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