. Miladi Gorji et al.

    Effects of morphine dependence on the performance of rats in reference and working versions of the water maze

    Physiol. Behav.

    (2008)
  • A. Mokhtari-Zaer et al.

    Effects of voluntary and treadmill exercise on spontaneous withdrawal signs, cognitive deficits and alterations in apoptosis-associated proteins in morphine-dependent rats

    Behav. Brain Res.

    (2014)
  • S.A. Neeper et al.

    Physical activity increases mRNA for brain-derived neurotrophic factor and nerve growth factor in rat brain

    Brain Res.

    (1996)
  • M.E. Roth et al.

    Sex differences in the vulnerability to drug abuse: a review of preclinical studies

    Neurosci. Biobehav. Rev.

    (2004)
  • M.J. Schaaf et al.

    Downregulation of BDNF mRNA and protein in the rat hippocampus by corticosterone

    Brain Res.

    (1998)
  • L.M. Schrott et al.

    Prenatal opiate exposure impairs radial arm maze performance and reduces levels of BDNF precursor following training

    Brain Res.

    (2008)
  • H. Soya et al.

    BDNF induction with mild exercise in the rat hippocampus

    Biochem. Biophys. Res. Commun.

    (2007)
  • B. Winter et al.

    High impact running improves learning

    Neurobiol. Learn. Mem.

    (2007)
  • H. Abush et al.

    Short-and long-term cognitive effects of chronic cannabinoids administration in late-adolescence rats

    PLoS ONE

    (2012)
  • D.A. Brown et al.

    Short-term treadmill running in the rat: what kind of stressor is it?

    J. Appl. Physiol.

    (2007)
  • D. Carlino et al.

    Is altered BDNF biosynthesis a general feature in patients with cognitive dysfunctions?

    Neuroscientist

    (2013)
  • R. De Graaf et al.

    Temporal sequencing of lifetime mood disorders in relation to comorbid anxiety and substance use disorders

    Soc. Psychiatry Psychiatr. Epidemiol.

    (2003)
  • S.K. Droste et al.

    Effects of long-term voluntary exercise on the mouse hypothalamic-pituitary-adrenocortical axis

    Endocrinology

    (2003)
  • L. Fattore et al.

    Sex differences in drug addiction: a review of animal and human studies

    Womens Health (Lond)

    (2008)
  • J. Fuss et al.

    Voluntary exercise induces anxiety-like behavior in adult C57BL/6J mice correlating with hippocampal neurogenesis

    Hippocampus

    (2010)
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