Sex differences in exercise and drug addiction:A m ini review of animal studies

Yuehui Zhou,Chenglin Zhou,*,Ren Li,b

aDepartment of Sport Psychology,School of Sport Science,Shanghai University of Sport,Shanghai 200438,China

bCenter for Hormone Advanced Science and Education,Roskamp Institute,Sarasota,FL 34243,USA

Sex differences in exercise and drug addiction:A m ini review of animal studies

Yuehui Zhoua,Chenglin Zhoua,*,Rena Lia,b

aDepartment of Sport Psychology,School of Sport Science,Shanghai University of Sport,Shanghai 200438,China

bCenter for Hormone Advanced Science and Education,Roskamp Institute,Sarasota,FL 34243,USA

Grow ing literature has demonstrated that exercise may be an effective prevention and treatment option for drug addiction.In the past few years,many studies have suggested that there were sex differences in all phases of drug addiction.However,very limited research has investigated sex differences in the effectiveness of exercise intervention in drug addiction and rehabilitation.In this mini review,we summarize the effectof sex on the results of using exercise to preventand treatdrug addiction.The studies we considerspan various animalmodels and use multiple types of exercise to examine the effectiveness of exercise on the neurobiologicalmechanism of exercise rehabilitation.We believe that exercise as an adjuvant intervention strategy can be applied better in drug addiction prevention and recovery.

Animal studies;Drug addiction;Exercise;Sex difference

1.Introduction

Drug addiction,also known as substance dependence,is a chronic disorder characterized by the compulsion to seek and take a drug,loss of control in lim iting intake,and emergence of a negative emotional state when access to a drug is prohibited.The neurobiology of drug addiction involves specific neuronal pathway dysfunctions and pathological neuropsychological dysfunctions.1Recent research has found that there are significant sex differences in many aspects of drug addiction,including its neurobiology mechanism.2-5In general,males are more likely to engage in risky behavior that includes experimenting with drugs of abuse compared to females,while females are more likely to begin taking drugs as self-medication to reduce stress or alleviate depression.6In addition,sex differences in patterns of drug-cue exposure, severity,and outcomes of drug addiction have also been reported.7,8Clinical studies also demonstrated that female subjects w ith substance dependence showed higher scores of approaching tendencies and more motor impulsivity than male individuals w ith drug dependence,9and female addicts are more unw illing to take part in detoxification treatment.10Moreover,studies of brain activation and subjective craving behavior showed that female cocaine users had a positive correlation between craving behavior and brain activation in the m idbrain,hippocampus,ventrolateral prefrontal cortex, and thalamus,whereas male cocaine users showed the correlations between craving and activation in the dorsolateral, dorsomedial,temporal,and parietal cortices as well as in the hippocampus.7In addition,studies also showed that female drug users are more likely to develop depression and anxiety than male subjects with drug addiction.11,12The sex differences in drug addiction are also confi rmed in animal studies. For example,female rats have higher levels of morphine and heroin intake than male rats,while female rats are morevulnerable and sensitive than males to the reinstatement of cocaine-seeking behavior.6,13,14Both human and animal studies demonstrated that circulating levels of ovarian steroid hormones account for these sex differences,and that progesterone and allopregnanalone counteract the effects of estrogen and reduce drug seeking behavior in females.15

Recently,an increasing evidence indicates that exercise leads to positive results in drug addiction prevention and recovery.16But few studies can elaborate on this phenomenon in more detail.We hypothesize that exercise may affect neuroplasticity and regulate the positive reinforcement of the drug through influencing the neurotransm itters system,cellsignaling molecules and its gene expression,epigenetics, neuroplasticity,and neurogenesis.In this review,we discuss the sex differences of addiction models,exercise intervention in drug addiction recovery and its underlying neurobiological mechanism.We believe that a better understanding of sex differences in exercise intervention in drug addiction prevention and recovery w ill provide a stronger theoretical basis for novel sex-specific rehabilitations.

2.Sex differences in animalmodel of drug addiction

2.1.Self-administration(SA)paradigm

The traditional animal models of drug abuse are framed by the behaviorist view that emphasizes the action of drugs as positive reinforcer,much like food,water,and other“natural”reinforcers.Studies showed that female rats go into stable SA behaviors more rapidly at a lower dose and are more sensitive to the positive reinforcement of drugs compare to male rats.17The female animals are also likely maintaining higher drug intake throughout the SA extinction than males.18In general, female animals learn to self-administervarious drugs(cocaine, methylphenidates,and amphetam ine)faster,and are more sensitive to the rewarding effects than males.19Further research indicated thatovariectom ized female rats showed the same craving behavior as males when reinstated by drug, slower acquisition,lower drug intake,and longer extinction in SA compared to intact female rats.17,20,21Together,these studies suggested thatovary hormones,such as estrogens,play critical roles in the sex differences in drug addiction behaviors, such as acquisition,maintenance,craving,extinction,and reinstatementof SA in animals.

2.2.Conditioned place preference(CPP)paradigm

In addition to SA,CPP experiments provide additional information on the rewarding effects of drug abuse.As reported in SA,female rats required shorter training cycle and lower doses of the drug to acquire CPP compared to male rats.22,23This sex difference in CPP between female and male rats was observed in both adolescent and adulthood.24However,some studies showed controversial results in the gender effect on CPP.For example,studies reported no gender difference in CPP acquisition at a low or high dose of cocaine(3 or 25 mg/kg),except that female rats were more reinstated than male rats.25At doses of morphine from 0.2 to 10.0 mg/kg, male and female rats showed the same level of preference for the drug-associated chamber,butwhen the dose was increased from 10.0 to 17.5 mg/kg,morphine lost positive reinforcer in males while female rats maintained a strong preference for the morphine-associated chamber at doses up to 30 mg/kg.26The controversial results in gender effects on CPP behavior are also associated w ith specific drugs and strain of animals. Studies reported that there was no sex difference in amphetamine induced CPP.27,28Furthermore,studies of nicotine addiction showed a dose dependentCPP only in male rats,not in female rats.29On the other hand,there is a significant gender difference in morphine induced CPP in W istar rats,30but not in SD rats.26In accordance w ith SA,the rewarding effect of drugs in CPP is also closely associated w ith ovary hormones.For example,ovariectom ized female rats showed a reduction of cocaine induced CPP behavior compared to intact females.31

There were few studies about the effect of exercise only on CPP,butenough data suggest that rats find long term voluntary wheel running rewarding,32,33which can develop and sustain significant CPP to brief periods or nightly,34,35and also produce plasticity in the mesolimbic reward pathway like repeated exposure to drug or natural rewards.33Therefore, there may be sex differences in exercise’s effecton drug based upon these animal models of drug addiction.

3.Sex differences in various types of exercises’effects on drug rehabilitation

In the animal experiments on drug addiction through exercise intervention,voluntary running wheel and forced treadmill running are the main modes of exercise.Running wheel is an active exercise and is w idely used,while forced treadm ill running is passive and less used.

A lthough exercising has been investigated as an intervention fordrug addiction and rehabilitation,few studieshave been done on the sex differences in the effectiveness of exercise on drug rehabilitation in animals.Sex differences in both wheel and treadmill running behaviors have been documented.For instance,female rats w ith drug addiction often run more laps (longer distance)in wheelexercise than males w ithin the same time frame.36-39In a 10-day forced treadm ill running training, male rats developed small reduction of serum corticosteroidbinding globulin,which was not found in female rats,40suggesting a differentphysiological response induced by treadm ill exercise in female and male rats.There were little studies about the psychological response between the two exercise models. Wheel running tended to attract individuals who are highly motivated to engage in frequent,sustained exercise,which reflected a voluntary,active physical and mental state,while treadm ill running attracts those that are forced to exercise, which reflects an attitude towardsexercise.41Only very recently have there been studies demonstrating the sex differences in exercise intervention for drug addiction and rehabilitation.In one such study,Sanchez and colleagues42found that 10-day wheel running after the formation of rat SA attenuatednicotine-seeking in male ratsonly under the conditionsofaccess to unlocked wheels.However,access to either locked or unlocked wheels was sufficient to suppress nicotine-seeking during extinction in females.Also 14-day wheel running during abstinence on subsequent cocaine-seeking of rat’s SA can effectively reduce relapse vulnerability in a dose dependent manner,and this effectdiffers by sex and estrous cycle.43

Since females perform wheel and treadm ill running differently than males,it is important to include the consideration of sex-specific effectiveness of exercise on drug rehabilitation in animal experiments.

In addition to wheel and treadm ill running,forced sw imm ing has also been used for studies of exercise rehabilitation. Forced sw imm ing exercises could be evaluated for exercise performance,psychological status (anxiety and stress), cognition(learning and memory),etc.44,45It also showed the same effectiveness as displayed in voluntary wheel running in alcohol conditioned place aversion(CPA),46,47suggesting that forced sw imm ing may be one mode for exercise intervention for drug addiction.Again,compared to male rats,female rats were more active in water48and swam faster in speed with less sign of fatigue.49,50

4.Sex differences in effectiveness of exercise in drugaddiction

Exercises attenuate drug-seeking behaviors during drug initiation,escalation,extinction,abstinence,and relapse.51,52It is crucial to decrease the susceptibility(preventive effect)atan early stage of drug addiction and reduce the drug craving (therapeutic effect)at later stages in order to prevent relapse.

4.1.Sex differences in preventive effects of exercise on drug addiction

As most of animal studies in biology research show,researches about exercise as a means of prevention on drug abuse are limited by investigating male animals only,53-68w ith a few studies on female animals,69-74while the others did notspecify the gender.75,76In regard to the sex differences as shown in Table 1,the results of these studies have been inconsistent.One study found that chronic forced treadm ill exercise for 6 weeks induced reduction of drug craving behavior in adolescent female and male rats,but only male rats showed inhibited CPP.77Another study reported that female rats,after 13-day unlim ited voluntary wheel exercise, showed decreased alcohol consummation(ethanol/total liquid) than non-exercised females,while no difference was found in males.78However,other studies of voluntary wheel running for 6 weeks after cocaine exposure demonstrated that exercise weakens cocaine SA under extended-access conditions in both sexes.Although the escalating intake was more in females than males,it was not statistically significant.38,39Together, evidence suggests a sex difference in the preventive effects of exercise on drug addiction.

4.2.Sex differences in therapeutic effects of exercise on drug addiction

Sim ilarly,in animal studies of therapeutic effects of exercise on drug abuse,most are investigated in male animals,47,79-96w ith very few studies in females.97-99In very lim ited literature as shown in Table 1,one study pointed outthat although voluntary wheel running was able to decrease drug intake in both male and female rats,wheel-running activity had a greater suppressant effect on cocaine SA in females than in males,and in females,wheel-running and cocaine SA are substitutable as reinforcers.100This was supported by the discoveries that female rats were more sensitive to the rewarding effects of the drug.101Sim ilarly,some research revealed that wheel running during abstinence differentially weakens subsequent nicotine-seeking in males and females that had extended access to nicotine SA of adolescent rats.42Peterson and his colleagues43also found wheel running dose-dependently decreased cocaine-seeking in both gendered rats,but males showed a greater attenuation of cocaine-seeking w ith longer access to wheel running than that in females,which might be related to interference of the estrous cycle phase in females.

Table 1 Sex differences in effects of exercise on drug addiction.

5.Sex differences in neurobiological mechanism of exercise intervention in drug addiction

Long-term drug abuse led to corresponding compensatory changes in the mesolimbic dopam ine reward system,including a series of molecular events induced by multiple kinds of neurotransmitters and their receptors in ventral tegmentalarea, nucleus accumbens and prefrontal cortex.102Exercise may affect neruoplasticity and regulate the positive reinforcement of drugs through influencing certain signaling molecules and neuroanatomy structure, depending on gonadal hormones.95,103

Firstly,the neurotransm itters system seem to play a crucial role in the process of the formation and development of drug addiction.104There was sexual dimorphism of dopam ine, noradrenalin,5-HT,and endocannabinoid in the hypothalamus of adult or new born rodents,which responded to steroid hormone differently.105,106Addicted males and females have different responses to dopam ine transport and the activity or inhibitory of the D1 and D2 dopam ine receptor.107,108On the otherhand,compared to male m ice w ith hypoactivity,females w ith higher exercise performance often show a reduced function of the D1 and D5 dopamine receptors.109In turn,an inhibition of dopam ine transporter w ill decrease the wheel running level of m ice that are high and active.110Lightfoot111pointed out that drug abuse,neurotransmitters,and exercise may be regulated by sex hormones and its receptors.Secondly, cell-signaling molecules and their gene expression to drug abuse and exercise were also different between males and females.Some studies reported that the brain regional basal levelof protein kinase A(PKA)and phosphorylated DARPP-32 in nucleus accumbens were higher in females than that of males before or after drug addiction,but not in the caudate nucleus.112,113Furthermore,cocaine-induced PKA would facilitate phosphorylation of cAMP response element binding protein(CREB),102which is also regulated by gonadal hormone.114Others reported that there was a sex-specific neuroimmunoendocrine response associated with signaling pathways and the transcription factor CREB to exercise in m ice.115Thirdly,the changes in epigenetics were considered to be the underlying mechanism by drug.116Sex differences in epigenetic processes such as acetylation and methylation(at least four related parameters:DNA methyltransferase 3,DNA methylation patterns,MeCP2,and nuclear co-repressors)may confer sexually dimorphic risks and a resilience to developing neurological and mental health disorders later in life.117Fourthly,drug addiction is a pathology of staged neuroplasticity,118which is also highly different between males and females.For example,the spine density of medium spiny neurons in nucleus accumbens is higher in female cocaine addiction rats during abstinence,as well as the spiculate protuberance compared to males.The magnitude of the cocaineinduced increase in spine density also appeared greater in females than that in males.Moreover,the changes of dendritic spine plasticity were associated w ith addicted behaviors in females only,and females showed greater locomotor activity and higher behavioral sensitization to cocaine than males.119Lastly,the sex differences in hippocampal neurogenesis would account for the susceptibility of drug addiction,and repeated drug abuse further inhibited the neurogenesis in certain brain regions,which caused a reinforcement of drug rewarding effect.120Studies demonstrated that male rats w ith drug experiences at adolescence showed greater reduction of hippocampus dentate gyrus neurogenesis compared to female rats.121Furthermore,aerobic exercise improved the spatial memory in normal or addicted individuals,which was dependent on hippocampus neurogenesis.This positive correlation w ith newborn cells in the hippocampus was more prom inent in female rats than in males.122In conclusion,the sex differences in neurobiological mechanisms of exercise intervention in drug addiction may be related to the sexspecific actions in neurotransmitters systems,cell-signaling molecules and their gene expression,epigenetics,neuroplasticity,and neurogenesis.

6.Conclusion and future directions

As briefl y reviewed above,it is clear that there are sex differences in exercise intervention in drug addiction prevention and recovery.The sex differences are found in various animal models,the types of exercise,and the effectiveness of exercise on drug addiction and rehabilitation.A lthough exercise intervention in treating drug addiction has been w idely recognized and used in human rehabilitation,the sex differences in exercise intervention’s effect on drug addiction and rehabilitation are understudied.One of the main reasons is that much of the animal studies were performed on one gender, particularly male.As a recent article published inNatureby Pollitzer123indicated,sex differences exist not only in basic cell biology,but also in clinical research including drug effectiveness and side effects.While the majority of animal studies used male subjects exclusively,the outcome from those animal studies may influence the future translational approaches in human studies since the gender differences were notspecified.In this review,we fi rstdiscussed sex differences in various drug addictions in two major animal models:SA and CPP paradigms.Then,we discussed the different effectsof active and passive exercises on drug rehabilitation on male and female animals.Lastly,we specifically summarized the preventive and therapeutic effects of exercise on drug addiction in male and female animals.Indeed,to furtherunderstand the sex differences in drug addiction and exercise intervention, more studies on the neurobiological mechanisms of exercise and its roles in preventing and treating drug addiction are needed.

Acknow ledgment

This work was supported by grants from the Shanghai Science and Technology Comm ission(NO.13490503600)and National Natural Science Foundation of China (NO.31171004).

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Received 25 February 2014;revised 23 March 2014;accepted 23 April 2014

*Corresponding author.

E-mail address:Chenglin_600@126.com(C.Zhou)

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