R

Ebc

AIa

b

Sc

h

•••

a

ARRAA

KMSCMB

1

impg

tS

h0

Neuroscience Letters 631 (2016) 79–84

Contents lists available at ScienceDirect

Neuroscience Letters

journa l homepage: www.e lsev ier .com/ locate /neule t

esearch article

ffects of swimming exercise on morphine-induced reward andehavioral sensitization in maternally-separated rat pups in theonditioned place preference procedure

tiyeh Taghavi-Khalil Abad a, Hossein Miladi-Gorji (PhD) (Associate Professor) b,∗,manollah Bigdeli c

Faculty of Psychology and Educational Sciences, University of Semnan, Semnan, IranLaboratory of Animal Addiction Models, Research Center and Department of Physiology, School of Medicine, Semnan University of Medical Sciences,emnan, IranFaculty of Educational Sciences and Psychology, Ferdowsi University of Mashhad, Mashhad, Iran

i g h l i g h t s

Maternal separation increased morphine preference and behavioral sensitization.Swimmer maternally separated pups exhibited a decrease in CPP in both sexes.Swimming decreased behavioral sensitization in maternally separated male pups.

r t i c l e i n f o

rticle history:eceived 19 February 2016eceived in revised form 6 August 2016ccepted 8 August 2016vailable online 9 August 2016

eywords:aternal separation

a b s t r a c t

This study was designed to examine the effects of swimming exercise during adolescence on morphine-induced conditioned place preference (CPP) and behavioral sensitization in maternally separated maleand female rat pups. Male Wistar rats were allowed to mate with female virgin Wistar rats. Pups wereseparated from the dam daily for 180 min during postnatal days 2–14. All pups were weaned on day21.The exercising pups were allowed to swim (60 min/d, five days per a week, for 30 days) during adoles-cence. Then, rat pups were tested for behavioral sensitization and the CPP induced by morphine. Maternalseparation produced a significant increase in morphine-induced CPP in both sexes, behavioral sensiti-

wimming exerciseonditioned place preferenceorphine

ehavioral sensitization

zation in male pups and tolerance to morphine-induced motor activity in female pups. Swimmer pupsseparated from the dam exhibited a decrease in morphine-induced CPP in both sexes and behavioralsensitization in male pups than those of their control pups. The present results have shown that swim-ming exercise during adolescence may exert a protective effect against morphine-induced reward andbehavioral sensitization in adult male and female rats following maternal separation.

© 2016 Elsevier Ireland Ltd. All rights reserved.

. Introduction

Several studies have shown that early maternal separation innfants (15 min to 6 h during the first 2 weeks of life) can per-

anently alter various aspects of behavior in adulthood [24,40],roduce structural disruptions in the brain [2,31,43], dopaminer-ic alterations [3,28]. Also, it reported that maternal separation

∗ Corresponding author at: Laboratory of Animal Addiction Models, Research Cen-er and Department of Physiology, School of Medicine, Semnan University of Medicalciences, P.O. Box 35131-38111, Semnan, Iran.

E-mail address: Miladi331@yahoo.com (H. Miladi-Gorji).

ttp://dx.doi.org/10.1016/j.neulet.2016.08.011304-3940/© 2016 Elsevier Ireland Ltd. All rights reserved.

increase ethanol preference [7,18], sensitivity to ethanol-inducedlocomotor activity [9], and lead to a basal hypoactivity of theenkephalinergic system and vulnerability to morphine dependenceand changes in sensitivity to morphine in adulthood rats [20,21,41].Thus, the reversal or prevention of the brain alterations inducedby maternal separation could be a useful method for the pre-vention and treatment of drug addiction in adulthood. We havepreviously shown that the swimming [8] and voluntary exercise[30] diminished the severity of physical and psychological depen-dence in both morphine-dependent and withdrawn rats and also

voluntary consumption of morphine in the rat pups borne frommorphine-dependent mothers after wheel running [16]. Previousstudies have shown exercise reduces the rewarding efficacy of

80 A.T.-K. Abad et al. / Neuroscience Letters 631 (2016) 79–84

ne of

maip[ocm

2

vthp[t1ffs2wCtt

hitgTdrsr

Fig. 1. Timeli

ethamphetamine [5] and cocaine [38], morphine [26] and self-dministration of morphine [17]. Taken together, these findingsndicate that exercise has a rewarding effect and elicits neuro-lastic changes in the mesolimbic dopaminergic reward pathway15]. Therefore, the aim of this study was to investigate the effectsf swimming exercise during adolescence on morphine-inducedonditioned place preference (CPP) and behavioral sensitization inaternally separated male and female rat pups.

. Materials and methods

Male Wistar rats (250 ± 10 g) were allowed to mate with femaleirgin Wistar rats (250 ± 10 g) during a 24 h period. After Observa-ion of vaginal plug, each pregnant dam (n = 16) was individuallyoused in polycarbonate cages with a 12 h light/dark cycle, at tem-erature 22 ± 4 ◦C and food and water were available ad libitum17]. Postnatal 0 (PND 0) was the day of birth and maternal separa-ion was conducted from PND2 to PND14 for 3 h from 10:00 AM to3:00 PM (see Fig. 1). Each separation consisted of removing damsrom the home cage and placing pups with their cages in a dif-erent room, such that the pups were kept together in the rearingite while room temperature was maintained at 32 ± 0.5 ◦C (days–5) or 30 ± 0.5 ◦C (days 6–14) for 3 h [13,44]. Dams and their littersere housed in polycarbonate cages filled with soft wood shavings.

ontrol dams and pups were reared under standard conditions andheir cages were cleaned twice-weekly that was similar to that ofhe pups separated from mothers, but never separated.

The pups were weaned at 21 days of age from the dams andoused together in cages with same-sex littermates. To attenuat-

ng litter-size-induced variability in body weight of pups, one orwo pups of each sex from each litter randomly assigned for eachroup. 56 male pups and 56 female pups were assessed in this study.he pups (n = 5–8/sex/experiment/rearing group) were randomly

ivided into four groups according to sex into two separate expe-iences; pups that were not separated from mothers and had nowimming exercise (No MS/No Swim); pups that were not sepa-ated from mothers and had performed swimming exercise (No

experiments.

MS/Swim); pups separated from mothers and had no swimmingexercise (MS/No Swim); and pups separated from mothers and hadperformed swimming exercise (MS/Swim). All the experimentalprocedures were conducted in accordance with the National Insti-tutes of Health’s Guide for the Care and Use of Laboratory Animals(were approved by University Ethics Committee).

2.1. Exercise protocol

Daily swimming exercise was performed in a blue circular pool(140 cm in diameter and 50 cm high) filled to a 25 cm depth with32 ± 1 ◦C water. The pool did not contain any place to rest. Exer-cise was performed between 9:00–11:00a.m., using our previouslydescribed system [9]. After swimming, rats were toweled dry andkept warm by electric heater. To acclimate to the new environment,all rats were adapted to water before beginning the experiment,which took four days. This adaptation started by placing the ani-mals for 5 min into the swimming pool with shallow water in whichthey could stand. At the second day, rats spent 5 min in head-highwater in which they might start swimming. At the third day, thewater was deep enough so they had to swim for 5 min. On thefourth day, rats had to swim for 15 min [37]. The training periodgradually and progressively began for 30 min on the first day until60 min continuous on the last day, and it was performed 5 days perweek for 4 weeks (Fig. 1).

2.2. Conditioned place preference

The conditioned place preference paradigm was used to studythe rewarding effects of morphine that was based on [5,40] models.It was made from wood and was composed of two distinct cham-bers (A and B) with (30 × 30 × 30 cm) dimensions, separated fromeach other by a neutral chamber (30 × 15 × 30 cm) with a red back-

ground and having guillotine gates. Each chamber of A and B hada black background or white with the different pattern of whiteor black stripes (vertical or horizontal), respectively. According tothe study of Xu, et al. [45], the procedure was performed for 9 days

A.T.-K. Abad et al. / Neuroscience Letters 631 (2016) 79–84 81

Fig. 2. Effect of swimming exercise on morphine-induced place preference in male and female separated rats using the CPP. A) Morphine-induced preference score. Then e scorw an ±SS

aecwu

2

atoioe

2

dpaol

2

ttit

2

c[fliTwt

umber of visits to the conditioning chambers in male (B) and female (C). Preferencas no difference in locomotor activity between groups. Data was expressed as me

wim groups, *P < 0.039 vs. MS/No Swim male rats.

nd behavioral activity (time spent and the number of visits to theach camber with back-and-forth motions during pre- and post-onditioning test sessions, to determine that locomotor activityas not different between groups) was recorded by a video camera,

sing a tracking system (EthoVision, Noldus, The Netherlands).

.2.1. Pre-conditioningOn day 1 (Habituation), rats were placed in the neutral chamber

nd allowed to explore both chambers for 20 min in order to adapto the environment. This test was repeated on day 2; the amountf time spent in each of the three chambers was recorded and the

nitial preference was calculated. If the animal spent more than 60%f the time on day 2 for either side (initial side preference) it wasliminated from the experiment.

.2.2. ConditioningRats were treated with morphine at the dose of 5 mg/kg, s.c. on

ays 3, 5, and 7 and saline on days 4, 6, and 8 during the conditioninghase. Drug and saline administration alternated daily such that, inny group, half of the rat received drug in the chamber A and thether half received drug in the chamber B. Conditioning sessions

asted 15 min.

.2.3. Post-conditioningOn day 9, rats were placed in the neutral chamber and allowed

o explore both chambers again for 20 min. Preference or condi-ioning score is calculated by subtracting the amount of time spentn the drug-paired chamber before conditioning (on day 2) fromhe amount of time spent after conditioning (Fig. 1).

.3. Measurement of locomotor sensitization

We have used the open field chamber consisted of a transparentylinder 25 cm in diameter and 30 cm high, as described previously36]; to assess the morphine-induced locomotor sensitization. Theoor of the cylinder was divided into four equal quadrants by two

ntersecting lines. First, baseline locomotor activity was evaluated.hen, to induce locomotor sensitization, morphine (5 mg/kg, s.c.)as injected once daily for 3 consecutive days without placing in

he open field chamber (for the last 2 days). However, the acute

e was more in MS/No Swim rats and less in MS/Swim rats in both sexes. Also, thereEM. ***P < 0.003, **P < 0.046 vs. No MS/No Swim, ∧P < 0.040, ∧∧∧P < 0.0004 vs. MS/No

locomotor response of morphine was then evaluated only after thefirst (acute) injection of morphine. Then, the rats did not receiveany treatment for the next 5 days. All rats were challenged withmorphine (1 mg/kg, s.c.) on the sixth day after a 5-day drug-freeperiod and evaluated for locomotor activity (post- morphine chal-lenge), so that rats allowed to explore the chamber for 10 min inorder to adapt to novel environments. Then, the number of linescrossed for each rats with all four legs were measured for the next10 min. The test room was illuminated with soft white light (Fig. 1).

The data expressed as the mean ±standard error of themean (S.E.M.). These data were analyzed by using three-wayanalyses of variance (ANOVA) with the fixed factors maternalcare × housing condition × sex followed by Tukey’s test for indi-vidual between-group comparisons. Statistical differences wereconsidered significant at P < 0.05.

3. Results

The results of the conditioned place preference (CPP) areillustrated in Fig. 2A. Three-way ANOVA revealed a signifi-cant effect of maternal care (F1, 48 = 20.15, P = 0.0001), exercise(F1, 48 = 16.94, P = 0.0001) and sex (F1, 48 = 11.63, P = 0.001).Also, three-way ANOVA indicated a significant interactionbetween maternal care × sex (F1, 48 = 6.06, P = 0.017) and maternalcare × exercise × sex (F1, 48 = 3.34, P = 0.027). Post hoc compar-isons showed that the morphine-induced place preference scorein MS/No Swim group was higher than No MS/No Swim group(P = 0.003, P = 0.046; for male and female rats, respectively). Also,morphine-induced place preference score in MS/Swim group wasless than MS/No Swim group (P = 0.040, P = 0.004; for male andfemale rats, respectively) (Fig. 2A). Also, preference score washigher in MS/No Swim male rats than female (P = 0.039). Therewere a significant effect of sex in the frequency of visits to theconditional and non-conditional chambers, respectively in pre-conditioning (F1, 48 = 42.9, P = 0.0001) and post-conditioning (F1,48 = 11.89, P = 0.001) periods using a three-way ANOVA, but no

effect of maternal care and exercise or any interaction (Fig. 2B).

The results of the open field chamber using a three-wayANOVA are illustrated in Fig. 3. There were no significanteffect of sex, maternal care and exercise and no interaction of

82 A.T.-K. Abad et al. / Neuroscience Letters 631 (2016) 79–84

F in mh d from∧ phine

matmcnwc4mcSsm(nmbmmMrhf

4

ptt

ig. 3. Effect of swimming exercise on morphine-induced locomotor sensitizationigher in male MS/No Swim rats, while it was less in male swimmer rats separate∧∧P < 0.0001 vs. MS/No Swim, $$$P = 0.0001, $$P = 0.016, ###P = 0.0001 vs. acute mor

aternal care × exercise × sex in the number of lines crossedfter baseline and the acute injection of morphine. However,he results in behavioral sensitization to morphine in post-

orphine challenge revealed a significant effect of maternalare (F1, 48 = 170, P = 0.0001), sex (F1, 48 = 5.74, P = 0.02) ando significant effects of exercise (F1, 48 = 0.1, NS). Also, three-ay ANOVA indicated significant interaction between maternal

are × exercise (F1, 48 = 13.87, P = 0.001), maternal care × sex (F1,8 = 15.27, P = 0.0001), exercise × sex (F1, 48 = 6.27, P = 0.016) andaternal care × exercise × sex (F1, 48 = 9.94, P = 0.003). Post hoc

omparisons showed that the number of lines crossed in MS/Nowim group was higher than No MS/No Swim group in bothexes (both, P = 0.0001). Also, the number of lines crossed amongale rats in MS/Swim group was less than MS/No Swim group

P = 0.0001). Also, Between-group comparisons showed that theumber of lines crossed were higher in MS/No Swim male rats afterorphine challenge than the acute response of morphine and the

aseline response (P = 0.0001, both), while was less in MS/Swimale rats after morphine challenge than the acute response oforphine (P = 0.0001). The number of lines crossed was less inS/Swim female rats after morphine challenge than the acute

esponse of morphine (P = 0.016). The number of lines crossed wereigher in MS/No Swim male rats after morphine challenge than

emale rats (P = 0.0001).

. Discussion

The results of our study indicated that maternally separatedups for only 3 h/day increased the morphine-induced condi-ioned place preference in both sexes. Previous studies have shownhat 3-h separation from mother increases the sensitivity to mor-

ale and female separated rats in the open field. The number of lines crossed was the mother. Data was expressed as mean ±SEM. ***P < 0.003 vs. No MS/No Swim,

, &&&P = 0.0001 vs. baseline.

phine’s rewarding effects [42,43] and amphetamine [4] in the CPPparadigm. It may be due to a decreased dopamine transporterexpression [3,29], a lower activity in enkephalinergic system, andthe more sensitivity of opioid receptors [42] following maternalseparation.

Also, we found that male and female swimmer rats separatedfrom the mother showed a decrease in place preference for mor-phine. In the swimmer maternally separated rats was observeda greater preference for the compartment associated with saline.This finding is in accordance with a previous study showing thattreadmill exercise decreases rewarding impacts of morphine [38],and self-administration of cocaine [7] and amphetamine-inducedCPP [12]. Also, it has been shown that long-term voluntary exercisedecreases sensitivity to the positive reinforcing effects of cocaine infemale rats [39]. It may be due to increase in the release of endoge-nous opioid peptides in the brain [26], activity of serotonergic,dopaminergic, and noradrenergic systems [6,11,30,39] in responseto maternal separation [1] and or the adaptive changes producedby exercise in the mesolimbic reward pathway [15]. Also, given theLack of group differences in locomotor activity; so, a greater prefer-ence for morphine in the maternally separated rats was not directlydue to an increase in the number of visits to the chambers.

A further analysis showed that the increase in morphinechallenge-induced locomotor activity in the male and femaleMS/No Swim pups were respectively higher and lower than theacute response of morphine, which was reduced by swimming inmale pups. Also, morphine challenge-induced locomotor activity

in the female MS/No Swim pups was very nearly the same as thatobtained in the basic response. These findings indicated that mater-nally separated male rats become sensitized to repeated morphinetreatments, supporting previous findings [10,21], which is proba-

cience

b(tnmssmtdpfteftzsiw[

5

esfsen

D

r

A

(I

R

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

[

A.T.-K. Abad et al. / Neuros

ly due to increased hypothalamic corticotrophin-releasing factorCRF) in maternally separated rats [34]. While, female rats becameolerant to the locomotor activity effects of morphine which haveot found in similar studies. Also, we found that place preference fororphine was higher in MS/No Swim male rats than female. These

ex related differences in morphine-induced reward and behavioralensitization may reflect differences in stress-reactivity followingaternal separation [34], the faster onset of corticosterone secre-

ion in female rats [46], sex differences in glucocorticoid receptor,opamine transporter expression [23] and higher levels of nore-inephrine in the hippocampus [28], emphasizing the need for

urther research. Swimming exercise decreased locomotor sensi-ivity to morphine in maternally separated male pups, but had noffect on the morphine challenge-induced locomotor activity inemale pups. No study with the same nature has been conductedhus far. However, wheel running decreased behavioral sensiti-ation to cocaine in male rats [14,35]. It has been suggested thatwimming exercise results in a decreased pituitary-adrenal activ-ty and transient alterations in the gene transcription of CRF [33],

hich in turn lead to increases in dopaminergic reward signaling24] that regulate motor activity.

. Conclusions

This study provides novel evidence that maternal separationnhanced morphine-induced CPP in both sexes and locomotor sen-itization in male pups, while tolerance to morphine developed inemale pups. Swimming attenuated morphine-induced CPP in bothexes and locomotor sensitization in male pups. Thus, swimmingxercise may have utility for prevention of drug abuse followingeonatal maternal separation during adolescence.

eclaration of interest

The authors report no conflicts of interest. The authors alone areesponsible for the content and the writing of the article.

cknowledgments

This work was supported by grants from University of SemnanSemnan, Iran) and Cognitive Science and Technologies Council ofran (CSTC).

eferences

[1] L. Arborelius, M. Eklund, Both long and brief maternal separation producespersistent changes in tissue levels of brain monoamines in middle-agedfemale rats, Neuroscience 145 (2007) 738–750.

[2] A.K. Berman, R.B. Lott, S.T. Donaldson, Periodic maternal deprivation maymodulate offspring anxiety-like behavior through mechanisms involvingneuroplasticity in the amygdala, Brain Res. Bull. 101 (2014) 7–11.

[3] W.G. Brake, T.Y. Zhang, J. Diorio, M.J. Meaney, A. Gratton, Influence of earlypostnatal rearing conditions on mesocorticolimbic dopamine and behaviouralresponses to psychostimulants and stressors in adult rats, Eur. J. Neurosci. 19(2004) 1863–1874.

[4] J. Campbell, L.P. Spear, Effects of early handling on amphetamine-inducedlocomotor activation and conditioned place preference in the adult rat,Psychopharmacology 143 (1999) 183–189.

[5] G.D. Carr, N.M. White, Conditioned place preference from intra-accumbensbut not intra-caudate amphetamine injections, Life Sci. 33 (1983) 2551–2557.

[6] H.I. Chen, Y.M. Kuo, C.-H. Liao, C.J. Jen, A.M. Huang, C.G. Cherng, S.-W. Su, L. Yu,Long-term compulsive exercise reduces the rewarding efficacy of3,4-methylenedioxymethamphetamine, Behav. Brain Res. 187 (2008)185–189.

[7] K.P. Cosgrove, R.G. Hunter, M.E. Carroll, Wheel-running attenuates

intravenous cocaine self-administration in rats: sex differences, Pharmacol.Biochem. Behav. 73 (2002) 663–671.

[8] L. Daoura, J. Haaker, I. Nylander, Early environmental factors differentiallyaffect voluntary ethanol consumption in adolescent and adult male rats,Alcohol. Clin. Exp. Res. 35 (2011) 506–515.

[

Letters 631 (2016) 79–84 83

[9] A. Fadaei, H. Miladi-Gorji, S. Makvand-Hosseini, Swimming reduces theseverity of physical and psychological dependence and voluntary morphineconsumption in morphine dependent rats, Eur. J. Neurosci. 747 (2015) 88–95.

10] M. Fernández, M.C. Fabio, M.E. Nizhnikov, N.E. Spear, P. Abate, R.M. Pautassi,Maternal isolation during the first two postnatal weeks affectsnovelty-induced responses and sensitivity to ethanol-induced locomotoractivity during infancy, Dev. Psychobiol. 56 (2014) 1070–1082.

11] T. Foley, M. Fleshner, Neuroplasticity of dopamine circuits after exercise:implications for central fatigue, NeuroMol. Med. 10 (2008) 67–80.

12] C.A. Fontes-Ribeiro, E. Marques, F.C. Pereira, A.P. Silva, T.R.A. Macedo, Mayexercise prevent addiction? Curr. Neuropharmacol. 9 (2011) 45–48.

13] D.D. Francis, J. Diorio, P.M. Plotsky, M.J. Meaney, Environmental enrichmentreverses the effects of maternal separation on stress reactivity, J. Neurosci. 22(2002) 7840–7843.

14] A. Geuzaine, E. Tirelli, Wheel-running mitigates psychomotor sensitizationinitiation but not post-sensitization conditioned activity and conditionedplace preference induced by cocaine in mice, Behav. Brain Res. 262 (2014)57–67.

15] B.N. Greenwood, T.E. Foley, H.E.W. Day, J. Campisi, S.H. Hammack, S.Campeau, S.F. Maier, M. Fleshner, Free wheel running prevents learnedhelplessness/behavioral depression: role of dorsal raphe serotonergicneurons, J. Neurosci. 23 (2003) 2889–2898.

16] B.N. Greenwood, T.E. Foley, T.V. Le, P.V. Strong, A.B. Loughridge, H.E.W. Day,M. Fleshner, Long-term voluntary wheel running is rewarding and producesplasticity in the mesolimbic reward pathway, Behav. Brain Res. 217 (2011)354–362.

17] S. Haydari, H. Miladi-Gorji, A. Mokhtari, M. Safari, Effects of voluntary exerciseon anxiety-like behavior and voluntary morphine consumption in rat pupsborne from morphine-dependent mothers during pregnancy, Neurosci. Lett.578 (2014) 50–54.

18] M. Hosseini, H.A. Alaei, A. Naderi, M.R. Sharifi, R. Zahed, Treadmill exercisereduces self-administration of morphine in male rats, Pathophysiology 16(2009) 3–7.

20] E. Izzo, P.P. Sanna, G.F. Koob, Impairment of dopaminergic system functionafter chronic treatment with corticotropin-releasing factor, Pharmacol.Biochem. Behav. 81 (2005) 701–708.

21] M. Kalinichev, K.W. Easterling, S.G. Holtzman, Early neonatal experience ofLong-Evans rats results in long-lasting changes in reactivity to a novelenvironment and morphine-induced sensitization and tolerance,Neuropsychopharmacology 27 (2002) 518–533.

23] T. Kikusui, S. Faccidomo, K. Miczek, Repeated maternal separation: differencesin cocaine-induced behavioral sensitization in adult male and female mice,Psychopharmacology 178 (2005) 202–210.

24] A.M. Knab, J.T. Lightfoot, Does the difference between physically active andcouch potato lie in the dopamine system, Int. J. Biol. Sci. 6 (2010) 133–150.

26] B.T. Lett, V.L. Grant, M.T. Koh, Naloxone attenuates the conditioned placepreference induced by wheel running in rats, Physiol. Behav. 72 (2001)355–358.

28] K. Matthews, J.W. Dalley, C. Matthews, T. Hu Tsai, T.W. Robbins, Periodicmaternal separation of neonatal rats produces region-and gender-specificeffects on biogenic amine content in postmortem adult brain, Synapse 40(2001) 1–10.

29] M.J. Meaney, W. Brake, A. Gratton, Environmental regulation of thedevelopment of mesolimbic dopamine systems: a neurobiologicalmechanism for vulnerability to drug abuse? Psychoneuroendocrinology 27(2002) 127–138.

30] R. Meeusen, K. De Meirleir, Exercise and brain neurotransmission, SportsMed. 20 (1995) 160–188.

31] H. Miladi-Gorji, A. Rashidy-Pour, Y. Fathollahi, Anxiety profile inmorphine-dependent and withdrawn rats: effect of voluntary exercise,Physiol. Behav. 105 (2012) 195–202.

33] E. Park, O. Chan, Q. Li, M. Kiraly, S.G. Matthews, M. Vranic, M.C. Riddell,Changes in basal hypothalamo-pituitary-adrenal activity during exercisetraining are centrally mediated, Am. J. Physiol. Regul. Integr. Comp. Physiol.289 (2005) R1360–R1371.

34] P.M. Plotsky, M.J. Meaney, Early, postnatal experience alters hypothalamiccorticotropin-releasing factor (CRF) mRNA, median eminence CRF contentand stress-induced release in adult rats, Mol. Brain. Res. 18 (1993) 195–200.

35] L. Renteria Diaz, D. Siontas, J. Mendoza, A. Arvanitogiannis, High levels ofwheel running protect against behavioral sensitization to cocaine, Behav.Brain Res. 237 (2013) 82–85.

36] H. Sahraei, Z. Faghih-Monzavi, S.M. Fatemi, S. Pashaei-Rad, S.H. Salimi, M.Kamalinejad, Effects of Papaver rhoeas extract on the acquisition andexpression of morphine-induced behavioral sensitization in mice, Phytother.Res. 20 (2006) 737–741.

37] A.R. Sigwalt, H. Budde, I. Helmich, V. Glaser, K. Ghisoni, S. Lanza, E.L. Cadore,F.L.R. Lhullier, A.F. de Bem, A. Hohl, F.J. de Matos, P.A. de Oliveira, R.D.Prediger, L.G.A. Guglielmo, A. Latini, Molecular aspects involved in swimmingexercise training reducing anhedonia in a rat model of depression,Neuroscience 192 (2011) 661–674.

38] M. Smith, D. Yancey, Sensitivity to the effects of opioids in rats with free

access to exercise wheels: �-opioid tolerance and physical dependence,Psychopharmacology 168 (2003) 426–434.

39] M.A. Smith, K.T. Schmidt, J.C. Iordanou, M.L. Mustroph, Aerobic exercisedecreases the positive-reinforcing effects of cocaine, Drug Alcohol Depend. 98(2008) 129–135.

8 cience

[

[

[

[

[

[45] Z. Xu, B. Hou, Y. Gao, F. He, C. Zhang, Effects of enriched environment onmorphine-induced reward in mice, Exp. Neurol. 204 (2007) 714–719.

[46] E.A. Young, M. Altemus, V. Parkison, S. Shastry, Effects of estrogen antagonistsand agonists on the ACTH response to restraint stress in female rats,Neuropsychopharmacology 25 (2001) 881–891.

4 A.T.-K. Abad et al. / Neuros

40] T.M. Tzschentke, Measuring reward with the conditioned place preferenceparadigm: a comprehensive review of drug effects, recent progress and newissues, Prog. Neurobiol. 56 (1998) 613–672.

41] M.B.M. van den Bree, E.O. Johnson, M.C. Neale, R.W. Pickens, Genetic andenvironmental influences on drug use and abuse/dependence in male andfemale twins, Drug Alcohol Depend. 52 (1998) 231–241.

42] V. Vazquez, J. Penit-Soria, C. Durand, M.J. Besson, B. Giros, V. Daugé, Maternaldeprivation increases vulnerability to morphine dependence and disturbs the

enkephalinergic system in adulthood, J. Neurosci. 25 (2005) 4453–4462.

43] V. Vazquez, S. Weiss, B. Giros, M.-P. Martres, V. Daugé, Maternal deprivationand handling modify the effect of the dopamine D3 receptor agonist, BP 897on morphine-conditioned place preference in rats, Psychopharmacology 193(2007) 475–486.

Letters 631 (2016) 79–84

44] A.L. Vivinetto, M.M. Suárez, M.A. Rivarola, Neurobiological effects of neonatalmaternal separation and post-weaning environmental enrichment, Behav.Brain Res. 240 (2013) 110–118.