Campbell and Carroll's Aquisition of Drug Self-Administration - Environmental and Pharmacological...

8/12/2019 Campbell and Carroll's Aquisition of Drug Self-Administration - Environmental and Pharmacological Interventions

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Experimental andClinical Psychopharmacology2000,Vol. 8.No. 3, 312 325

Copyright2000by theAmerican PsychologicalAssociation,Inc.1064-1297AXV 5.00 DOI: 10.I037//1064-1297.8.3.312

AcquisitionofDrug Self-Administration: EnvironmentalandPharmacological InterventionsUnaC. Campbell andMarilynE. CarrollUniversityof MinnesotaMedicalSchool

The development of drug-reinforced behavior is a transition process characterized by arelativelyrapid shift from little or no drug-maintainedrespondingtohigh, stablelevelsofresponding. Animal studies of drug self-administration focus on how rapidly thisprocesstakesplaceorwhatpercentageofanimalsacquiredrug self-administration. Tt isessentialtohaveanimalmodelsofacquisitionbecausetheprocessisdifficult tostudywith drug-naivehumans.Animalstudiesreveal a wide range offactors thatcaneitheraccelerateordecreaseacquisition of drug self-administration, such as environmental conditions (e.g., feedingconditions,palatabledietarysubstances, stress), pharmacological variables (e.g.,drugdose,drug history, pretreatment drugs),andindividual differences (e.g.,reactivitylevel,age, sex,dietarypreferences,genetics).Thisarticlediscussesthe methodsusedtostudyacquisition ofdrug-reinforcedbehavior inlaboratoryanimals and the variablesthathavebeen reportedtoaccelerateorpreventthe acquisition ofdrug-reinforced behavior.An understanding of theconditionsthatcanenhanceacquisitioninanimalsmayhelp predictvulnerabilitytodruguseinhumansandlead to successfulmethodsfor preventionofdrugabuse.

The acquisition of intravenous drug-reinforced behavioroccurs rapidly. Usually in 2 to 5 days the number of infu-sionsself-administeredby ananimalrangesfrom very fewto amaximumnumber. With psychomotor stimulants, sub-sequent behavior will level off at that maximum level,whereas withopioids,the number ofinfusions self-admin-istered continuetoincreaseover severalweeks.Therearefew methods tosystematically, objectively, and quantita-tivelydescribethis transition behavior.Threemethodsaredescribedthataremost commonly reportedin theliterature.In most studies, intravenous drug delivery is dependent onan operant response (e.g., lever press, nose poke).

First, themost simple method is toexpose animalsto adrug for afixed amount of time each day (e.g., see Xi &Stein, 1999), and acquisition of drug self-administration issaidtooccur when responding initiates,passesthroughanerratic escalating phase, then stabilizesat asteadydailyratethatis considerably higher than responding in agroupthatreceivedaccessto only thevehicle(e.g., saline). This typeofanalysiscan beusedtostudytheeffectsofsession length(e.g., Ahmed & Koob, 1999), medication pretreatments(e.g., Xi & Stein, 1999), or other variables.

A second method that has often been used is similarexcept that one or two experimenter-administered priminginjectionsare given at thestartof the session, and latency toacquisition of drug-reinforced behavior is also measured(Schenk & Davidson, 1998). It isbasedon the assumption

Una C.Campbelland Marilyn E. Carroll,DepartmentofPsy-chiatry,UniversityofMinnesotaMedicalSchool.

Correspondenceconcerningthisarticleshouldbe addressed toMarilynE.Carroll,Departmentof Psychiatry,UniversityofMin-nesotaMedical School,Box 392 UMHC, Minneapolis,Minnesota55455.Electronicmailmay besentto [email protected].

thatthestrengthof areinforcerand thelatency toacquisi-tion of a response are inversely related. Acquisition isdefined by comparing the upper limit of 99% confidenceintervals for responses on the drug-reinforced leverand asecond nonreinforced lever. When these confidenceinter-valsare nolonger overlapping, acquisitionhasoccurred (seeSchenk & Davidson, 1998, for a review). The priminginjcction(s)usedwiththese methods reduce the intersubjectvariability,which can be very high when animals are com-ing into contact with the response manipulanda and learningtheresponse-drugcontingency atdifferent rates. Anotherwayof reducing the intersubjectvariabilityis to pretrain theanimals to respond on the manipulandum for food. Thedisadvantage is that this pretraining mayacceleratethe drugacquisition processandproduceaceilingeffect wherebytheprocedure would not be sensitive to manipulations thatincrease acquisition of drug self-administration behavior.

A third method is an adaptation (Carroll & Lac, 1993;Carroll, 1998) of an autoshaping procedure that was origi-nallyused to train pigeons (Brown & Jenkins, 1968) andrats (Messing,Kleven, &Sparber, 1986) to acquire food-reinforced responding. In this procedure the response isshaped by pairing a stimulus associated with the manipu-landum (e.g., lever extension or key light)withautomaticreinforcer delivery. Daily sessions consist of a 6-hr au-toshaping component that is followed by a 6-hr self-admin-istration component. During eachofthe 6 hr of autoshaping,a retractable lever is extended into the operant chamber 10times under a random-interval schedule. The lever is re-tracted if the animal touches it or after 15 s, whicheveroccursfirst. A cocaineinfusionisdeliveredto the animal 1 saftereach leverretraction. Deliveryof the 10cocaineinfu-sions occurs according to a random-time 90-s scheduleduringthe first15-20minofeach hour. These experiment-er-administered priming infusions have some face validity

312


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SPECIALISSUE:DRUGSELF-ADMINISTRATION 313in that first-time drug users often receive their first fewexposures to a drug at minimal effort or monetary cost.Duringtheself-administration session,theretractable leverremains extended, andcocaine infusions arecontingentonlever pressing undera fixed-ratio 1 (FR 1)schedule. Withthis method, the acquisition process can be standardized(thus decreasing intersubject variability) and quantifiedacrosssubjects.Inaddition,theacquisition criteriacan beadjusted depending on thedrugdoseand pharmacologicalclasssothattheentire acquisitionprocessiscaptured (i.e.,from little or no responding to high, stable levels of re-sponding). The dependent variables in these studies arenumberofsessionsto meet criterion, numberof infusionsself-administered, and percentage of animals acquiring drugself-administration.

Using the autoshaping procedure, there is a pattern ofbehavior that is similar across rats acquiring intravenousdrug self-administration. Figure 1 shows individual datafrom eight rats that acquired intravenouscocaine self-ad-ministration,foureach from two drug pretreatment studiesthatarediscussed later.Thenumberofcocaineinfusions isplotted over the 5-day period for each rat that met thecriterion (ameanof 100infusions over5days)foracqui-sition of intravenous cocaine self-administration.All rats

reached their maximum number ofinfusionsby Day 5, andsomehadbeguntoleveloff at Day 2, 3, or 4. Therats showthelowest intersubject variabilityonDays1 and 5,whereasDays2, 3, and 4representthemore erratic,escalatingphasethatresultsinhigher intersubject variability.

Acquisitionofdrug self-administrationvia theoral routehasbeen studied using procedures suchasschedule-inducedpolydipsia, food-induced drinking, drug-fading,andchoiceorpreferencetests.Schedule-induced polydipsiais the in-crease in drinking that results when animals receive foodpellets under an intermittent schedule of reinforcement andhaveaccesstoliquidbutthereis noprogrammed schedulefordrinking(Falk,1961). Polydipsicdrinkingceaseswhenthefood pelletsare nolongerdelivered.Using thisproce-dure, acquisition of drug self-administration is considered tooccur ifdrug-maintained drinking persists after the gener-ating food schedule is removed and drug intake occurs athigherlevels than water drinking. Another method similartoschedule-induced polydipsiaisfood-inducedorpostpran-dial drinking. With this method, animalsareusually food-restricted and given their daily food ration prior to theexperimental session. When the drug solution is the onlyliquid available, postprandial drinking results. Subse-quently,whentheanimalsare fed after thesession, ifdrug

2 3 4 5 0 1Consecutive Days

Figure 1. Individual data are presented for 8 rats during the last 5 days of the autoshapingprocedurewhenthey metcriterion(a mean of 100infusionsfor 5days)foracquisitionof ivcocaine(0.2 mg/kg)self-administration. Representative rats were taken from control groups (saline orvehicle pretreated)from twoexperimentsin which rats were pretreatedwith medications duringacquisitionofcocaineself-administration.TheleftpanelcontainsdatafromCampbellandCarroll's(2000a) study with baclofen pretreatment, and the right panel shows data from Campbell andCarroll's(2000b)studywithketoconazolepretreatment.


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314 CAMPBELL ANDCARROLLdrinking continuesand isgreater than waterdrinking,thenacquisition of drug self-administration is established. Afading procedurehas also been used with orally delivereddrugs tomask aversive taste.The general approachof thefadingprocedureis totrain animalstoorallyself-administera drug (e.g., DrugA). Inorder toestablish asecond drug(e.g., DrugB) as areinforcer, increasing concentrations ofDrugB areplaced in Drug SolutionA, andgradually theconcentration ofDrug SolutionA isdecreased until DrugBis the only drug present in the solution. Acquisition ofdrug-reinforced responding occurs if the animals consumemoreofDrugBthanthedrug vehicle,usuallywater.Choiceor preference methods simply involve giving animals con-current accessto twoliquids (e.g.,drugandvehicle). Ac-quisitionismeasuredbyassessingpreferencefordrug overthevehicle.

Environmental VariablesFeeding Conditions

In an early study, Carroll, France, and Meisch (1981)showed that reduced accesstofood increased theacquisi-tionofintravenousPCPself-administrationinrats thathadcontinuous accessto the drug. Studiesin rhesus monkeysalso showed that feeding conditions affected the acquisitionof oral PCP self-administration (Carroll, 1982). In thisstudy,two groups of monkeys went through an acquisitionproceduretoestablish orallydeliveredPCP as a reinforcer.One group of monkeys was food-restricted throughout theexperiment,and the other group was fed ad libitum. Thecriterion for acquisition oforalPCP self-administration waswhen PCP intake wasgreater than concurrently availablewater. Although both groupsacquired PCP-reinforced be-havior, PCPconsumptionwaslowerin thegroup thatwasfed adlibitum. Furthermore,the within-session patterns ofdrinking differed between the two groups. The food-re-stricted group started drinking assoonas the 3-hr sessionbegan,andtheyconsumed most of theirdrugwithin the firsthour. The group that was fed ad libitum did not initiatedrinking until several minutes afterthesession started,andthey consumed their drug intermittently throughout thesession.

Theseearly studiesled to amore systematic evaluationofthe effects ofdifferentfeeding conditions on the acquisitionof drug self-administration (Carroll & Lac, 1993, 1998).Usinganautoshaping method (e.g., Brown&Jenkins, 1968;Messing et al., 1986), Carroll and Lac (1993) comparedboth therateof acquisitionand thepercentage ofanimalsacquiringivcocaine-reinforced behaviorinthree groupsofratsthatweregiven 10g, 20 g, or ad libamountsof foodeachday. The criterion for acquisition of drug self-admin-istration was a 5-dayperiodduring which an average of atleast 100 infusions were obtained during the self-adminis-tration component. The experiment was terminated if ananimal did not meet the criterionwithin30 days. The groupsthat received 10 g, 20 g, or ad libamountsoffood acquiredinameanof 6,9.5,and16.1days, respectively.Inaddition,in the two food-restricted groups, 100% of the animals

acquired, whereasonly77% of the group thatwas fed adlibitum acquired.Thus, increasingtheavailability of foodduring initial drug exposure interfered withthe acquisitionof drug self-administration.

DeVry, Donselaar,and van Ree(1989)showed that rateofacquisition ofintravenous cocaine self-administration isdirectly relatedto themagnitude ofbody weight reductionproduced byfoodrestriction.Inthis study,threegroupsofratsreceived 10 g, 7.5 g, or 5 g offood each day,andtheysustained body weight losses of5-15%, 15-25%,and 25-35%, respectively. The rats' behavior wasmaintainedbyintravenousinfusions ofcocaineor saline under an FR 1schedule during daily 6-hrsessions.The criterion foracqui-sition of drug self-administration was a significant differ-encebetween thenumber ofcocaine and saline infusionsself-administered over5consecutive days. Results showedthat rats withthelowest levelofbody weightloss(5-15%)did notacquire cocaine self-administration,and alevelof atleast 15-25%body weight reduction was required for ac-quisition.Together,the findingsfromthe twostudies sug-gestthatit is themagnitudeofbody weight lossdue tofoodrestriction that affects the acquisition of drug-reinforcedbehavior.

A history ofreduced accesstofoodhasalso been shownto facilitate acquisition of intravenous cocaine self-admin-istration in rats using an animal model of binge eating(Specker, Lac, &Carroll, 1994). Hagan andMoss(1991)developed an animal model of binge eating to simulateacondition that wouldbeanalogousto abinge-fast patternthat iscommoninhumanswhohaveaneating disordersuchasbulimia. In thecocainestudy(Speckeret al.,1994), onegroupofyoung female ratswasgivenad libaccess tofoodthroughout the experiment. Another group was food-re-strictedfor3-18 days when they were25, 95, and 143daysold. After each food-restriction period, these rats receivedad lib amounts of food. After the last food-restriction pe-riod, when body weights returned to control levels, theeffects of butorphanol pretreatment on food consumptionwas measured for 4 hr. Butorphanol, an agonist atthekappaopioid receptor, has been shown to increase food intake(Levine & Morley, 1983). Following pretreatment withbutorphanol, rats thathad aprevious historyoffood restric-tion were foundto eatfoodfor alongerperiodoftimeandalso eatsignificantlymorefood atHour4compared withcontrols. Given that food-restriction during early develop-ment produced increased feeding (bingeing)inresponse toa butorphanol injection, the investigators suggestedthat thisprocedure may provide an animal model of binge eating.After several months of ad lib feeding, acquisition of intra-venous cocaine self-administration was assessed in thesetwo groups of rats using the autoshaping paradigm. Acqui-sitionofcocaine self-administration wasfoundtooccurat afaster rate and in a greater percentage of rats with thefood-restriction history (86%) compared with control rats(69%) that werefed adlibitum throughoutthe experiment.These results suggest that a history of dieting may be avariable thatcanenhance vulnerabilitytodrug addictioninhumans.There ishigh comorbidity between drug abuseandeatingdisorders bothindrug-dependent populationsand in


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SPECIAL ISSUE:DRUGSELF-ADMINISTRATION 315those with eating disorders (Bulik et al., 1992), but thiscorrelational datainhumansdoesnotreveal whether dietingincreases vulnerabilitytodrug abuse. Animal studiescan beusedtotestthesepredictions.AlternativeNondrug Reinforcers

Carroll,Lac, and Nygaard (1989) examined theeffectsofconcurrent availability of a palatable glucose and saccharin(G+ S)solutionon ivcocaine-reinforced behaviorinrats.Insome rats,accesstococaine preventedtheacquisitionofG+ Sself-administration, andconversely,inother rats,thepresence of G + Spreventedthe acquisitionofcocaine-reinforced behavior. However, when accessto thesubstancethat initially maintained responding wasterminated lor 5days, acquisition of responding reinforced by the othersubstance rapidly occurred. Therefore, thepresenceof onereinforcing substance blocked the acquisition of the otherreinforcing substance, suggesting that therewas aninterac-tion between the drug and nondrug substances such thattheysubstituted for one another as reinforcers.

Ina more systematic analysis, the effects of alternativenondrug reinforcers (i.e., food, a G + S solution)on theacquisition of intravenouscocaineself-administration wereevaluatedin afollow-upexperiment (Carroll&Lac, 1993).Inthis study, the acquisition process wasquantifiedin fivegroups ofratsusing the autoshaping procedure describedearlier.The differences across groups was in whether or notthe rats had G + S exposure or food available ad libitumbefore and/or during autoshaping. Table 1describes theexperimental design and results. Acquisition of drug self-administration was inversely related to the extentor dura-tion that alternative reinforcers were available.Forexample,whennoalternatives (i.e.,unlimited food or G + S)wereavailable during autoshaping (Groups3 and 4),100%of theanimals acquired, and availability of G + S (Groups 1 and2) or food (Group 5) reduced acquisition of cocaine self-administration to 50, 75, or 82%, respectively.Theseresultssuggestthatacquisitionof drug-reinforced behavior is re-duced or prevented in an environment enrichedwith alter-native reinforcers such as food or other palatable dietarysubstances.

Ratshave been reported to consume large quantities of aG + Ssolution because it ishighly palatable (Valenstein,Cox, &Kakolewski, 1967), and it has been suggested thatexcessive consumption is due to palatability rather thancalories (Smith & Foster, 1980; Smith, Williams, &Jue,

Table1Experimental Design and Results

Homecage AutoshapingGroup (3weeks) (up to 30 days) Food(g) %acquired12345

G + SwaterG + Swaterwater

G + SG + Swaterwaterwater

20202020ad libitum

507510010082Note. G + S glucoseand saccharinsolution.

1976). A subsequent experiment was conducted todeter-mine whetherit was thecaloriccontentorpalatability of theG+ Sthat reduced acquisitionofcocaine self-administra-tion(Carroll& Lac, 1998). Usingthe autoshaping proce-dure, acquisition of intravenous cocaine-reinforced re-spondingwascomparedin sixgroupsofrats.Threegroupsreceivedeither 10g, 20 g, or ad libitum amounts of standardfoodeachday. Another three groups hadaccessto the sameamounts of food; however, powdered saccharin (0.2% wt/wt)wasaddedtoincrease palatability.Becausesaccharinisa noncaloric sweetener, palatability of the food was in-creased, butcaloricvalueremained unchanged. The resultsof the three standard food conditions were described ear-lierasfood availabilityincreased,the rate ofacquisitionand percentage of animals acquiringcocaine self-adminis-tration decreased (Carroll &Lac, 1993). When saccharinwasadded to the food, the rate of acquisition of cocaineself-administration was reduced under all three feeding con-ditions; however, the suppressant effect of saccharin onacquisition was more apparent in the ad lib food group.Only 38% of this group acquired when saccharin was addedto the food, compared with 77% of the standard ad lib foodgroup. Data from these experiments clearly show that theeffectivenessof analternative nondrug reinforcer inreduc-ing or preventing acquisition of drug self-administration canbe enhanced by increasing its quantity, quality (e.g., palat-ability),orboth.

Recently the effects of sequential availability of a sac-charin solution were evaluated in drug-naive rhesus mon-keys acquiring oral PCP self-administration (Campbell,Thompson, &Carroll, 1998).In this study, acquisition ofPCP-reinforced behavior was compared in two groups ofmonkeys that had access to a high dose of PCP (0.15rag/delivery) from two drinking spouts during daily 3-hrsessions. However, during the 17.5-hr intersession period,one group was trainedwithwater, and the other group hadconcurrentaccess to water and a saccharin solution duringthis time. The two groups wereexposed to an acquisitionprocedurethathad beenusedinearlierstudies toestablishPCPdrinkingin monkeys(Carroll, 1982). Initially, duringthedaily3-hr session, water was availablefromboth drink-ingspouts under an FR 1 schedule, and subjects were fed adlibitum. Once responding stabilized, PCP was substitutedforwater. Subsequently, food intake was restricted, and themonkeys were given this limited amount of food before thedaily session. The FR for liquid deliveries was then in-creasedfrom 1 to 2 to 4 to 8. At FR 8, themonkeyswerefedafter thesession,and feeding remained at this time for therest of thestudy.The final step of the procedure waswhensubjects hadaccessto PCP and waterfrom thetwo drinkingspouts under concurrent FR 8 schedules.At this step, thecriterion for acquisition of PCP reinforcement was that PCPintake was consistently greater than water intake. Resultsshowed that 43% of the group with intersession saccharinaccessacquired, whereas86% of thegroupwithintersessionwater availability acquired. Thus, the acquisition of oralPCPself-administrationwasreducedin thegroup thathadaccessto a sequentially available saccharin solution. At theend of the experiment, in the interscssion saccharin group,


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316 CAMPBELLAND CARROLLthe saccharin wasremoved andreplaced with water.PCPintake subsequently increased inall subjects, indicatingasin the ratstudy(Table 1, Group 3) that a history of exposureto saccharin did notblock acquisition of cocaine self-ad-ministration. In the previous intravenous cocaine self-ad-ministration studies in rats, the drug and the alternative wereconcurrently available. Thus, the results from Campbell etal.'s (1998) study extend these earlier findings to rhesusmonkeysand to a condition in which the drug and alterna-tive were temporally separated. Overall, the datafromthesestudies indicate that access to alternativenondrugreinforc-ersduringthefirstexposure todrugsofabusemayreducethe acquisition ofdrug-reinforced behavior.

Consistent with the findings in nonhuman animals, alter-native reinforcers have also been reported to reduce theinitiationofdrug self-administrationinhumans.Forexam-ple, Project Northland initiateda 3-year intervention pro-gram in northeast Minnesota to prevent alcohol use inyoung adolescents (6th-8th graders; Perry et al., 1996).Duringthe 3years, adolescentsin theintervention conditionwere exposed to avariety ofprograms, suchas parentalinvolvement, behavioralandeducational programs, oppor-tunitiesfor peer leadership, andsocialactivities. The initialresultsof theprogram showed thattheintervention districtsreported lower past-monthandpast-week alcoholusecom-pared withthedistrict-matched control groups.Inaddition,theintervention program appearedto bemoreeffectivewithadolescentswho had noprevious experience drinking alco-hol (baseline nonusers) than among adolescents who hadprior drinking experience (baseline users). Thesefindingsclearlydemonstrate thatearly exposure to anenvironmentthat isenriched withavarietyofalternative nondrug rein-forcers can effectively reduce or prevent the initiation ofdruguse inhumans.Stress

Exposure to different kindsof stressors has repeatedlybeen shown to affect the initial acquisition of drug-rein-forced behavior in laboratory animals. There are manydifferent typesof stress that can be categorized into physicalstress and social stress. Generally, most forms of stressincrease theacquisition andmaintenance of drug self-ad-ministration; however, some negativefindingsalso pervadethe literature. It is not always clear whether the negativefindings are due to the type of stress used, history andcurrenthandlingof theanimals,orotherspecificlaboratoryconditions. Rats have been subjected to various forms ofphysical stress, such as repeated tail pinch (Piazza, Dcmi-niere, LeMoal,& Simon, 1990) and noncontingent electricfootshock(Goeders&Guerin,1994), and inmostcasestheyacquire psychostimulant self-administration more rapidlythannonstressed control rats. Similarly, brief exposure torestraintstressincreases the acquisition of oralfentanyl-andmorphine-reinforced behavior in rats (Shaham, Alvares,Nespor,& Grunberg, 1992).

Food restriction,whichhas already been discussed andhasbeen shown to enhance acquisition of drug self-admin-istration, is thoughtto be another formof physical stress

(Piazza, Deroche, Rouge-Pont, & Le Moal, 1998). Thishypothesis was tested in a preliminary studyconducted todetermine whether the accelerated acquisition of heroinself-administrationthat occurs during foodrestrictioncouldbe blockedbyketoconazole,which inhibitscorticosteronesynthesis.Initialresults withtwogroupsofrats (maleandfemale)indicated that female rats self-administer more her-oin infusions during the acquisition phase, food-restrictionincreasesinfusions bynearly 100%,andketoconazole sup-pressed this increase in female but not in male rats (seeFigure2).Current studiesarebeing conductedtodeterminewhethercortisol injections willreversethe effect ofketo-conazole. These data and other evidence (Piazza et al.,1998) supportthehypothesis thatfoodrestriction functionslikeother physical stressors.

Acquisition of drug-reinforced behavior is also acceler-ated following exposure tovarious forms of social stress,such as aggressive attack or threat (Haney, Maccari, LeMoal, Simon,&Piazza,1995; Miczek& Mutschler, 1996;Tidey&Miczek, 1997), isolated (Bozarth, Murray,&Wise,1987;Schenk,Lacelle, Gorman,&Amit, 1987;Weinhold,Sharpe, &Jaffe, 1993)orstablesocialhousing conditions(Maccariet al., 1991),anovel environment (Piazza,Demi-niere, Maccari, et al., 1990), and the emotional stress ofbeingexposed toanotherratreceiving footshock (Ramsey&vanRee, 1993).Therearealsoequivocal data regarding

Females

= 300

a 200

Euiin

Males

Food SatiatedFood Restricted

V K V V K V

Pretreatment - Ketoconazole K) or Vehicle V)Figure2. Mean(SEM) heroininfusionsarepresentedfor6-dayblocksformaleandfemalerats during successiveperiodswhenthey were pretreated with ketoconazole (25 mg/kg) or vehiclebefore the heroin (0.015 mg/kg) self-administration session.Hatchedbarsreferto thefood-satiationcondition,whenunlimitedfood was available, and solid bars refer to the food-restrictedcondition, when 16 g(male)or 12 g (female) of food was avail-able.Eachbarrepresentsa mean of 6(male)or 7(female)rats.


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SPECIAL ISSUE:DRUGSELF-ADMINISTRATION 317the effects of social isolation on the acquisition of drugself-administration. For example, in one study, rats thatwerehoused alone weremorelikely to self-administer co-caine than those housed in groups (Schenk et al., 1987).However, in another study no differences were reported(Boyle,Gill,Smith,&Amit, 1990).Social stress, sex,orother factorsmay alsointeract.Forexample,ZimmerbergandBrett(1992)gave rats a choice between stimulant anddepressant drugs. When socially isolated, female rats pre-ferredthe depressantdrug,whereas male rats preferred thestimulantdrug. Finally, prenatal stress (rat dam subjected to45-minof immobilization for 7 days during the last week ofpregnancy) has been shown to enhance the acquisition ofintravenous amphetamine self-administration in adultoffspring.

The results fromthesestudiesillustratethatexposure tostressors canincrease vulnerabilitytoinitiate drug-reinforcedbehavior. The stress-induced enhancement of acquisition isthoughtto be due to a behavioral sensitizationprocessinvolv-ingactivation of the hypothalamo-pituitary-adrenalaxis andthemesocorticolimbicdopaminergic system (for reviews,seePiazza& Le Moal, 1996, 1998; Piazza et al., 1996).

PharmacologicalVariablesDrugDose

The initialdoseof drug available to drug-naive animalshasbeen showntoplayanimportant rolein theacquisition

From Schenk et al. 993

Cocaine Dose mg/kg)0.1250.250.5

ofdrug-reinforced behavior. When Schenk, Valadez, Mc-Namara, et al. (1993) applied their confidence interval cri-teria to three groups of rats exposed to three doses ofcocaine(0.125,0.25,and 0.5mg/kg),theyfoundthat60-80% of each group acquired self-administration, but thelatencyto acquire cocaine self-administration was inverselyrelated to dose.Carrolland Lac(1997)evaluated the effectsof drug dose on the acquisition of iv amphetamine andcocaine self-administration in rats using the autoshapingprocedure. Three unit doses of amphetamine (0.03,006and 0.12 mg/kg) andcocaine (0.05,02and 0.8 mg/kg)were studied in six separate groups of rats. Rate of acqui-sitionandpercentageofanimals acquiring drug self-admin-istrationwere compared using standardized criteria (aspec-ified mean number of infusions over 5 days). Resultsshowedthatas thedoseof eachdrugincreased,agreaterpercentageof rats per group acquired drug-taking behavior,andthe mean number of days to meet the acquisition crite-rion decreased. Figure 3 compares the Schenk, Valadez,McNamara, et al. (1993) and Carroll and Lac(1997)datausingthe twodifferentprocedures.Overall,the acquisitionof drug-reinforced behavior was reduced at lower drugdoses,and forsome rats these doses weretoo low tosupporttheacquisition ofdrug self-administration. Itappears thatthethresholddosefor acquisition of cocaine self-adminis-trationis between 0.05 and 0.125 mg/kg.

Inanearlierstudy,vanRee, Slangen,and deWied(1978)quantitativelyassessedtheeffects ofincreasingthedoseof

From Carroll and Lac 997Cocaine Dose mg/kg)

0.050.20.8

1 0KXXXX>CKXXXX>C>C>OO

15 0 5 10 15DaysFigure 3. Data are adapted from twostudiesofacquisitionof ivcocaineself-administration inwhich unit dose wasvaried (Schenk etal.,1993;and Carroll &Lac, 1997,respectively). Thepercentageof thegroupsmeetingtheacquisitioncriterion ispresentedfor the first 15daysof theacquisition test. Opencirclesrefer to the lowestdose,solidcirclesindicate themiddledose, andsolid triangles represent thehighestdose.


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318 CAMPBELLAND CARROLLseveral drugs(e.g.,heroin, amphetamine)on theacquisitionofivdrugself-administration. Inthisstudy,ratsrespondedundera continuous reinforcement schedule, and the acqui-sition criterionwas aminimumof 60druginfusionsperday.Similar to thefindingsof Carroll and Lac(1997),increasingthedoseofheroin (from 0.082to0.188 to 0.375 mg/kg)produced a dose-dependent increase in the percentage ofanimals acquiring heroin self-administration (50%, 100%,and 100%, respectively). Conversely, when a range of am-phetaminedoses were tested (0.105, 0.24, 0.54, and 1.2mg/kg),doses higher than those used in the Carroll and Lac(1997)study,aninverted U-shapedfunctionfor thepercent-age of animals acquiring amphetamine self-administration(17%, 100%,57%,and 0%,respectively)wasfound.Thus,high unit doses may have a direct suppressant effect onlocomotor activityor anaversiveeffectthat interfereswithacquisition ofdrug self-administration. Theymayalsohavea satiating effect such that the high priming doses of thedrug during autoshaping interferes with acquisitionduringthe self-administration component. Janak, Rodriguez, andMartinez (1997)reportedadose-dependent impairment ofautoshaped food-maintained responding when rats werepretreated with intraperitoneal cocaine at doses (5.6-19mg/kg) much higher than those used in the acquisitionstudiesdescribedhere.

In a recent study, theeffects of drugdoseon the acqui-sitionoforalPCPself-administration were evaluatedin twogroups of drug-naive rhesus monkeys (Campbell et al.,1998).Onegrouphadaccessto a lowdoseof PCP(0.0375mg/delivery), and the other group had access to a high doseofPCP(0.15mg/delivery)fromtwo drinking spouts duringdaily 3-hr sessions. In order to establish PCP as a reinforcer,the two groupswentthrough an acquisition procedure thatwasdescribed previously. Results showed that PCP con-sumption was significantly greater than water consumptiononly in the group of monkeys that had access to the highdose of PCP. Furthermore, ananalysisof theindividualdatashowed that6 of 7 monkeys (86%) in thehighdose groupmet the acquisition criterion, whereas only 3 of 7 (43%)monkeys in the low dose group met the criterion. Thus,these findings indicated that acquisitionof oral PCP self-administration was reduced when subjects were initiallygiven access to low doses of PCP. At the end of theexperiment, the 4 monkeys in the low dose groupthatdidnotacquire wentthrough the acquisition procedure again;however, this timewith thehigh doseofPCP. Thistime,allbut one animal met the acquisition criterion. Overall, thedatafromthesestudies clearly showthat theacquisitionofdrug self-administrationis adose-dependent phenomenon,andtheinitialdose of drug available to naive animals is animportant determinant in whether the acquisition ofdrug-reinforced behaviorwill occur.

Drug HistoryPriorexposure to thesameor adifferent drug than that

whichisself-administeredhasbeen showntoacceleratetheacquisitionofself-administrationofthat same drug, suchasa psychomotor stimulant in laboratory animals. This has

been reported for rats self-administering amphetamine(Piazza, Deminiere, Le Moal, & Simon, 1990; Schenk& Davidson, 1998), caffeine (Carroll & Lac, 1998; Hor-ger, Wellman, Morien, Davies, &Schenk, 1991), cocaine(Horger, Shelton, & Schenk, 1990), methamphetamine(Woolverton, Cervo, & Johanson, 1984), and nicotine(Shoaib, Schindler, &Goldberg, 1997). However, Schenk,Snow, and Horger(1991) found that nicotine did not sen-sitizerats to cocaine self-administration. In most of thesestudies,theanimals were pretreatedwiththedrugfor7-12daysbefore testingfor acquisition ofdrug self-administra-tion1 dayaftertreatment.In onestudy, ValadezandSchenk(1994) pretreated rats with amphetamine or saline for 9 daysand assessed acquisition of amphetamine self-administra-tion 45 days after the pretreatment period. They foundenhanced acquisition of amphetamine self-administration(reduced latency)in therats pretreated with amphetamine(3days)compared withtherats pretreated with saline. Similarfindings were reported for caffeine (Schenk &Davidson,1998).Thus, preexposure to adrugmayhave long-lastingeffects on the subsequent acquisition of drug-reinforcedbehavior.

Aclinical implication of this important laboratory findingmaybefound inchildren exposed toRitalin (methylpheni-date) early in life for the treatment of attention deficit-hyperactivity disorder (ADHD). Retrospective human dataindicate that a high percentage of adults seeking treatmentfor cocainedependence have a previous ADHD diagnosis(Cocores, Davies, Mueller, &Gold, 1987; Rounsavillcetal., 1991). In a recent study, two groups of students whowerediagnosed withADHDandeither treatedor nottreatedwith methylphenidate, and a third group of age-matchedclassmates, were questioned 15-20 years later regardingtheir drug use. The medicated ADHD participantsshowedthe highest percentage of cocaine abuse (Schenk & David-son, 1998).

The enhancement of acquisition of drug self-administra-tionfollowing prior exposure to psychomotor stimulants hasbeen suggested to be due to a sensitization process thatinvolves activation of the mesocorticolimbic dopaminergicsystem(Kalivas,Sorg, & Hooks, 1993;Kalivas& Stewart,1991; Sorg & Kalivas, 1991). Cross-sensitization betweenpsychomotor stimulants has also been demonstrated. Forexample, pretreatment with amphetamine (Horger, Giles, &Schenk, 1992), caffeine (Carroll & Lac, 1997; Horger,Wellman, Morien, Davies, & Schenk, 1991) and nicotine(Horger etal., 1992) accelerates the acquisition of iv co-caineself-administration inrats. Furthermore, pretreatmentwith caffeine enhances the acquisition of nicotine-rein-forced behaviorinrats (Shoaib, Swanner,Yasar,&Gold-berg, 1999). Similar findings have also been reported innonhuman primates. For instance, Wojnicki and Glowa(1996) assessed theacquisitionof iv GBR 12909(along-actingselectivedopamincreuptake inhibitor)self-adminis-tration in drug-naive and cocaine-experienced rhesus mon-keys. They found that only the cocaine-experienced mon-keysacquired low-doseGBR12909-reinforced behavior.

Inaddition to pretrealment with a drug prior to testing foracquisition of drug self-administration, prenatal exposure


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SPECIALISSUE:DRUG SELF-ADMINISTRATION 319hasalso beenshown toaffectthe initial acquisition of drugself-administration. Ramsey, Niesink,and van Ree (1993)showed that prenatal exposure to morphine from the 7th dayof gestation until parturition accelerated the acquisition ofcocaineandheroin self-administration inadultrats. Perina-talA9-tetrahydrocannabinol (A9-THC)exposure during ges-tationandlactationenhances morphine self-administration(Vela etal.,1998).Together,thesefindingsindicate that ananimal'sdrug historycanmodify thereinforcingeffects ofdrugs and increase susceptibility to acquire drug-reinforcedbehavior.

DrugPretreatmentofAcquisitionofDrugSelf-Administration

Recently,theeffectsof pretreatmentdrugsthatmayhavea preventive effect on the acquisition of drug-reinforcedbehavior have been examined. For example, Campbell andCarroll (1999b) evaluated the effects of ketoconazole, aninhibitor of corticosteronesynthesis, on the acquisition ofintravenouscocaineself-administration during food restric-tion. It was hypothesized that food restrictionis aformofstress (Broocks, Schweiger, &Pirke, 1990; Marinelli, LeMoal, Piazza, 1996) that increases glucocorticoids andthatblockadeof thisprocesswould suppress increasesindrug self-administration. Inthisstudy,acquisitionwasstud-ied in two groups of rats using the autoshaping method. Onegroup waspretreatedwith ketoconazole (25mg/kgip) be-fore the autoshaping and self-administration components,and theothergroup was pretreated with vehicle (intraperi-toneally). Results showed that 100% of the rats in thevehicle-pretreatedgroup acquired, whereasonly78% ofratsinthe ketoconazole-pretreatedgroup acquired. Inaddition,thevehicle-pretreatedgroupacquired in ameanof 7.2days,whereas the ketoconazole-pretreated group acquired in amean of18.1days. In this same study, ketoconazole had noeffect on theacquisitionof cocaine-reinforced behavior infood-satiated rats or on the acquisition of food-reinforcedbehavior. Thus,ketoconazoleselectively reduced theacqui-sition of intravenous cocaine self-administration duringfood restriction without producing a general suppressanteffect on motor activity. These results concur with thosediscussed earlier (Figure2) showing that ketoconazole sup-pressed heroin self-administration during food restrictionbut notduring food satiation. However, with heroin, thiseffect appeared infemalebut notmalerats.

In another autoshaping study,theeffects ofbaclofen, aGABAB agonist, on the acquisition of iv cocaine self-administration were examined in two groups of rats (Camp-bell & Carroll, 2000a). One group of rats was pretreatedwith baclofen (2.5 mg/kg ip), and the other group waspretreated with saline (intraperitoneally). In the saline-treated group, 100%of therats acquiredin ameanof12.7days. However, only 78% of the baclofen-treated groupacquired, in a mean of 19.2 days. Thus, the acquisition ofcocaine self-administration was reduced following admin-istrationofbaclofen. Thiswas thesameas thepercentageofketoconazole-pretreated rats(Campbell&Carroll, 2000b),or seven out ofninerats.Another recent studyreported that

baclofen decreasedboth maintenance and reinstatement ofintravenous cocaine-reinforced responding in rats (Camp-bell, Lac, &Carroll,1999).Therefore, the resultsfromthisexperiment extend previous findings of the suppressant ef-fects of baclofen to the acquisition ofcocaineself-admin-istrationandindicate that baclofen mayhaveapreventiveeffect onacquisitionofcocaine self-administration. Otherstudieshave shown that baclofen suppresses maintenancelevels ofcocaineself-administration in ratsbut not food-maintained responding (Roberts& Andrews,1997;Roberts,Andrews,& Vickers, 1996; Shoaib,Swanner,Beyer, Gold-berg, & Schindler, 1998). A recent report indicates thatbaclofen coadministered with iv heroin or intracerebrallyinto the ventral tegmental area reduces theacquisitionofintravenous heroin self-administration inrats (Xi &Stein,1999).

Drugs acting at receptor sites other than dopamine orGABA can also interfere with the acquisition of cocaineself-administration.For example, Schenk, Valadez, Worley,andMcNamara (1993) showed that pretreatment with MK-801, a noncompetitive W-methyl-D-aspartate (NMDA) re-ceptor antagonist, reduced the acquisition of iv cocaine-reinforced behavior, indicating that the NMDA receptormay play arole in the initial acquisition ofcocaine self-administration.It ispossiblethat injectionswith drugssuchas those mentioned in this section could serve as primingstimuli and potentially increase rather than decrease drugself-administration; however, this is unlikely for severalreasons:(a)manyof thetreatment drugsdo notfunction asreinforcers foranimals; (b)they areusuallynotgivenviatheintravenous routeas are theautoshapinginfusions;and(c) pretreatments usually occur 30minbeforeaccessto drugself-administration, a delay that may be too long for theinjection toserveas aprimingstimulus.

Individual DifferencesReactivity Level

Piazza, Deminiere, Le Moal, and Simon (1989, 1990)suggested that individual differencesinactivity level fol-lowing exposure to a novel environment can predict vulner-abilityto acquire drug self-administration. In these studies,theyfoundthatratswithhigher locomotor responses (HRs)to novelty (an open field) acquired intravenous amphet-amine self-administration at faster rates than rats with lowerlocomotor responses (LRs).In another study, Poulos, Le,and Parker (1995) used a delay-of-reward procedure toassessimpulsivityandevaluated therelationship betweenimpulsecontrolandsubsequentoral alcohol-reinforced be-havior. Although the acquisition process was notquantified,they showed that rats with high impulsivity scoressubse-quentlyconsumed morealcoholthan ratswith low scores.Thus, consistent withthe findings ofPiazzaet al.(1989)andPiazza,Deminiere, LeMoal,and Simon (1990), vulnerabil-ity to develop or initiate drug-reinforced behavior in ratswaspredicted by individual differences.

Recently, Alessi, Greenwald, and Johanson (1999) re-ported that humans also display different activity levels


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320 CAMPBELL AND CARROLLwhen exposed to a novel environment and can also beclassified as HRs andLRs.Inaddition, similarto theresultsobtained innonhumananimal studies (Piazzaetal., 1989),the HRs show greater increases in activity than the LRsfollowingadministrationofamphetamine.Theseinvestiga-torsarecurrentlyevaluating whether thereis arelationshipbetween activitylevelandsubjectiveorreinforcing effectsofamphetamine. Ifthese findings concur with the animalstudies, theresultsofthis studymayhave important impli-cations regardingtheidentificationofindividuals thatare athigh risk for developing drug-taking behavior.

Age DifferencesStudies in humans have shown that the percentage of

individuals consuming alcohol decreases as a function ofage and indicated that the decrease in alcohol use is acharacteristicofnormal aging (Adams, Garry, Rhyne, Hunt,&Goodwin, 1990).Fewstudiesinanimals have systemat-ically evaluated age effects on the acquisition of drug-reinforced behavior. In onestudy, Juarez, Guzman-Flores,Ervin, and Palmour (1993) compared voluntary alcoholintakeinsexually mature adult(5yearsold ormore)andjuvenile (7-36 months old) maleandfemale vervet mon-keys. Theyfoundthat on the first fewdaysofaccessto asweetened alcohol solution,thejuveniles initiated drinkingsooner thantheadults.Inaddition,thejuvenilesdrankmorefrequently throughout thestudy compared withtheadults.Consistent with these results, younger (juveniles and ado-lescents) vervet monkeys have been showntodrink greateramountsofsweetened alcohol than older (sexually matureadults)monkeys(Ervin,Palmour, Young, Guzman-Flores,&luarez, 1990).However, further workisneeded inthisarea to quantitatively evaluate age effects onacquisition.These kinds of studies may help identify the age groupsmostatriskforinitiating drug use, and,inturn,preventionprograms can specifically target these individuals.

Sex DifferencesNumerousanimal studies havereportedthat maintenance

levels of drug intake differ between males and femaleanimals; across arange of drug classes, female animalsappear toself-administer more drug than their male coun-terparts. However, only a few studies haveevaluatedgendereffects on the acquisitionofdrug self-administration. In arecent study, LynchandCarroll(1999) compared ratesofacquisition of intravenous cocaineandheroin-reinforcedbehavior in drug-naive male and female rats using theautoshapingmethod.Therats were trainedtoself-adminis-ter low doses of cocaine (0.2 mg/kg) or heroin (0.015mg/kg)under food-satiated conditions.Theseexperimentalconditions have been previously shownto produce slowratesof acquisition and were thus optimal for detecting anydifferences between maleandfemale rats. Results showedthat the female rats acquired both cocaine- and heroin-reinforcedbehaviorfaster thanthemale rats.In addition, agreater percentage of the female rats acquired comparedwith the male rats. Similar to these results, Juarez et al.

(1993) reported that both the juvenile and adult femalevervet monkeysdrankmore alcoholduringinitial exposurecompared with the juvenile and adult male monkeys. Otherstudies, however, havereportednodifferencesinacquisi-tion ofdrug self-administration between malesandfemaleanimals.Forexample, Haneyet al.(1995) compared acqui-sitionofhigh-dose intravenouscocaine(0.32 mg/kg)self-administration in male and female ratsby looking at thenumber ofinfusionsself-administered duringthe first 5daysofexposure to cocaine. Theyfoundthat bothsexesacquiredrapidly, and nodifferencesinratewere apparent betweenthe sexes. Consistent with these findings, Stewart, Wood-side,andShaham(1996)showed that maleandfemaleratsdid notdiffer in theacquisition of intravenous heroin self-administration. Inthis study, acquisitionwastested usingfourdosesofheroin that werepresentedinascending fash-ion. Subjects had access to each dose for 3 days (foursessionsperday) underan FR 1schedule. Similarto theHaneyet al.(1995)study,acquisitionofheroin self-admin-istrationwasquantifiedbymeasuring themean numberofinfusions self-administeredat each dose. Taken together,theresultsfrom thegender studiesindicatethat differencesbetween maleandfemale ratsmayonlybeapparent underconditions threshold ofdrug self-administration (i.e., lowdoses,nonrestrictedfeeding conditions).

Further studies areneeded in this area to identify themechanisms responsibleforthesesexdifferences.It ispos-sible that thisis anexampleofenhanced learningabilitythathas been demonstrated in female versus male rats (e.g.,Korol & Manning, inpress; Shors, Lewczyk, Pacynski,Matthew,&Picket, 1998).Thedifferencesmay be due tocirculating levels of hormones. For example, Roberts, Ben-nett, and Vickers (1989) reported that in female rats re-sponding for intravenous cocaine under progressive ratioschedules,higherbreak points were maintained duringes-trus(when estrogen is rapidly declining) than during theother stagesof thecycle, suggesting thatthemotivationtoself-administercocainemay be influenced byovarian hor-mones. Also, KorolandManning(inpress) reported varia-tions inY-maze alternation as a function of phase of theestrous cycle. However, although ovarian hormones arethoughtto play a major role, it is notclearto what extentotherfactorsmayinfluencethedifferencesobserved.On thebasis ofthesefindings,prevention methodsmay differ formaleandfemale rats.

Dietary PreferencesNumerous animal studies have reported a relationship

between individual dietary or taste preferences anddrugself-administration, and these findings suggest that thesepreferences can predict vulnerability to drug abuse.Forexample, Gosnell and Krahn (1992) gave drug-naive ratsaccessto a saccharin solution(0.1% wt/vol) during daily1-hr sessions,and on thebasisoftheir intake overa3-dayperiod,they dividedtherats into three groups representinglow, intermediate, and high saccharin drinkers. Subse-quently,therats were given accesstoethanol(2-8 )underfood-restrictedand-satiated conditions.Therewerenodif-


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SPECIALISSUE:DRUGSELF-ADMINISTRATION 321ferencesamongthegroups under food-restricted conditions;however, the intermediate and high saccharin drinkersdrank moreethanol thanthe lowdrinkersunder food-sati-atedconditions. Thus,theamountofalcoholintake follow-ing initialexposure is greater in rats with high preferencesforsaccharin than in rats with a low preference for saccha-rin. Note that the drug and saccharin are not givensimul-taneously; rats are first screened for their preference forsweet tastes,andtheyarelatertestedforacquisitionofdrugself-administration. Thesefindingssuggest that higher lev-els ofexploratory behavior with regardto newtastes, justlike higherlevelsoflocomotor exploratory behavior (Piazzaet al., 1989), are related to greater vulnerability to drugabuse.

Others havereplicatedthese resultsingenetically heter-ogeneous and inbred rats strains(Overstreetet al., 1993).Bell, Gosnell,Krahn, and Meisch (1994) extended thesefindings to rats responding on alever for orally deliveredethanol inoperantchambers. In this study, both FR valueand ethanol concentration were varied, and theyfoundthatundermost conditions, behavior maintained by ethanol washigher in the high saccharin drinkers than in the low sac-charin drinkers. Consistent with these results, Gahtan,LaBounty, Wyvell,&Carroll (1996) also reported a posi-tive relationship between saccharin consumptionandetha-nolconsumption.Inaddition, ratswithhigh preferences forsaccharin have been showntoself-administer moreintrave-nous morphine than rats with low preferences (Gosnell,Lane,Bell, & Krahn, 1995). In contrast, other studieshaveshown no difference inrateof acquisition of intravenouscocaine self-administration (Gahtanetal.,1996)orcocaineintake following initial exposure (Gosnell, Krahn, Yracheta,&Harasha,1998) between highand lowsaccharindrinkers.Thus,apreferenceforsaccharindoesnotappeartopredictvulnerabilityto initiate intravenous cocaine self-administra-tionas reliably as it does ethanol or opioid self-administra-tion. Preferences for other dietary substances such as fatshave also been reported to be positively correlated withalcohol (Krahn&Gosnell, 1991)andmorphine(Kanarek,Mathes,& Przypek, 1996) preference. Thus, preferreddi-etary substances, like drugsof abuse,function asreinforc-ers. These drugandnondrug substancesmayshareacom-mon reward mechanism and substitute for one another asreinforcers.The significanceof theresultsfrom these stud-ies is that vulnerability to initiate or develop drug self-administration may bepredictedbypreferences for palat-able dietary substances.

Genetic DifferencesGeneticdifferences in the acquisition of drug self-admin-

istration have been studiedinratsandmiceselectively bredfor high and low intakes of ethanol,opioids, and psycho-stimulants. For instance, rats selected for high ethanol pref-erences consume greater amountsof saccharin than thoseselected for low ethanol preferences (Sinclair, Kampov-Polevoy,Stewart, & Li, 1992;Kampov-Polevoy, Kasheff-skaya, & Sinclair, 1990). Recently, Dess, Badia-Elder,Thiele,Kiefer, andBlizard (1998)reported that rats selec-

tivelybred for high and low saccharin preferences showedhigh and low ethanol preferences, respectively. Further-more, Nichols andHsiao (1967) found that rats bred forhigh and low morphine preferences consumed high and lowamounts of alcohol, respectively. Hyytia and Sinclair (1993)compared oral etonitazene andcocaine self-administrationin drug-naive alcohol-preferring (AA), alcohol-avoiding(ANA), and Wistar rats using a two-bottle choice test.Hyytia and Sinclair showed that intake ofetonitazene, apotent agonistat the muopioid receptor,andcocaine wasgreater in the AA rats than in the other two groups. How-ever,AA rats have previously been shown to have greaterpreferences for salt and citricacidsolutions than other ratstrains (Sinclairetal., 1992). Therefore, inordertodeter-mine whethertheincreased intakeof the AAratswas due tothe sensitivityof the strains to bitter taste a quinine prefer-ence testwasconducted.The AArats also consumed morequinine; however, this difference was only significantathigh concentrations of quinine, and the investigators con-cluded that the differential intakes were not due to tastefactors.In asubsequentstudy, Hyytia,Schulteis,andKoob(1996) showed thatAA rats acquired intravenous heroinself-administration more rapidly than ANArats,indicatingthat there is a genetic correlation between ethanol andopioid consumption in this rat line.Alsoin this study, whenintravenousethanolwassubstitutedforheroin,the AAratsself-administered more ethanol than the ANArats, furthersuggesting thatthedifference inalcohol intake inthisratline doesnotdepend solelyontaste factors.

DiscussionProspective studiesof theacquisitionofdrug self-admin-

istration are ethically impossible to conduct in humans.Animalstudies are essential for this type of work, and theyusuallyinvolve between-groups designs requiring drug-na-ive subjects for each experimental condition. This strategyis generally too expensive to use in nonhuman primates;thus, most of the acquisition research has been conductedwithrats. Several models of acquisition of drug self-admin-istration have beenusedin rats, rangingfromunstructuredmethods ofallowing theanimaltocome into contact withtheresponse-drug contingencies tomore structured meth-ods that use experimenter-induced priming injections orautoshaping to more uniformly introduce the drug to allsubjects,thus reducing the intersubject variability. Findingsfrom different laboratories are often in agreement whendifferent methods of measuring acquisition of drug self-administration have been used. Successful acquisition isoften measured by the percentage of animals in a groupmeeting a predetermined acquisition criterion, the amountoftime required to meetsucha criterion, or both. The majoradvantage of having ananimalmodel tostudythe acquisi-tion of drug self-administration anddragdependence is thatfactors can beidentified that may explain vulnerability todrug abuseinsome organismsandinvulnerabilityorresil-ience in others. The information is useful in predictingcharacteristics of humans who may be at risk and in design-ing strategiesfor thepreventionofdrug abuse.


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322 CAMPBELLAND CARROLLThis articlediscusseshow theanimalmodelshave been

used to identify environmental and pharmacological vari-ables as well as innate individual differences thatpredicttheanimals' readinesstoacquire drug self-administration. Fac-torsin theenvironment thatareparticularly salientare (a)thepresenceorabsenceofstressand (b) theavailabilityofalternative nondrug rewards, suchasfoodorotherpalatablesubstances. Stress increases the acquisition of drug self-administration, and the absence or removal of nondrugalternative reinforcers accelerates theacquisition of drugself-administration.It is notsurprising that drug abusein theanimallaboratoryismore likelyto beacquired whenstressis high and there is an impoverished environment thatcontains few alternative activities. In contrast, a dose-response relationship seems toexist between adding pre-ferred substances, activities, or both to an impoverishedsetting and thedegreeto which acquisition of drug abuse isdelayedor prevented.

Aspects of the drug itself arealsoimportant to the acqui-sition of drug self-administration. For example, drug historysuchaspreexposure topsychomotor stimulantsor opioidsincreases the subsequent rate of acquisition of amphet-amine, cocaine, and heroin self-administration. Thus, thegateway phenomena regarding human drug abusers canclearly bemodeled inlaboratory animals.This lends sup-port to the hypothesis that it is the drug experience and notonly sociocultural factors that facilitate subsequent poly-drug abuse. The initial drugdoseis also an important factor.The rate and percentage of subjects acquiring drug self-administration increases with dose. This suggeststhat lim-itingaccesstocigarettes, alcohol, andother drugsinado-lescents may have a beneficialeffect. Acquisition of drugself-administration is also reduced or prevented in somesubjects bypretreating them withmedications thatreduceongoing drug self-administration in experienced animals. Inthisreview,drugs suchasketoconazole, which blocks cor-ticosterone synthesis (stress response), or baclofen, aGABAB agonist that may inhibitdopamine-mediated ef-fects, were discussed aseffective agents to prevent acqui-sition of drug self-administration in drug-naive animals.The use of medications to prevent drug abuse in humansmay not be realistic except for those who are especiallyvulnerable to drug abuse or in those who have justrecentlyinitiated drug use.

Finally, the animal studies that we have reviewed areespecially useful for identifying innate individual differ-ences that predict vulnerability or resilience to drug abuse.Ratsthat are selected for certain types of excessive behav-ior, such as high levels of motor activity or ingestion ofsweet or fat-containing foods, are more likely to acquiredrug self-administration than others; the same is true forfemaleversus male rats, and young versus old rats.Selec-tive breedingfordrugintakeandother factorssuchassweetpreference also produces animals that are predisposed toacquire drug self-administration more rapidly than others,supporting the importance of the genetic contribution todrug abuse vulnerability. These studies will enable re-searchers to identify behaviors that maybeearly signs ofdrug abuse so that preventionefforts can be focused on the

relevant populations. These initial findings with animalssuggesta number of key variables that should be taken intoaccount in the developmentofstrategies toreduceor pre-vent the initiation of drug abuse in humans.

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ReceivedAugust 1 1999Revisionreceived December 14, 1999

AcceptedJanuary13,2000

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