Effects of voluntary exercise on anxiety-like behavior and voluntary morphine consumption in rat pups borne from morphine-dependent mothers during pregnancy

doi:10.1016/j.neulet.2014.06.026

Neuroscience Letters

Volume 578, 22 August 2014, Pages 50-54

https://doi.org/10.1016/j.neulet.2014.06.026 Get rights and content

Highlights

•
Morphine during pregnancy produces long-term behavioral effects in new born rats.
•
Exercise decreases the anxiety levels in both morphine-dependent and withdrawn rats.
•
Maternal exercise reduces the anxiety and voluntary consumption of morphine in pups.

Abstract

Exposure to morphine during pregnancy produced long-term effects in offspring behaviors. Recent studies have shown that voluntary exercise decreases the severity of anxiety behaviors in both morphine-dependent and withdrawn rats. Thus, the aims of the present study were to examine whether maternal exercise decreases prenatal dependence-induced anxiety and also, voluntary consumption of morphine in animal models of craving in rat pups. Pregnant rats were made dependent by chronic administration of morphine in drinking water simultaneously with access to a running wheel that lasted at least 21 days. Then, anxiety-like behaviors using the elevated plus-maze (EPM) and voluntary consumption of morphine using a two-bottle choice paradigm (TBC) were tested in male rat pups. The results showed that the rat pups borne from exercising morphine-dependent mothers exhibited an increase in EPM open arm time (P < 0.0001) and entries (P < 0.05) as compared with the sedentary groups. In animal models of craving showed that voluntary consumption of morphine in the rat pups borne from exercising morphine-dependent mothers was less in the second (P < 0.032) and third (P < 0.014) periods of intake as compared with the sedentary group. This study showed that maternal exercise decreases the severity of the anxiogenic-like behaviors and voluntary consumption of morphine in rat pups.

Introduction

Opiates such as morphine can be transferred from the mother to the developing central nervous system of the offspring through the placenta and breast milk [19]. Maternal opiates result in neurobiological alterations in offspring. These alterations include growth, behavior, cognitive and learning in preschool children [27] and in rodents include social and play behaviors [9], the brain reward circuitry and the modulation of opioid systems [6], the expression of morphine-induced conditioned place preference (CPP) [7], sympatho-adrenal axis activity and serotonin metabolism [11] and stress response to drug vulnerability of the offspring [25]. These harmful effects of maternal opiates may be prevented or reversed by exercise. Because it has shown that maternal exercise during pregnancy protected the pups from anxiety in early and late periods of life [2], improved antioxidant status in the offspring brain [13], attenuated maternal deprivation-induced stress and serum corticosterone levels [23], enhanced the spatial learning acquisition in pups [1]. We have previously shown that the access to running wheels diminished the severity of physical dependence and anxiety behavior in both morphine-dependent and withdrawn rats [14], [15]. Exercise also reduces self-administration of morphine [10]. Given the well-known beneficial effects maternal physiological responses to exercise during pregnancy and post-partum [2], [24], the aim of the present study was to investigate whether free access to a running wheel during pregnancy would attenuate morphine-dependent mothers-induced anxiety and also, voluntary consumption of morphine in animal models of craving in rat pups.

Section snippets

Materials and methods

Male Wistar rats (250 ± 10 g) were allowed to mate with female virgin Wistar rats (250 ± 10 g) during a 24 h period. Observation of vaginal plug was considered as gestational day 0 (G0) [1]. Then, pregnant rats were randomly divided into four groups of control-sedentary (Con/Sed), control-exercise (Con/Exc), dependent-sedentary (D/Sed), and dependent-exercise (D/Exc), and were housed individually in cages with a 12 h light/dark cycle at 22–24 °C temperature. Food and water were available ad libitum. All

Results

The mean amount of water intake and morphine during the administration of the highest dose (0.4 mg/ml) in D/Sed rats were 410 ml/kg and 168 mg/kg per day, respectively and also in D/Exc rats were 406 ml/kg and 162 mg/kg per day, respectively. There were no significant differences between the two groups (P > 0.05).

The average distance run (m) during pregnancy after 21–22 days of voluntary exercise did not differ significantly between exercising groups. Two-way ANOVA with repeated measure (day) for the

Discussion

The results of our study indicated that a period of 21 days of voluntary exercise using wheel running during pregnancy significantly decreases the severity of naloxone-precipitated morphine withdrawal signs in mothers after delivery, which are consistent with our previous results and others [3], [14], [15]. Exercise can activate the same pathways as morphine and may also lead to neuroplastic changes in the mesolimbic reward pathway [8] including decrease of potency and sensitivity to morphine

Conclusion

This study provides novel evidence that access to running wheels during pregnancy of morphine-dependent mothers can decrease the anxiogenic-like behaviors and the voluntary consumption of morphine in pups. Our findings may have a potential therapeutic application in the prevention of prenatally morphine-induced behavioral sensitization and relapse in the offspring rats.

Conflict of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and the writing of the paper.

Authors’ contributions

S.H carried out the experiments and data collection and helped to draft the manuscript. H.M.G participated in its design, data analysis and wrote the manuscript. A.M helped to collect data. M.S carried out scientific adviser to pregnant animals. All authors read and approved the final manuscript.

Acknowledgment

This work was supported by grants from the Semnan University of Medical Sciences (522).

References (28)

I. Aksu et al.
Maternal treadmill exercise during pregnancy decreases anxiety and increases prefrontal cortex VEGF and BDNF levels of rat pups in early and late periods of life
Neurosci. Lett.
(2012)
J. Belknap
Physical dependence induced by the voluntary consumption of morphine in inbred mice
Pharmacol. Biochem. Behav.
(1990)
R. Gagin et al.
Prenatal exposure to morphine alters analgesic responses and preference for sweet solutions in adult rats
Pharmacol. Biochem. Behav.
(1996)
R. Gagin et al.
Prenatal morphine enhances morphine-conditioned place preference in adult rats
Pharmacol. Biochem. Behav.
(1997)
T. Hol et al.
Prenatal exposure to morphine affects juvenile play behavior and adult social behavior in rats
Pharmacol. Biochem. Behav.
(1996)
M. Hosseini et al.
Treadmill exercise reduces self-administration of morphine in male rats
Pathophysiology
(2009)
C. Laborie et al.
Prenatal morphine exposure affects sympathoadrenal axis activity and serotonin metabolism in adult male rats both under basal conditions and after an ether inhalation stress
Neurosci. Lett.
(2005)
B. Lett et al.
Wheel running simultaneously produces conditioned taste aversion and conditioned place preference in rats
Learn Motiv.
(2001)
T. Marcelino et al.
Evidences that maternal swimming exercise improves antioxidant defenses and induces mitochondrial biogenesis in the brain of young Wistar rats
Neuroscience
(2013)
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.

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.

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

Physiol. Behav.

(2008)

S. Pietropaolo et al.

The impact of voluntary exercise on mental health in rodents: a neuroplasticity perspective

Behav. Brain Res.

(2008)

M.A. Riley et al.

Mid-to late gestational morphine exposure does not alter the rewarding properties of morphine in adult male rats

Neuropharmacology

(2006)

Cited by (35)

Effects of prenatal opioid exposure on synaptic adaptations and behaviors across development
2023, Neuropharmacology
In this review, we focus on prenatal opioid exposure (POE) given the significant concern for the mental health outcomes of children with parents affected by opioid use disorder (OUD) in the view of the current opioid crisis. We highlight some of the less explored interactions between developmental age and sex on synaptic plasticity and associated behavioral outcomes in preclinical POE research. We begin with an overview of the rich literature on hippocampal related behaviors and plasticity across POE exposure paradigms. We then discuss recent work on reward circuit dysregulation following POE. Additional risk factors such as early life stress (ELS) could further influence synaptic and behavioral outcomes of POE. Therefore, we include an overview on the use of preclinical ELS models where ELS exposure during key critical developmental periods confers considerable vulnerability to addiction and stress psychopathology. Here, we hope to highlight the similarity between POE and ELS on development and maintenance of opioid-induced plasticity and altered opioid-related behaviors where similar enduring plasticity in reward circuits may occur. We conclude the review with some of the limitations that should be considered in future investigations.
This article is part of the Special Issue on ‘Opioid-induced addiction’.
Maternal morphine intake during pregnancy and lactation affects the circadian clock of rat pups
2021, Brain Research Bulletin
Early-life morphine exposure causes a variety of behavioural and physiological alterations observed later in life. In the present study, we investigated the effects of prenatal and early postnatal morphine on the maturation of the circadian clockwork in the suprachiasmatic nucleus and the liver, and the rhythm in aralkylamine N-acetyltransferase activity in the pineal gland. Our data suggest that the most affected animals were those born to control, untreated mothers and cross-fostered by morphine-exposed dams. These animals showed the highest mesor and amplitude in the rhythm of Per2, Nr1d1 but not Per1 gene expression in the suprachiasmatic nuclei (SCN) and arrhythmicity in AA-NAT activity in the pineal gland. In a similar pattern to the rhythm of Per2 expression in the SCN, they also expressed Per2 in a higher amplitude rhythm in the liver. Five of seven specific genes in the liver showed significant differences between groups in their expression. A comparison of mean relative mRNA levels suggests that this variability was caused mostly by cross-fostering, animals born to morphine-exposed dams that were cross-fostered by control mothers and vice versa differed from both groups of natural mothers raising offspring. Our data reveal that the circadian system responds to early-life morphine administration with significant changes in clock gene expression profiles both in the SCN and in the liver. The observed differences between the groups suggest that the dose, timing and accompanying stress events such as cross-fostering may play a role in the final magnitude of the physiological challenge that opioids bring to the developing circadian clock.
Prenatal opioid exposure and vulnerability to future substance use disorders in offspring
2021, Experimental Neurology
Citation Excerpt :
Interestingly, Haydari et al. 2014, showed that voluntary exercise in morphine-dependent mothers during pregnancy can reduce morphine consumption in offspring. These findings are consistent with exercise activating the same rewarding pathways as morphine (Greenwood et al. 2003), which in turn may lead to neuroplastic changes in the mesolimbic reward pathway and decrease morphine sensitivity in opioid dependent mothers during pregnancy (Smith and Lyle 2006; Hosseini et al. 2009; Haydari et al. 2014). Future studies will need to further investigate environmental cues that may influence later addiction as potential therapeutic targets.
The heightened incidence of opioid use during pregnancy has resulted in unprecedented rates of neonates prenatally exposed to opioids. Prenatal opioid exposure (POE) results in significantly adverse medical, developmental, and behavioral outcomes in offspring. Of growing interest is whether POE contributes to future vulnerability to substance use disorders. The effects of POE on brain development is difficult to assess in humans, as the timing, dose, and route of drug exposure together with complex genetic and environmental factors affect susceptibility to addiction. Preclinical models of POE have allowed us to avoid methodological difficulties and confounding factors of POE in humans. Here, we review the effects of maternal opioid exposure on the developing brain with an emphasis on the neurobiological basis of drug addiction and on preclinical models of POE and their limitations. These studies have indicated that POE increases self-administration of drugs, reward-driven behaviors in the conditioned place paradigm, and locomotor sensitization. While addiction is multifaceted and vulnerability to drug addiction is still inconclusive in human studies of prenatally exposed infants, animal studies do provide a noteworthy corroboration of negative behavioral outcomes.
Swimming exercise during morphine abstinence in parents-to-be attenuated morphine-induced conditioned place preference and locomotor sensitization only in male rat offspring
2021, Neuroscience Letters
This study was designed to examine the effects of swimming exercise during morphine abstinence in parents-to-be before mating on morphine-induced conditioned place preference (CPP) and locomotor sensitization in the pubertal male and female rat offspring. Male and female Wistar rats were injected with bi-daily doses (10 mg/kg, 12 h intervals) of morphine for 14 days. The exercising rats exposed to a regular swimming exercise (45 min/d, five days per a week) during 30 days of morphine abstinence before mating. Then, the pubertal male and female rat offspring were tested for morphine-induced CPP and locomotor sensitization (using the open field). The results showed that the pubertal male offspring of the morphine-abstinent parents-to-be exhibited an increase in CPP to morphine and locomotor activity after morphine challenge than the offspring from the control group. While, swimming exercise in morphine-abstinent parents-to-be decreased CPP score and locomotor activity in the pubertal male offspring than control offspring. Thus, exposure to swimming exercise in morphine-abstinent parents-to-be before mating may exert a protective effect against morphine-induced reward and locomotor sensitization in their pubertal offspring which may prevent the vulnerability of the first generation to drug abuse following opiate-addicted parents before mating.
The Opioid-Addicted Tetrapartite Synapse
2020, Biological Psychiatry
Opioid administration in preclinical models induces long-lasting adaptations in reward and habit circuitry. The latest research demonstrates that in the nucleus accumbens, opioid-induced excitatory synaptic plasticity involves presynaptic and postsynaptic elements as well as adjacent astroglial processes and the perisynaptic extracellular matrix. We outline opioid-induced modifications within each component of the tetrapartite synapse and provide a neurobiological perspective on how these adaptations converge to produce addiction-related behaviors in rodent models. By incorporating changes observed at each of the excitatory synaptic compartments into a unified framework of opioid-induced glutamate dysregulation, we highlight new avenues for restoring synaptic homeostasis that might limit opioid craving and relapse vulnerability.
Early life opioid exposure and potential long-term effects
2019, Neurobiology of Stress
The long-term consequences of perinatal opioid exposure and subsequent development of neonatal opioid withdrawal syndrome is largely unknown and likely dependent on a multitude of factors, including co-morbid drug use, pre- and post-natal care, and individual factors including the maternal-infant relationship and home environment. This review summarizes the current literature from clinical and preclinical studies on perinatal opioid exposure, focusing on the consequences in the offspring. Although a large number of preclinical studies have been conducted examining the impact of prenatal opioid exposure, the models employed are not necessarily representative of clinical use patterns, making it challenging to translate these results to the impacted population. Use of more clinically-relevant models of perinatal opioid exposure are requisite for the development of improved pharmacological and behavioral treatment strategies to improve quality of life for this vulnerable population.

View all citing articles on Scopus

View full text

Effects of voluntary exercise on anxiety-like behavior and voluntary morphine consumption in rat pups borne from morphine-dependent mothers during pregnancy

Highlights

Abstract

Introduction

Section snippets

Materials and methods

Results

Discussion

Conclusion

Conflict of interest

Authors’ contributions

Acknowledgment

Neurosci. Lett.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Pathophysiology

Neurosci. Lett.

Learn Motiv.

Neuroscience

Physiol. Behav.

Neurobiol. Learn. Mem.

Physiol. Behav.

Behav. Brain Res.

Neuropharmacology