The effects of aerobic exercise on cocaine self-administration in male and female rats

ORIGINAL INVESTIGATION

The effects of aerobic exercise on cocaine self-administrationin male and female rats

Mark A. Smith & Katherine L. Walker &

Kathryn T. Cole & Kimberly C. Lang

Received: 16 July 2010 /Accepted: 18 April 2011 /Published online: 13 May 2011# Springer-Verlag 2011

AbstractRationale In drug self-administration procedures, extended-access test sessions allow researchers to model maladaptivepatterns of excessive and escalating drug intake that arecharacteristic of human substance-abusing populations.Objectives The purpose of the present study was toexamine the ability of aerobic exercise to decreaseexcessive and escalating patterns of drug intake in maleand female rats responding under extended-accessconditions.Methods Male and female Long–Evans rats were obtainedat weaning and divided into sedentary (no running wheel)and exercising (running wheel) groups immediately uponarrival. After 6 weeks, rats were surgically implanted withintravenous catheters and allowed to self-administercocaine under positive reinforcement contingencies. Inexperiment 1, cocaine self-administration was examinedduring 23-h test sessions that occurred every 4 days. Inexperiment 2, the escalation of cocaine intake wasexamined during daily 6-h test sessions over 14 consecutivedays.

Results In experiment 1, sedentary rats self-administeredsignificantly more cocaine than exercising rats duringuninterrupted 23-h test sessions, and this effect wasapparent in both males and females. In experiment 2,sedentary rats escalated their cocaine intake to a signifi-cantly greater degree than exercising rats over the 14 daysof testing. Although females escalated their cocaine intaketo a greater extent than males, exercise effectively attenu-ated the escalation of cocaine intake in both sexes.Conclusions These data indicate that aerobic exercisedecreases maladaptive patterns of excessive and escalatingcocaine intake under extended-access conditions.

Keywords Cocaine . Self-administration . Rat . Exercise .

Binge . Escalation

Introduction

A growing number of preclinical studies report that exercisereduces cocaine-seeking behavior in a variety of experi-mental procedures. For instance, a history of physicalactivity reduces cocaine-maintained breakpoints in ratsresponding on a progressive-ratio schedule of reinforce-ment (Smith et al. 2008), and concurrent access to arunning wheel reduces cocaine self-administration in ratsresponding on a fixed-ratio schedule of reinforcement(Cosgrove et al. 2002). Aerobic exercise also reducesdrug-primed and cue-induced reinstatement in rats with ahistory of cocaine self-administration (Lynch et al. 2010;Zlebnik et al. 2010), suggesting that exercise may attenuatesome of the underlying behavioral processes that areresponsible for maladaptive patterns of drug intake.

Traditional laboratory procedures measuring drug self-administration are normally limited to 1 or 2 h in duration

Electronic supplementary material The online version of this article(doi:10.1007/s00213-011-2321-5) contains supplementary material,which is available to authorized users.

M. A. Smith (*) :K. L. Walker :K. C. LangDepartment of Psychology, Davidson College,Davidson, NC 28035, USAe-mail: [email protected]

M. A. Smith :K. T. Cole :K. C. LangProgram in Neuroscience, Davidson College,Davidson, NC 28035, USA

M. A. Smith :K. T. Cole :K. C. LangCenter for Interdisciplinary Studies, Davidson College,Davidson, NC 28035, USA

Psychopharmacology (2011) 218:357–369DOI 10.1007/s00213-011-2321-5

http://dx.doi.org/10.1007/s00213-011-2321-5

and generate very stable levels of drug intake over time.This pattern of drug intake contrasts with that typicallyobserved in substance-abusing individuals, who exhibit“binges” of excessive drug use (Burkett et al. 1994) andwho progressively escalate their drug use over time (Gawin1991). Such patterns of maladaptive drug intake are acardinal feature of drug addiction and comprise a criticalcomponent of the diagnostic criteria for substance usedisorders (American Psychiatric Association 1994). Thesepatterns of excessive and escalating drug intake can bemodeled in the laboratory by giving subjects prolongedaccess to a drug during test sessions lasting 6 h or longer (i.e.,extended access). For instance, animals given 24-h access tococaine exhibit high levels of drug intake that are associatedwith a loss of circadian patterns of activity, a dysregulation ofhomeostatic autonomic functions, and acute withdrawalsymptoms upon termination (Mutschler and Miczek 1998;Tornatzky and Miczek 2000; Fowler et al. 2007). Similardisruptions in behavioral and physiological processes areobserved in human laboratory studies (Foltin and Fischman1997; Pace-Schott et al. 2005; Reed et al. 2009), suggestinga high degree of homogeny between human and animalmodels of excessive drug intake. Furthermore, animals given6-h access to cocaine in daily self-administration sessionsescalate their drug intake over a period of several days, oftendoubling their daily cocaine intake in as little as 30 days(Ahmed and Koob 1998; Ahmed et al. 2005). Similarincreases in drug intake are seen in human populations andmay mark a transition into pathological states of substanceuse (Gawin and Kleber 1988). Thus, extended-accessprocedures model critical aspects of the addictive processand provide a platform from which to examine potentialinterventions for these maladaptive patterns of drug use.

The primary aim of the present study was to examine theeffects of aerobic exercise on maladaptive patterns of drugintake during extended-access test sessions. In one exper-iment, excessive drug intake was examined in sedentaryand exercising rats during 23-h “binges” of cocaine self-administration. Although the use of the term “binge” hasvaried across studies using animal models of repeated drugadministration (cf. Maisonneuve and Kreek 1994; Morganet al. 2005; Fowler et al. 2007), a binge was operationallydefined in the present study as a loss of circadian control ofdrug intake, with high levels of responding extending intothe inactive phase of the light/dark cycle (see Roberts et al.2002 for example and discussion). In a second experiment,the escalation of cocaine intake was examined in sedentaryand exercising rats during daily 6-h test sessions. In bothexperiments, no limit was placed on the number of cocaineinfusions that could be earned, other than those set by thesession length and post-infusion timeout. Previous studiesreport that females maintain higher levels of exercise outputthan males (Eikelboom and Mills 1988) and show greater

dysregulation of responding under extended-access con-ditions than males (Lynch and Taylor 2004). Consequently,both male and female rats were examined in the presentstudy.

Methods

General methods

Animals Male and female Long–Evans rats were obtainedat weaning from Charles River Laboratories (Raleigh, NC)and divided into sedentary and exercising groups uponarrival. Sedentary rats were housed in polycarbonate cages(50×28×20 cm) that permitted no exercise beyond normalcage ambulation; exercising rats were housed in cages ofequal dimensions with attached running wheels (HarvardApparatus, Holliston, MA, USA). Running wheels werestainless steel (35 cm diameter) and connected to mechan-ical switches and electronic counters that recorded eachrevolution. All rats were housed individually in atemperature- and humidity-controlled colony room main-tained on a 12-h light/dark cycle (lights on 0700). Exceptduring the brief period of lever-press training (see below),food and water were continuously available in the homecages. For the female rats, estrous phase was allowed tocycle normally and was not monitored. All subjects weretreated in accordance with the guidelines of the AnimalCare and Use Committee of Davidson College and theGuide for the Care and Use of Laboratory Animals(Institute of Laboratory Animals Resources 1996).

Apparatus All training and test sessions took place inaluminum and polycarbonate operant conditioningchambers from Med Associates, Inc. (St. Albans, VT).Each chamber contained a food receptacle, a house lightfor general illumination, two retractable response levers,and two white stimulus lights located above theresponse levers. All experimental events wereprogrammed with software and interfacing from MedAssociates, Inc. The left lever was designated as theactive lever for all rats.

Lever-press training Five weeks after arrival, all rats werelightly food restricted and trained to respond on a fixed-ratio 1 (FR1) schedule of food reinforcement. On thisschedule, each lever press produced a 45-mg Noyes foodpellet delivered from the pellet dispenser to the foodreceptacle. Sessions terminated once 40 reinforcers hadbeen earned or after 2 h elapsed, whichever occurred first.

Catheter implantation Six weeks after arrival and at least48 h after termination of lever-press training, all rats were

358 Psychopharmacology (2011) 218:357–369

anesthetized with a combination of ketamine (100 mg/kg,ip) and xylazine (8.0 mg/kg, ip) and surgically implantedwith intravenous catheters (CamCaths, Cambridge, UK)according to methods described previously (Smith et al.2008; 2009). A solution of heparinized saline (200 U/ml,iv) and ticarcillin (20 mg/kg, iv) was infused through thecatheter daily to prevent infection and maintain patency.After 7 days, ticarcillin was discontinued and onlyheparinized saline was used to maintain catheter patency.

Self-administration training Three days after surgery, ratswere placed into the operant conditioning chambers andconnected to infusion pumps via Tygon tubing. Each self-administration session began with illumination of the houselight, extension of the response lever into the chamber, andillumination of the white stimulus light above the responselever. During the initial training sessions, lever presses werereinforced on an FR1 schedule of reinforcement. On thisschedule, each lever press activated the infusion pump for2.0–3.5 s (based on body weight) and delivered 0.5 mg/kgcocaine (Research Triangle Institute, Research Triangle Park,NC, USA). Coincident with each infusion, the response leverretracted, and the stimulus light turned off to signal a timeoutperiod during which cocaine was not available. After 20 s, thestimulus light turned back on and the lever extended back intothe chamber. In the past, we observed seizure activity inpreviously food-trained rats on the first day of cocaine trainingdue to exceptionally high rates of responding. Consequently,the number of available infusions was capped at 21 during thefirst two training sessions. Beginning in the third session, noartificial limit was placed on the number of infusions thatcould be earned, other than those set by the post-infusiontimeout.

Experiment 1

Self-administration training A total of 32 rats (16 female, 16male) started the experiment and were implanted withintravenous catheters; rats that lost catheter patency wereremoved from the study and not replaced (see figure captionsfor final number of subjects in each group). Self-administration training sessions were conducted as describedabove and continued for 10 days, with the FR value increasingfrom FR1 to FR5 according to the following schedule: days 1–4 (FR1), day 5 (FR2), day 6 (FR3), day 7 (FR4), days 8–10(FR5). All ten sessions were conducted during the light phaseof the light/dark cycle so as not to interfere with nocturnalrunning. All sessions terminated automatically after 2 h.

Self-administration testing (23-h sessions) Two days afterthe conclusion of self-administration training, rats wereplaced in the operant conditioning chambers for a 23-h test

session. During this session, lever presses produced aninfusion of cocaine on an FR5 schedule of reinforcement.Each session began 30 min after the start of the dark phaseof the light/dark cycle (start time, 1930) and ended thefollowing day, 30 min before the start of the next darkphase (end time,1830). A small amount of food and waterwas placed in each chamber at the beginning of the session;otherwise, conditions were identical to those used duringthe ten training sessions (see above). Three doses ofcocaine (0.5, 1.0, and 2.0 mg/kg/infusion) were tested inan irregular order 73 h apart. No limit was placed on thenumber of infusions that could be obtained, other than thatset by the post-infusion timeout.

Self-administration testing (2-h sessions) Three days afterthe final 23-h session, the cocaine dose–effect curve wasdetermined in five daily 2-h test sessions. Each test sessionwas conducted during the light phase of the light/darkcycle. During each session, cocaine (0.03, 0.1, 0.3, or1.0 mg/kg/infusion) or saline was available on an FR5schedule of reinforcement. Doses of cocaine were tested inan irregular order.

Data analysis All self-administration data were analyzedvia mixed-factor ANOVA, with sex and conditionserving as between-subjects factors and session (or dose)serving as a within-subjects factor. For exercising rats, aPearson product–moment correlation was used to deter-mine the correlation between exercise output andresponding at each dose of cocaine. Data from the 23-h sessions were also analyzed by examining thecumulative record of each rat to determine the relativerate of responding and duration of responding over the23-h test period. The relative rate of responding wascalculated for each individual rat by determining theslope of a regression line fitted to the data for the periodof active lever pressing. The period of active leverpressing (i.e., the duration of responding) was operation-ally defined as the elapsed time between the beginning ofthe session and the occurrence of the lever pressrepresenting the 99th percentile of total lever pressesemitted during that session. Due to a programming error,the cumulative record was truncated at 1,000 responsesfor female rats responding at the two lower doses ofcocaine (but the session otherwise continued normallyand data for total number of infusions were unaffected).Consequently, cumulative record data from males andfemales were analyzed separately. For males, relative rateof responding and duration of responding were analyzedvia mixed-factor ANOVA, using condition as a between-subjects factor and dose as a within-subjects factor.Because of differences in variance in the duration ofresponding between groups, these data were also rank

Psychopharmacology (2011) 218:357–369 359

ordered and analyzed via a nonparametric Mann–Whit-ney U test. For females, relative rate of responding wasanalyzed via mixed-factor ANOVA, with the caveat thatonly data from the first 1,000 responses were used in theanalysis. For duration of responding, data obtained at thehigh dose were analyzed via independent-samples t testusing condition as the factor.

Experiment 2

Self-administration training A total of 40 rats (16 female,22 male) started the experiment and were implanted withintravenous catheters; rats that lost catheter patency wereremoved from the study and not replaced (see figurecaptions for final number of subjects in each group). Self-administration training sessions were conducted asdescribed above (see “General methods”) for seven con-secutive days in which responding was always reinforcedon an FR1 schedule of reinforcement. All sessionsterminated automatically after 1 h.

Self-administration testing (6-h sessions) After 7 days oftraining, self-administration sessions were lengthened to6 h with no limit on the number of infusions that couldbe earned, other than that set by the post-infusiontimeout. All other experimental events were identical tothose used during the training sessions. These conditionsremained in effect for 14 consecutive days. All self-administration training and testing sessions began at theonset of the light phase of the light/dark cycle (starttime, 0700) so as not to interfere with nocturnal running.The dose of cocaine was maintained at 0.5 mg/kg/infusion in all sessions.

Data analysis Drug self-administration data wereexpressed as number of infusions obtained andanalyzed via three-way ANOVA, with sex and condi-tion serving as between-subjects factors and sessionserving as a within-subjects factor. In exercising rats,a Pearson product–moment correlation was used todetermine the correlation between exercise output andcocaine self-administration. Relative rate of responding

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Fig. 1 Exercise output over the course of experiment 1 in female (n=7) and male (n=7) rats. Vertical axes depict exercise output inrevolutions per day (rev/day); horizontal axes depict time expressed inweeks (weeks 1–6, 11) and days (days 43–68). Vertical reference linesindicate transitions between different experimental events: weeks 1–6,

home cage, lever press training, and surgery; days 43–44, recoveryfrom surgery (Rec); days 45–54, self-administration training (2 h);days 55–68, self-administration testing (23 h); and week 11, self-administration testing (2 h)


and duration of responding were calculated for thefirst (day 1) and last (day 14) day of testing accordingto the methods described above, with the exceptionthat duration of responding was operationally definedas the elapsed time between the beginning of thesession and the occurrence of the final lever press ofthe session. These data were then analyzed via three-way ANOVA, with sex and condition serving asbetween-subjects factors and session serving as awithin-subjects factor.

Results

Experiment 1

Exercise output Females increased their running at afaster rate than males and achieved greater maximallevels of exercise output than males over the first6 weeks of the study (Fig. 1). Wheel running decreasedsharply after each 23-h session, and this effect wasapparent in both males and females. Running recovered

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Fig. 2 a Cocaine self-administration in female and male rats during23-h test sessions. Vertical axes depict total cocaine intake inmilligram per kilogram; horizontal axes depict dose of cocaine inmilligram per kilogram per infusion. Open symbols depict datacollected in sedentary rats (n=8 female; n=8 male); filled symbolsdepict data collected in exercising rats (n=7 female; n=7 male). bCumulative records from sedentary and exercising male rats during

23-h sessions in which responding was maintained by 1.0 mg/kg/infusion cocaine. Vertical axes depict cumulative number ofresponses; horizontal axes depict time expressed in hours. Insetgraphs depict a magnified view of the cumulative record during thefirst hour of the session to show the step-like response pattern that istypical of an FR5 schedule of reinforcement. Colored lines representdata from individual rats


during the 3 days following each session but did not returnto pre-surgery levels in most instances. There was a trendfor exercise output to recover more slowly following eachsession, such that exercise output was only 50% of pre-surgery levels by the end of this phase of the study.Running remained suppressed in both groups in the finalweek of the study during which cocaine was self-administered in daily 2-h test sessions.

Self-administration training All rats responded on thefirst day of self-administration training and showedstable response rates with regular post-reinforcementpauses by the third day. Over the last 8 days of training(sessions 3–10), responding varied from day to day[main effect of session, F (7, 182)=4.030, p<0.001], butno increasing or decreasing trends were observed in anygroup (Online Resource 1). Females responded more thanmales throughout the training period [main effect of sex, F(1, 26)=6.942, p=0.014], but no significant differences inresponding were observed between sedentary and exercis-ing rats of either sex.

Self-administration testing (23-h sessions) Responding var-ied across dose and condition during the 23-h sessions(Fig. 2). Cocaine intake increased significantly across thedoses tested [main effect of dose, F (2, 52)=36.032,p<0.001]. At all three doses, cocaine intake was signifi-cantly greater in sedentary rats than exercising rats [maineffect of condition, F (1, 26)=12.570, p=0.002], and thiseffect was apparent in both males and females. Nosignificant sex or order effects were observed.

An analysis of individual cumulative records revealedthat all subjects displayed patterns of responding typical ofan FR5 schedule of cocaine reinforcement (i.e., a rapid runof five responses followed by a post-reinforcement pause,the length of which was related to the dose of cocainemaintaining the behavior). To compare relative responserates across conditions, regression lines were calculated forthe period of active lever pressing, and the slopes of theseregression lines were determined for each rat (Table 1;Fig. 2). In males, slopes varied as a function of dose, withsteeper slopes (i.e., faster response rates) observed at thelower doses of cocaine [main effect of dose, F (2, 26)=

Table 1 Relative response rate and duration of responding across conditions in experiment 1 (data reflect the mean (SEM))

Sex/condition Relative response ratea Duration of respondingb

0.5 mg/kg 1.0 mg/kg 2.0 mg/kg 0.5 mg/kg 1.0 mg/kg 2.0 mg/kg

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Sedentary 1.65 (0.11)c 0.74 (0.04)c 0.53 (0.04) –d –d 1,189.43 (60.72)

Exercise 1.49 (0.13)c 0.67 (0.03)c 0.50 (0.04) –d –d 1,089.14 (110.89)

Male

Sedentary 1.39 (0.08) 0.70 (0.02) 0.45 (0.02) 1,375.44 (0.45) 1,373.01 (0.76) 1,370.20 (1.10)

Exercise 1.32 (0.08) 0.70 (0.02) 0.47 (0.05) 1,244.24 (74.19) 1,204.91 (108.05) 1,224.95 (118.93)

a Relative response rate was calculated as the slope of the regression line fitted to the portion of the cumulative record covering the period of activerespondingb Duration of responding was defined as the time in minutes between the beginning of the session and the occurrence of the lever pressrepresenting the 99th percentile of total lever presses emittedc Values derived from first 1,000 responses onlyd Could not be determined

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Fig. 3 Dose–effect curve of co-caine in female (left panel) andmale (right panel) rats as deter-mined during 2-h test sessions.Vertical axes depict number ofinfusions obtained; horizontalaxes depict dose of cocaine inmilligram per kilogram perinfusion. Open symbols depictdata collected in sedentary rats(n=6 female; n=6 male); filledsymbols depict data collected inexercising rats (n=4 female;n=4 male)


193.547, p<.001]. Response rates were similar betweensedentary and exercising male rats at each dose of cocaine,and no significant differences were observed between thetwo groups. In females, relative response rates varied as afunction of dose [F (2, 26)=164.017, p<.001] but notcondition. Omitting data from the first hour of the session(i.e., from the initial “load-up” phase) revealed a similarpattern of effects in both sexes. An analysis of post-reinforcement pause data, which were highly correlatedwith relative response rates (r=−0.88; p<0.001), alsoproduced a similar pattern of results.

In order to compare the duration of responding acrossconditions, the period of active lever pressing (i.e., theperiod of time before responding ceased) was determinedfor each rat (Table 1; Fig. 2). In males, a mixed-factorANOVA revealed that the duration of active lever pressingdid not vary across dose, but sedentary rats responded forsignificantly longer periods of time than exercising rats[main effect of condition, F (1, 13)=5.035, p=0.043]; thelatter finding was confirmed by a nonparametric analysis ofthe data (p=0.002). For females, the duration of active leverpressing was longer in sedentary rats than exercising rats atthe high dose of cocaine (2.0 mg/kg/infusion), but thiseffect was not statistically significant. Collapsing across sexand dose, sedentary rats responded, on average, 2.3 hlonger than exercising rats. An examination of thecumulative record revealed that sedentary rats respondedin the last 15 min of the session in 27 out of 32 instancesfor which data were available, whereas exercising ratsresponded in the last 15 min of the session in only 14 out of28 instances.

Self-administration testing (2-h sessions) Three days afterthe final 23-h session, the full dose–effect curve of cocaine(i.e., both the ascending and descending limb) wasdetermined in all groups during 2-h test sessions conductedover five consecutive days (Fig. 3). Responding wascharacterized by an inverted U-shaped dose–effect curvein all groups [main effect of dose, F (3, 48), 120.483,p<0.001]. Exercise did not impact responding maintainedby cocaine under these conditions (no significant maineffect of condition or significant dose×condition interac-tion), and no significant sex differences were observed.

Correlation between exercise output and cocaine self-administration Responding during the 23-h sessionswas not strongly associated with exercise output duringthe various phases of the study (e.g., before surgery,before a session, after a session). Only two significantcorrelations (out of a possible 18) were obtained. Forfemales, there was a significant negative correlationbetween the number of infusions maintained by thelow dose of cocaine and exercise output during the

3 days immediately preceding the session (r=−0.817;p=0.025) and the 3 days immediately following thesession (r=−0.807; p=0.028).

Experiment 2

Exercise output Exercise output differed markedly betweenmales and females during the first 6 weeks of the study(Fig. 4). Females ran more during the first week of wheelexposure than males, increased their running at a faster ratethan males, and reached a greater maximal level of exerciseoutput than males. Following catheter implantation, runningdecreased markedly in females to approximately 50% of

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Fig. 4 Exercise output over the course of experiment 2 in female(n=6) and male (n=8) rats. Vertical axes depict exercise output inrevolutions per day (rev/day). Horizontal axes depict timeexpressed in weeks. Vertical reference lines after weeks 6 and 7indicate transitions between different experimental events: homecage and running wheel acclimation (weeks 1–6); self-administration training (week 7); extended-access cocaine self-administration (weeks 8–9)


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that observed prior to surgery. In males, running declinedslightly after surgery and was comparable to that of femalesfor the remainder of the study.

Self-administration training All rats responded on thefirst day of self-administration training and stableresponse rates were observed by the third day of training.Over the next 5 days of training, females respondedmore than males, but no differences were observedbetween sedentary and exercising rats (Online Resource2). Consistent with these observations, a repeated-measures ANOVA revealed a significant main effect ofsex [F (1, 24)=31.435; p<0.001], but no other significanteffects were obtained.

Self-administration testing (6-h sessions) Significant differ-ences in responding were observed between males and females,between sedentary and exercising rats, and across the 14 testsessions (Fig. 5). Progressive increases in responding wereobserved in all groups across the 14-day period [main effect ofsession, F (13, 312)=11.235; p<0.001]. Females respondedmore than males throughout the testing period [main effect of

sex, F (1, 24)=35.201; p<0.001], and this effect was apparentin both sedentary and exercising rats. Sedentary rats of bothsexes responded to a significantly greater degree thanexercising rats [main effect of condition, F (1, 24)=6.742;p=0.016]. Importantly, for both females and males, sedentaryand exercising rats did not differ on the first day of testing, butdifferences between groups emerged rapidly over subsequenttest sessions.

The relative rate of responding and duration of respond-ing were determined for all rats using data from individualcumulative records (Table 2; Fig. 5). The relative rate ofresponding was greater in females than males [main effectof sex, F (1, 24)=22.927; p<0.001] and greater on the lastday of testing than on the first day of testing [main effect ofsession, F (1, 24)=32.250; p<0.001]. Importantly, responserates did not differ between sedentary and exercising rats onthe first day but were significantly greater in sedentary ratson the last day [condition×session interaction, F (1, 24)=4.795; p=0.039]. In contrast, no significant main effects orinteractions were observed for duration of responding. Allrats responded until the end of the session (i.e., obtained atleast one infusion during the final 10 min of the session) onboth the first and last day of testing.

Correlation between exercise output and cocaine self-administration Pearson product–moment correlations failedto reveal a significant relationship between exercise outputduring any phase of the study [before surgery (weeks 1–6);during testing (weeks 8–9); throughout the entire study(weeks 1–9)] and responding on day 1 of testing, respond-ing on day 14 of testing, and the difference between day 1and day 14 of testing (correlations not shown).

Discussion

The principal finding of this study is that aerobic exercisereduces maladaptive patterns of drug intake in male and

Fig. 5 a Escalation of cocaine intake over 14 daily 6-h test sessions infemale and male rats. Open symbols depict data collected in sedentaryrats (n=7 female; n=7 male); filled symbols depict data collected inexercising rats (n=6 female; n=8 male). Vertical axes depict numberof infusions obtained during 6-h test sessions (note different axes formales and females). Horizontal axes indicate session number relativeto the beginning of extended-access conditions. Short-dashed linesindicate control responding for sedentary rats (data from day 1); long-dashed lines indicate control responding for exercising rats (data fromday 1). The dose of cocaine was 0.5 mg/kg/infusion in each session. bCumulative records from sedentary and exercising male rats duringthe first (day 1) and last (day 14) test session. Vertical axes depictcumulative number of responses; horizontal axes depict timeexpressed in hours. Inset graphs depict a magnified view of thecumulative record during the first hour of the session. Colored linesrepresent data from individual rats; colors representing individual ratsare consistent within a group

�

Table 2 Relative response rate and duration of responding across conditions in experiment 2 (data reflect the mean (SEM))

Sex/condition Relative response ratea Duration of respondingb

Day 1 Day 14 Day 1 Day 14

Female

Sedentary 0.33 (0.02) 0.50 (0.05) 357.76 (0.85) 358.69 (0.38)

Exercise 0.32 (0.03) 0.41 (0.02) 357.82 (0.63) 358.54 (0.61)

Male

Sedentary 0.24 (0.02) 0.37 (0.01) 358.29 (0.28) 357.73 (0.51)

Exercise 0.27 (0.02) 0.32 (0.02) 358.71 (0.37) 358.73 (0.26)

a Relative response rate was calculated as the slope of the regression line fitted to the portion of the cumulative record covering the period of activerespondingb Duration of responding was defined as the time in minutes between the beginning of the session and the occurrence of the final lever press


female rats self-administering cocaine under extended-access conditions. In experiment 1, exercise reduced theduration of responding during uninterrupted, 23-h testsessions. In experiment 2, exercise reduced the escalationof responding during daily, 6-h test sessions over 14consecutive days. These data add to a growing body ofpreclinical literature reporting that physical activity reducescocaine self-administration and attenuates maladaptivepatterns of drug intake that are characteristic of substanceuse disorders (Cosgrove et al. 2002; Smith et al. 2008;Zlebnik et al. 2010).

Consistent with previous studies reporting that femalesrun more than males (Eikelboom and Mills 1988; Boakes etal. 1999), females in both experiments increased theirrunning at a faster rate than males and achieved greatermaximal levels of exercise output than males. Wheelrunning was reduced immediately after catheter implanta-tion in both sexes and was reduced further when theextended-access phase of the experiments began. Inexperiment 1, exercise output on the day following each23-h test session was only 10–20% of that observed on theday preceding the session. Mutschler and Miczek (1998)reported that termination of a 12- or 48-h binge results in awithdrawal syndrome as indicated by ultrasonic vocal-izations during the first 24 h after the session. It is likelythat the reduction in wheel running after each test sessionwas the result of acute withdrawal from cocaine. Consistentwith this possibility, Santucci et al. (2008) reported thatwithdrawal from experimenter-delivered cocaine is associ-ated with a significant reduction in both locomotor activityand wheel running. In the present study, wheel runningincreased during the 3 days following each test session,suggesting that physical and/or affective withdrawal symp-toms gradually abated over time. Interestingly, wheelrunning typically did not return to the level observed priorto the session, and there was a tendency for recovery to beprogressively less robust following each subsequent testsession. Tornatzky and Miczek (2000) reported that whilesome autonomic processes return to normal within 3 daysafter a prolonged binge (e.g., heart rate), other autonomicprocesses remain dysregulated for up to 15 days (e.g., corebody temperature). It is likely that autonomic processesrelated to wheel running and physical activity had not fullyrecovered before the start of the next test session and thateach subsequent binge further exacerbated the dysregula-tion of those processes.

In experiment 1, physical activity markedly reducedcocaine self-administration during the 23-h test sessions.These effects were observed in both males and femalesand across all three doses of cocaine. Because decreasesin cocaine intake on a fixed-ratio schedule could be dueto either a slower rate of responding or to an earliercessation of responding, we calculated both relative

response rate and duration of responding for each rat.The slopes of regression lines fitted to cumulativerecords did not differ between sedentary and exercisingrats, indicating that response rates were similar betweenthe two groups. In contrast, the duration of respondingwas shorter in exercising rats, indicating that this groupterminated the binge earlier than sedentary rats. In fact,exercising rats ended their binge before the conclusion ofthe 23-h session in 14 of the 28 instances for which datawere available; in sedentary rats, early termination wasobserved in only 5 of 32 instances. Given that themajority of sedentary rats were still responding at theend of each session, the differences in cocaine intakebetween the two groups likely reflect a conservativeestimate of exercise's protective effects. All rats thatceased responding before the end of the session did soduring their inactive phase (i.e., during the last 12 h of thesession). Given that voluntary exercise entrains circadianrhythms in both rodents (Edgar and Dement 1991) andhumans (Buxton et al. 2003), it is possible that exercise'sability to synchronize behavioral rhythms is responsiblefor the early termination of responding in exercising ratsand for its protective effects against excessive cocaineintake under extended-access conditions.

Responding under fixed-ratio schedules of drug rein-forcement is characterized by an inverted U-shaped dose–effect curve, and all doses tested during the 23-h sessionsfall on the descending limb of the curve. This is potentiallysignificant because reductions in responding on thedescending limb could indicate either a leftward shift inthe dose–effect curve or a downward shift in the dose–effect curve. Exercising rats have lower body weights, lessadipose tissue, and smaller livers than sedentary rats (Pittsand Bull 1977), all of which could lead to differences in thepharmacokinetics of cocaine between sedentary and exer-cising groups. A previous study reported that plasmaconcentrations of an intravenous infusion of cocaine weregreater in a group of forced-exercise rats while they wereexercising than in a group of rested controls (Han et al.1996). Although running wheels were never concurrentlyavailable during test sessions in the present study, increasedplasma concentrations at the time of testing could increasethe effects of cocaine in exercising rats. To examine thispossibility, the full dose–effect curve (i.e., both ascendingand descending limbs) was determined during 2-h testsessions over five consecutive days. In these tests, nodifferences in sensitivity to cocaine were apparent betweensedentary and exercising rats.

In experiment 2, female rats escalated their cocaineintake under extended-access conditions to a greater degreethan male rats. Although this finding contrasts with the lackof sex differences noted in experiment 1, it is consistentwith a large body of literature reporting that females self-


administer more cocaine than males (see reviews by Carrollet al. 2004; Roth et al. 2004; Lynch 2006) and escalate theircocaine intake to a greater extent than males (Roth andCarroll 2004). In females, hormonal fluctuations due to theestrous cycle influence both wheel running (Steiner et al.1982; Kent et al. 1991) and cocaine self-administration(Roberts et al. 1989; Feltenstein and See 2007). Althoughfemales ran more than males in both experiments, no sexdifferences were observed in the effects of exercise oncocaine self-administration in either experiment.

In experiment 2, sedentary rats escalated their cocaineintake to a significantly greater degree than exercising rats,even though the two groups did not differ during training orduring the first day of responding under extended-accessconditions. Thus, any effect of exercise on the escalation ofcocaine intake cannot be attributed to differences inpharmacological history or to baseline differences incocaine sensitivity. Similar to that observed in experiment1, differences between sedentary and exercising rats did notemerge until cocaine was available during extended-accesstest sessions, under conditions specifically designed tomodel maladaptive patterns of drug intake. Unlike that seenin experiment 1, the differences observed between seden-tary and exercising rats after 14 days of 6-h test sessionswere due to differences in the rate of responding, ratherthan to differences in the duration of responding. Thesedata suggest that different mechanisms are likely responsi-ble for the protective effects of exercise in these twoprocedures.

Identifying the physiological mechanisms responsiblefor exercise's protective effects in extended-accessmodels is difficult, primarily because the underlyingprocesses contributing to excessive and escalating pat-terns of drug intake are poorly understood. For instance,previous investigations have suggested that tolerance(Oleson and Roberts 2009), sensitization (Ferrario et al.2005), and changes in homeostatic set points (Ahmed andKoob 1998) may all be involved in the escalation of drugintake in extended-access models. Complicating mattersfurther, exercise may be engaging satiety or “stop”mechanisms under some conditions (e.g., 23-h testsessions) and engaging mechanisms responsible for theincentive value of cocaine under other conditions (e.g.,repeated 6-h test sessions). Nevertheless, several mech-anisms that influence cocaine self-administration areknown to be modulated by exercise.

Cocaine self-administration is associated with anincrease in the number of dendritic spines on striatalmedium spiny neurons in the nucleus accumbens andpyramidal neurons in the cortex (Robinson et al. 2001),and these changes may contribute to the development ofcompulsive patterns of drug intake (Robinson and Kolb2004). Wheel running promotes neuroplastic changes

throughout brain (van Praag 2008) and modulates theneuroplastic changes produced by cocaine (Willuhn et al.2003). Acute exercise also stimulates the release ofdopamine (Meeusen and De Meirleir 1995), and pro-longed exercise leads to alterations in dopamine bindingproteins (MacRae et al. 1987; Fisher et al. 2004). Thesealterations could blunt the impact of prolonged exposureto cocaine and attenuate excessive and escalating patternsof cocaine intake. Exercise also stimulates the release ofthe opioid peptides beta-endorphin (Mehl et al. 2000) anddynorphin (Fontana et al. 1994), which serve as endoge-nous ligands at mu and kappa receptors, respectively. Theopioid receptor system plays an important modulatory rolein the reinforcing effects of cocaine (Herz 1998; Melloand Negus 2000), and the kappa opioid receptor system iscritically involved in cocaine self-administration underextended-access conditions (Wee and Koob 2010). Exercisealso induces neurogenesis in the hippocampus (Rhodes et al.2003; Uda et al. 2006). Reductions in hippocampal neuro-genesis have been implicated in cocaine-seeking behavior(Noonan et al. 2010), and exercise may enhance the abilityof this structure to buffer against compulsive patterns of drugintake. Exercise also alters mRNA levels for severalcatecholaminergic proteins in both reward (Greenwood etal. 2011) and motor (Foley and Fleshner 2008) pathways,any of which may mitigate the maladaptive changes inmotivational circuits caused by cocaine. Given the diffusenature of exercise's effect on the central nervous system,multiple mechanisms are likely at play and isolating any onemechanism will remain a challenge.

Acknowledgements This study was supported by the NationalInstitutes of Health (NIDA Grants DA14255 and DA027485 toMAS). Additional support was provided by the Howard HughesMedical Institute (Grant 52006292), the Duke Endowment, andDavidson College. The authors wish to thank the National Instituteon Drug Abuse for supplying the study drug and Amy Sullivan forproviding expert animal care. Portions of these data were presentedat the annual meeting of the College on Problems of DrugDependence in Reno, NV on June 24, 2009 and the annualmeeting of the Society for Neuroscience in San Diego, CA onNovember 16, 2010.

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The effects of aerobic exercise on cocaine self-administration in male and female rats