Abstract Drugs, like other reinforcers, can vary in theirrelative abilities to support operant responding. Consid-erable research has been designed to obtain useful mea-sures of a given drug’s or dose’s “reinforcing efficacy”and to identify the ways in which a variety of behavioraland pharmacological variables impact these measures.Progressive-ratio schedules of drug delivery generate anindex of a drug’s or dose’s reinforcing efficacy (thebreaking point) and are being used increasingly as toolsin the analysis of drug self-administration. Progressive-ratio schedules of drug delivery have been used to char-acterize the effects of pretreatment drugs, lesions, drugdeprivation, physical dependence, and repeated non-con-tingent drug exposure on breaking points. Behavioralfactors, including food restriction and electric shock, andorganismic factors, including gender and strain, havealso been investigated using progressive-ratio schedulesof drug delivery. To the extent that breaking points pro-vide an index of reinforcing efficacy, these studies dem-onstrate that a wide range of variables can influence thereinforcing efficacy of self-administered drugs. The ob-jectives of this review are to critique existing researchthemes, outline potential limitations of progressive-ratioprocedures, and to suggest potentially fruitful uses ofthese procedures in future research.

Key words Progressive ratio · Drug self-administration ·Reinforcement · Reinforcing efficacy · Craving ·Behavioral economics · Cocaine · Opiates · Humans ·Non-humans

Introduction

The response-contingent delivery of many drugs canfunction as a reinforcing event under many circumstanc-es. Rats, monkeys, cats, dogs, and other species will self-

administer many of the drugs that are known to be abusedby humans (Deneau et al. 1969; Schuster and Thompson1969; Collins et al. 1984; Johanson and Fischman 1989).Perhaps because of this correspondence, self-administra-tion of drugs by laboratory subjects has become a fre-quently used research tool among investigators interestedin understanding the factors controlling drug abuse in hu-man populations. Some of the questions often asked bythese investigators include (a) does drug A or dose Afunction as a reinforcer in a given context?, (b) isdrug/dose A more or less reinforcing than drug/dose B?,and (c) can the reinforcing effects of drug/dose A be al-tered by a particular treatment?

These questions, especially (b) and (c), are concernedwith assessing the reinforcing “effectiveness” or “effica-cy” of self-administered drugs. The term “reinforcing ef-ficacy” implies that drugs or doses may differ in the ex-tent to which they can establish or maintain drug self ad-ministration and thus can be ranked on an ordinal scale(Katz 1990). We conceive of reinforcing efficacy as amalleable aspect of a dose/drug that is determined by in-teractions between the dose/drug’s pharmacological ef-fects, the prevailing environmental circumstances, theconcurrent presence or absence of other drugs, and theorganism’s behavioral and pharmacological history, rath-er than as a fixed physical property inherent in eachdose/drug. Following sections will provide data that sup-port this conception. Further, we agree with Arnold andRoberts’ (1997) contention that a definitive index of adose/drug’s reinforcing efficacy is unlikely to be ob-tained using a single procedure; instead, data generatedfrom several procedures may be useful in characterizinga dose/drug’s relative reinforcing efficacy. For example,if (a) subjects reliably choose drug A/dose A over drugB/dose B (e.g. Johanson 1976), (b) subjects learn a newdrug-producing response more rapidly or completelywith drug A/dose A (e.g. Carroll and Lac 1997), (c) it ismore difficult or time-consuming to extinguish or inter-fere with behavior maintained by drug A/dose A (e.g.Grove and Schuster 1974; Johanson 1977; Beardsley andBalster 1993), and/or (d) subjects regularly complete rel-

D. Stafford · M.G. LeSage · J.R. Glowa (✉)Pharmacology Department, Louisiana State University MedicalCenter at Shreveport, 1501 Kings Highway,Shreveport, LA 71130-3932, USA

Psychopharmacology (1998) 139:169–184 © Springer-Verlag 1998

R E V I E W

David Stafford · Mark G. LeSage · John R. Glowa

Progressive-ratio schedules of drug delivery in the analysisof drug self-administration: a review

Received: 3 May 1997 / Final version: 19 March 1998

atively large response requirements when drug A/dose Ais available but not when drug B/dose B is available (e.g.Yanagita 1973), one could reasonably conclude that drugA/dose A functioned as a more efficacious reinforcerthan drug B/dose B.

It is important to stress that reinforcing efficacy andpharmacological efficacy are distinctly different con-cepts. The former refers specifically to the relative abili-ty of a given drug to establish and/or maintain patternsof self-administration; the latter refers to the degree ofreceptor stimulation produced by a given degree of re-ceptor occupancy following administration of a drug.One should not assume that drugs that are highly effica-cious at a particular receptor will be highly efficaciousreinforcers. There is some indication, however, that thepotency of a psychostimulant drug as a reinforcer is cor-related with its potency in binding to the dopamine trans-porter (Ritz et al. 1987). General relations between thepharmacological and behavioral efficacies of drugs re-main a largely unexplored issue and will be discussed inmore detail in a later section (see Future directions).

One procedure often used to assess the reinforcing ef-ficacy of drugs is the progressive-ratio (PR) schedule, inwhich subjects must meet increasing response require-ments to produce a drug. For example, ten lever pressesmight be required for the first drug infusion, 20 pressesfor the second, 40 presses for the third, and so on (i.e. inthis example, the ratio requirements are doubled witheach successive reinforcer delivery). According to thePR schedule, response requirements would continue toincrease until responding becomes erratic or ceases com-pletely. Although all investigations using PR scheduleshave required subjects to complete increasing work re-quirements to earn drug deliveries, different laboratorieshave employed otherwise very different procedures (seeProcedural issues, below).

According to the PR procedure, a drug’s reinforcingefficacy may be indexed by the “breaking point” it main-tains. Breaking points have been defined as the largestratio requirement that the subject completes (e.g. Hodos1961), or as the number of ratios completed by the sub-ject per session (e.g. Loh and Roberts 1990; Depoortereet al. 1993). Early work with PR schedules and non-drugreinforcers (e.g. food or electrical stimulation of thebrain) demonstrated that greater reinforcer magnitudesmaintained greater breaking points (Hodos 1961; Hodosand Kalman 1963; Keesey and Goldstein 1968) andfood-deprivation increased food-maintained breakingpoints (Hodos and Kalman 1963).

Because the PR schedule generates an index of rein-forcing efficacy – the breaking point – that is not tieddirectly to rate of responding, many interpretive prob-lems associated with using rate of responding as a mea-sure of reinforcing efficacy are avoided. As Johansonand Fischman (1989) put it “[in a PR procedure] it doesnot matter how long an animal takes to complete the ra-tio (within limits) but simply whether or not it is fin-ished” (p. 27). Hence, if a drug is observed to maintainrelatively low rates of responding, it is not necessarily

judged to be a marginally efficacious reinforcer; con-versely, high rates of responding are not necessarily in-dicative of a drug with considerable reinforcing effica-cy. Breaking points and rate of responding are not nec-essarily correlated (Smith et al. 1995; Richardson andRoberts 1996).

The first use of PR schedules in the area of drug self-administration was reported by Stretch et al. (1971). Fig-ure 1 depicts the cumulative number of published, em-pirical reports that have since employed PR schedules ofdrug delivery. The figure shows steady, but modest, useof this schedule between 1971 and 1988. After 1988,however, the yearly number of reports utilizing PRschedules increased markedly. Several excellent reviewpapers have discussed procedures relevant to the study ofdrug self-administration, including PR schedules (e.g.Johanson and Fischman 1989; Katz 1990; Markou et al.1993), but, so far as we know, none of these has provid-ed a detailed description of the overall body of experi-mental data generated using the PR procedure. Severalother reviews have focused upon methodological issuesor data obtained only with rodents (Roberts and Richard-son 1992; Richardson and Roberts 1996; Arnold andRoberts 1997). The objectives of this review are to (a)describe and critique the major “themes” of research us-ing PR schedules of drug reinforcement, (b) outline thePR procedure’s potential limitations and/or drawbacks,and (c) suggest potentially fruitful uses of PR proceduresin future research.

Major themes of research using PR schedulesof drug delivery

Identifying reinforcing compoundsand characterizing their dose-response functions

Perhaps the most basic types of experimental questionsthat the PR schedule of drug delivery has helped to an-swer are (a) can a particular drug function as a reinforc-er?, and (b) do breaking points maintained by a drug in-

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Fig. 1 Cumulative number of empirical papers employing PRschedules of drug delivery as a function of year (complete refer-ence list is available from the authors)

crease as a function of increasing dose? [A variety ofother procedures, including fixed-ratio (FR) schedulesand place-preference conditioning, are also capable ofanswering this question.] Many of the earliest uses of PRschedules of drug delivery attempted to answer one orboth of these questions. For example, Yanagita (1973)demonstrated that, across four monkeys, breaking pointsmaintained by several doses of cocaine were higher thanbreaking points maintained by saline, indicating that co-caine functioned as a reinforcer. The breaking pointswere between 400 and 1600 responses when a relativelysmall dose of cocaine (0.03 mg/kg per injection) wasavailable; when a larger dose of cocaine (0.48 mg/kg perinjection) was made available, breaking points increased,ranging between 6400 and 12 800 responses. An inter-mediate dose of cocaine (0.12 mg/kg per injection) gen-erally maintained intermediate-sized breaking points.Thus, these data showed that for cocaine, breaking pointsincreased with increasing doses.

This outcome has since been replicated and extendedacross drug reinforcer categories (e.g. Bedford et al.1978; McLeod and Griffiths 1983; Roberts et al. 1989b;Carroll et al. 1990; Depoortere et al. 1993; Li et al. 1994;Ritz et al. 1994; Caine and Koob 1995). Hoffmeister(1979), for example, showed that in rhesus monkeys,breaking points for heroin and codeine increased as afunction of drug dose. Breaking points for the opioidsdextropropoxyphene and pentazocine in this experiment,however, increased across small to mid-sized doses, butdeclined at the highest doses tested. The observation ofan inverted U-shaped dose-response function for breakingpoints had been reported earlier by Griffiths et al. (1978)in an experiment involving cocaine and the amphetaminederivatives diethylproprion, chlorphentermine, and fen-fluramine, and has since been noted by other investiga-tors using a variety of different drugs (Griffiths et al.1979; Risner and Silcox 1981; Risner and Goldberg1983; Winger and Woods 1985; Risner and Cone 1986;Roberts and Bennett 1993; Woolverton 1995).

The decreasing portion of the dose-effect function hasbeen interpreted by some investigators to be a conse-quence of direct, operant-behavior-disrupting effects ofrelatively large doses of the self-administered drug (e.g.Griffiths et al. 1978; Woolverton 1995; Rowlett et al.1996). Rowlett et al. (1996) found that increasing the du-ration of post-drug-infusion time-out (TO) periods elimi-nated the downturn in the breaking point dose-effectfunction observed with cocaine reinforcement; thus, thenotion that direct, operant behavior disrupting effects oflarge doses are responsible for the downturn in breakingpoints has received some empirical support. Other in-stances of this phenomenon, however, remain unex-plained. Katz (1990) noted that breaking-point down-turns at large unit doses have been observed even whenlengthy TOs separate periods of access to a drug (e.g.Griffiths et al. 1979; Hoffmeister 1979; Risner and Sil-cox 1981; Risner and Goldberg 1983), and suggestedthat, in some circumstances, “the highest doses might beless effective reinforcers than lower doses” (p. 289).

Such observations directly question the notion thatthe relation between reinforcing efficacy and drug dosemust be described by a simple monotonically increasingtrend, and that deviations from this trend must be a resultof direct, operant-behavior-disrupting effects of the drug.It is clear that as unit dose increases, the possibilities of asubject enduring increasingly severe behavior-disruptingeffects of the drug, such as stereotypies, convulsions, orimmobility also increase. But it is also possible that atrelatively large unit doses, a drug with reinforcing ef-fects may also exert unconditioned aversive effects (Wil-son et al. 1971) or may result in a temporary period ofsatiation (Wise 1987). Although no data generated usingPR procedures are available to judge whether aversive orsatiating effects of large doses are responsible for thedose-effect downturn, data obtained with other proce-dures suggest that this is a realistic possibility. Spealman(1979), for example, showed that squirrel monkeyswould reliably press a lever that produced infusions ofcocaine and would, during the same sessions, concur-rently press a lever that produced a TO from the sched-ule of cocaine self-administration. Hence, the scheduleof cocaine availability not only maintained “drug-seek-ing” behavior, but it also set the occasion for respondingmaintained by escape from cocaine availability. Other in-vestigators, using a runway procedure (Ettenberg andGeist 1991) and the conditioned taste aversion methodol-ogy (Wise et al. 1976; van Haaren and Hughes 1990;Glowa and Williams 1992), have also demonstrated thatdrugs known to support self-administration can exertnoxious effects. In our view, the reduction in breakingpoints observed at large unit doses remains an issue to beexplored in more detail.

Ranking the reinforcing efficacy of different drugs

A second major use of PR schedules of drug delivery hasbeen to rank the reinforcing efficacies of different drugsin terms of the maximum breaking points obtained witheach drug. As Katz (1990) noted, the reinforcing effica-cies of different drugs may be precisely compared only ifthe dose-response functions for each drug were obtainedunder functionally identical experimental procedures.Since potentially important methodological details of PRschedules have varied considerably across laboratories(see below), such comparisons of reinforcing efficaciesare best, as of yet, confined to ordinal, rather than intervalor ratio scales of measurement (see Katz 1990 for moreon this issue). In the earliest reported experiment inwhich PR schedules were used to rank-order the reinforc-ing efficacies of different drugs, Griffiths et al. (1975)found that cocaine and secobarbital maintained greaterbreaking points than did methylphenidate. Table 1 pro-vides a summary of studies that used PR schedules torank-order the reinforcing efficacies of different drugs.For each study, a rank-ordering of the maximum breakingpoints (in absolute terms) observed with the drugs testedis shown. Table 1 shows that cocaine and heroin have

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generally been observed to maintain the highest breakingpoints. The current body of data is certainly suggestive,but it is not definitive. A considerable amount of futureresearch using the PR schedule would be required to con-struct a comprehensive rank-ordering of the reinforcingefficacies of different drugs. Further, it is unclear to whatdegree other factors, such as procedural variations, gen-der, strain, or species of subject, and behavioral or phar-macological histories of subjects might influence therank-orderings obtained in experiments of this sort.

Treating drug-maintained behavior as a baseline

A third major theme of research involving PR schedulesof drug delivery has been to assess the effects of variousfactors on drug-maintained behavioral baselines. To date,the factors assessed have been predominantly pharmaco-logical in nature, that is, they commonly involve admin-istration of a treatment drug or a lesion-producing drugbefore sessions in which a second drug is delivered ac-cording to a PR schedule. Non-pharmacological vari-ables, which we have classified as either behavioral ororganismic, have also been shown to affect drug-main-tained PR performance.

Table 2 provides a summary of reports that have as-sessed the effects of acute drug pretreatments on behav-ior maintained by PR schedules of drug delivery. Mostexperiments have employed cocaine as the maintenancedrug (i.e. as the reinforcer), and the majority of these

were designed to characterize the effects of drugs actingon dopaminergic or serotonergic receptors or the conse-quences of lesioning dopaminergic or serotonergic neu-rons. Relatively few experiments have examined howdrugs with primary effects on other receptors influencecocaine-maintained PR performance.

Pharmacological treatments

Acute exposure to dopamine-receptor agonistsor antagonists or dopaminergic neurotoxinson cocaine reinforcement

In general, the administration of dopaminergic antago-nists, including haloperidol (Roberts et al. 1989b), SCH23390 (Hubner and Moreton 1991; Depoortere et al.1993; McGregor and Roberts 1993, 1995; Ward et al.1996), spiperone (Hubner and Moreton 1991), remoxi-pride (Bourland and French 1995), eticlopride (Ward etal. 1996), (1)-3-PPP, SDZ 208-912, and SDZ MAR 327(Roberts and Ranaldi 1995) has resulted in a dose-depen-dent reduction in cocaine-maintained breaking points ifadministered systemically, in the nucleus accumbens, or inthe medial prefrontal cortex (but see Loh et al. 1992). Fur-ther, exposure to long-acting (decanoate) forms of the do-pamine antagonists haloperidol and flupenthixol resultedin sustained decreases in breaking points (Richardson etal. 1994). Similarly, pretreatment with the putative dopa-mine autoreceptor-selective antagonists (+) AJ 76 (Rich-

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Table 1 Published reports in which the reinforcing efficacies of different drugs were compared using the maximal breaking pointsmaintained by PR schedules of drug delivery

Subjects Rank-ordering (and dose range tested)a Author(s) (year)

Comparisons between cocaine and other drugs

Baboons Cocaine (0.4–1.6)≥secobarbital (6.0–12.0)>methylphenidate (0.1–0.8) Griffiths et al. (1975)

Baboons Cocaine (0.01–3.0)>diethylproprion (0.1–10.0)>chlorphentermine (0.03–10.0)>fenfluramine (0.02–5.0) Griffiths et al. (1978)

Beagle dogs Cocaine (0.2–1.6)>d-amphetamine (0.035–0.28)≥mazindol (0.0225–0.18)>fenfluramine (0.0625–4.0) Risner and Silcox (1981)

Beagle dogs Cocaine (0.2–1.6)>nicotine (0.05–0.4) Risner and Goldberg (1983)

Rhesus monkeys Cocaine (0.03–1.0)>nomifensine (0.01–0.32) Winger and Woods (1985)

Beagle dogs Cocaine (0.01–1.0)=fencamfamine (0.01–1.0) Risner and Cone (1986)

Rats Cocaine (0.75)>magnesium chloride (6.0) Kantak et al. (1991)

Rats Cocaine (0.187–1.5)=GBR 12909 (0.187–1.5) Roberts (1993)

Rats Cocaine (0.33)=BTCPb (0.33)>PCPc (0.33)>TCPd (0.33) French (1994)

Rhesus monkeys Cocaine (0.012–0.1)>procaine (0.12–2.0) Woolverton (1995)

Rats Cocaine (0.125–0.6)=BTCP (0.125–0.6)>PCP (0.15–3.0)>TCP (0.125–0.6) French et al. (1995)

Comparisons between heroin and other drugs

Rhesus monkeys Heroin (0.001–0.5)>codeine (0.01–16.0)≥dextropropoxyphene (0.05–10.0)>pentazocine (0.05–10.0) Hoffmeister (1979)

Macaque monkeys Heroin (0.01–0.1)>buprenorphine (0.01–0.10)=methadone (0.03–0.25) Mello et al. (1988)

a All doses are expressed as mg/kg per infusionb Benzothienyl-cyclohexylpiperidine

c Phencyclidined Thienyl-cyclohexylpiperidine

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Table 2 Published reports in which behavior maintained by a PR schedule of drug delivery served as a baseline against which the ef-fects of pharmacological pretreatments were assessed

Maintenance drug(s) Treatment drug(s)/location(s) administered/(dose range)a Effect Author(s) (year)

Psychostimulant-maintained baselines. 1. Exposure to a dopamine antagonist

Cocaine Haloperidol/systemic/(0.025–0.05) Decrease Roberts et al. (1989a)

Cocaine SCH 23390/systemic/(2.0–20.0) Decrease Hubner and Moreton (1991)Spiperone/systemic/(2.0–40.0) Decrease

Cocaine Clozapine/systemic/(5.0–20.0) Increase Loh et al. (1992)

Cocaine SCH 23390/nucleus accumbens/(0.001–0.002) Decrease McGregor and Roberts (1993)SCH 23390/amygdala/(0.001–0.002) No effect

Cocaine (+)-AJ 76/systemic/(1.88–30.0) Decrease Richardson et al. (1993)

Cocaine SCH 23390/systemic/(3.2–32.0) Decrease Depoortere et al. (1993)

Cocaine Flupenthixol deanoate/systemic/(2.0) Decrease Richardson et al. (1994)Haloperidol decanoate/systemic/(2.5) Decrease

Cocaine Remoxipride/systemic/(2.5–15.0) Decrease Bourland and French (1995)

Cocaine SCH 23390/medial prefrontal cortex/(0.001–0.002) Decrease McGregor and Roberts (1995)SCH 23390/striatum/(0.001–0.002) No effect

Cocaine (–)-DS 121/systemic/(7.5–15.0) Decrease Smith et al. (1995)(+)-UH 232/systemic/(7.5–30.0) Decrease

Cocaine (–)-3-PPP/systemic/b Decrease Roberts and Ranaldi (1995)SDZ 208–912/systemic/b DecreaseSDZ MAR 327/systemic/b Decrease

Cocaine SCH 23390/systemic/(0.01) Decrease Ward et al. (1996)Eticlopride/systemic/(0.1–0.32) Decrease

Psychostimulant-maintained baselines. 2. Exposure to a dopamine agonist

Cocaine 7-OH-DPAT/systemic/(0.004) Increase Caine and Koob (1995)

Cocaine 7-OH-DPAT/systemic/b Increase Roberts and Ranaldi (1995)B-HT 920/systemic/b IncreasePramipexole/systemic/b Increase

Cocaine Phentermine/systemic/(0.1–5.6) Decreasec LeSage et al. (1997)

Psychostimulant-maintained baselines. 3. Exposure to a dopaminergic neurotoxin

Cocaine 6-OHDAd/nucleus accumbens/(0.008/0.002 ml/side) Decrease Koob et al. (1987)6-OHDAd/corpus striatum/(0.008/0.002 ml/side) No effect

Apomorphine 6-OHDAd/nucleus accumbens/(0.008/0.002 ml/side) Increase Roberts (1989)

Cocaine 6-OHDAd/amygdala/(0.004/0.001 ml/side) Increase McGregor et al. (1994)

Cocaine 6-OHDAd/medial prefrontal cortex/(0.004/0.001 ml/side) Increase McGregor et al. (1996)

Psychostimulant-maintained baselines. 4. Exposure to a serotonergic antagonist

Cocaine MDL 7222/systemic/(0.0075–1.92) No effect Lacosta and Roberts (1993)Ketanserin/systemic/(0.4–6.4) No effectMethysergide/systemic/(2.5–20.0) No effect

Cocaine Ondansetron/systemic/(0.001–1.0) No effect Depoortere et al. (1993)

Psychostimulant-maintained baselines. 5. Exposure to a serotonergic agonist

Cocaine Fluoxetine/systemic/(2.5–20.0) Decrease Richardson and Roberts (1991)

Cocaine L-Tryptophan/systemic/(100.0) Decrease McGregor et al. (1993)

Psychostimulant-maintained baselines. 6. Exposure to a serotonergic neurotoxin

Cocaine 5,7-DHTe/medial forebrain bundle/(0.008/0.002 ml/side) Increase Loh and Roberts (1990)5,7-DHTe/amygdala/(0.008/0.002 ml/side) Increase

Cocaine 5,7-DHTe/intraventricular/(0.01/0.002 ml/side) Increasec Roberts et al. (1994)

(continued)

ardson et al. 1993), (–) DS 121, or (+) UH 232 (Smith etal. 1995) decreased cocaine-maintained breaking points.Administration of SCH 23390 into the amygdala (Mc-Gregor and Roberts 1993) or into the striatum (McGregorand Roberts 1995), however, had little or no effect.

Relatively less is known regarding the effects of di-rect or indirect dopamine agonists on behavior main-tained by PR schedules. When 7-OH-DPAT was includedduring each of the reinforcing infusions of cocaine,breaking points were increased (Caine and Koob 1995).Roberts and Ranaldi (1995) tested the effects of a num-ber of dopaminergic agents on cocaine-maintained be-havior and concluded that agonists – those with greaterintrinsic pharmacological efficacy (e.g. 7-OH-DPAT, B-HT 920, and pramipexole) – tended to increase breakingpoints. Data collected in our rhesus-monkey laboratory,however, indicated that pretreatment with the indirectdopamine agonist phentermine generally resulted in de-creased breaking points maintained by cocaine (LeSageet al. 1997). Future research will be required to identifythe factors responsible for these conflicting findings.

The effects of lesioning dopaminergic neurons withmicroinfusions of 6-hydroxydopamine (6-OHDA) havedepended upon site of administration and unit dose of themaintaining drug. With a cocaine reinforcer, lesions ofthe nucleus accumbens reduced breaking points signifi-cantly, whereas lesions in the corpus striatum did not(Koob et al. 1987). Lesions of the amygdala increasedbreaking points maintained by large unit doses (McGregoret al. 1994), whereas lesions of the medial prefrontalcortex increased breaking points only at small unit doses(McGregor et al. 1996). Thus, dopamine neurons in theamygdala and the medial prefrontal cortex appear to play

an inhibitory role in cocaine reinforcement. When the di-rect-acting dopamine agonist apomorphine reinforced le-ver pressing, 6-OHDA lesions of the nucleus accumbensincreased breaking points (Roberts 1989). In this study,the author suggested that increased breaking points ob-served following the lesion were due to an enhanced sen-sitivity of postsynaptic dopamine receptors. According tothis explanation, increases in breaking points followingnucleus accumbens lesions would only be observed whendirect-acting dopamine agonists are self-administered.This is consistent with the findings of Koob et al. (1987),in which similar lesions of the nucleus accumbens re-duced breaking points maintained by cocaine.

Ibotenic acid-produced lesions of the ventral palli-dum, which has been considered an output region of thenucleus accumbens, but also receives dopaminergic inputfrom the ventral tegmental area (Gong et al. 1996), de-creased breaking points maintained by cocaine (Hubnerand Koob 1990). Two other output regions of the nucleusaccumbens have been lesioned with ibotenic acid in ani-mals responding on PR schedules of cocaine delivery: le-sions of the sublenticular region of the extended amyg-dala resulted in reduced breaking points, but lesions ofthe subcommissural ventral pallidum had little or no ef-fect (Robledo and Koob 1993).

Acute exposure to serotonin-receptor agonistsor antagonists or serotonergic neurotoxinson cocaine reinforcement

The effects of serotonin-receptor agonists, antagonists,or neurotoxins on breaking points maintained by cocaine

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Psychostimulant-maintained baselines. 7. Exposure to other drugs

Cocaine Diazepam/systemic/(0.2–0.25) Decrease Dworkin et al. (1989)

Cocaine Buprenorphine/systemic/(0.003–0.8) Decrease Carroll et al. (1992)

Cocaine Naltrindole/systemic/(3.0–10.0) Decrease Reid et al. (1995)

Cocaine MK-801/systemic/(0.05–2.0) Increase Ranaldi et al. (1996)

Cocaine Baclofen/systemic/(1.25–5.0) Decrease Roberts et al. (1996)

Psychostimulant-maintained baselines. 8. Exposure to other neurotoxins

Cocaine Ibotenic acid/ventral pallidum/(0.005/0.0005 ml/side) Decrease Hubner and Koob (1990)

Cocaine Ibotenic acid/SEAf/(0.005/0.0005 ml/side) Decrease Robledo and Koob (1993)Ibotenic acid/SVPg/(0.005/0.0005 ml/side) No effect

Opiate-maintained baselines. 1. Exposure to an opiate antagonist

Heroin Naloxone/systemic/(0.002) Decrease Roberts and Bennett (1993)

Opiate-maintained baselines. 2. Exposure to a neurotoxin

Heroin Ibotenic acid/ventral pallidum/(0.005/0.0005 ml/side) Decrease Hubner and Koob (1990)

Table 2 (continued)

Maintenance drug(s) Treatment drug(s)/location(s) administered/(dose range)a Effect Author(s) (year)

a Unless otherwise noted, doses are in mg/kgb Dose range tested was not reportedc A similar effect was also observed in other subjects in whichbreaking points were maintained by food

d 6-Hydroxydopaminee 5,7-Dihydroxytryptaminef Sublenticular region of the extended amygdalag Subcommissural ventral pallidum

have been somewhat equivocal. One early report indicat-ed that pretreatment with the serotonin-selective reup-take inhibitor fluoxetine resulted in decreased breakingpoints (Richardson and Roberts 1991). This observationled the authors to propose that increases in serotonergicactivity specifically antagonize cocaine’s ability to func-tion as a reinforcer. Subsequent reports, however, haveindicated that the reverse of this relation is not alwaysobserved; that is, administration of serotonin-receptorantagonists does not increase cocaine-maintained break-ing points. Depoortere et al. (1993) found that the seroto-nin-receptor antagonists MDL 7222, ketanserin, andmethysergide had little or no effect on cocaine-main-tained PR performance, and similar results were obtainedby Lacosta and Roberts (1993) with ondansetron. Lohand Roberts (1990), however, found that lesioning sero-tonergic neurons in the medial forebrain bundle or in theamygdala with 5,7-dihydroxytryptamine resulted in in-creased breaking points maintained by cocaine. The fac-tors contributing to the variability in effects of serotonin-receptor agonists, antagonists, or lesions on cocaine rein-forcement remain to be determined.

Acute exposure to other drugs on cocaine reinforcement

The effects of non-dopaminergic or serotonergic drugshave simply not received much attention. One recent pa-per (Ranaldi and Roberts 1996) indicated that pretreat-ment with the NMDA receptor antagonist MK-801 result-ed in a biphasic effect on behavior maintained by a PRschedule of cocaine delivery: small doses of the drug in-creased breaking points, whereas large doses decreasedbreaking points. Reid et al. (1995) found that breakingpoints maintained by cocaine were reduced followingpretreatment with naltrindole, a delta-selective opioid an-tagonist, and Carroll et al. (1992) found that the mixedopioid agonist/antagonist buprenorphine slightly de-creased breaking points maintained by smoked cocainebase. Dworkin et al. (1987) showed that pretreatmentwith the GABAA indirect agonist diazepam reduced co-caine-maintained breaking points, and Roberts et al.(1996) showed that pretreatment with the GABAB agonistbaclofen reduced cocaine-maintained breaking points atdoses that did not affect food-maintained responding. Inour opinion, one clear challenge for future research usingPR schedules of reinforcement will be to describe theconsequences of treatment with non-dopaminergic or se-rotonergic drugs on cocaine-maintained breaking pointsin greater detail.

Acute exposure to opiate-receptor antagonistsor neurotoxins on heroin reinforcement

Only two reports have investigated the consequences ofdrug treatments on PR responding maintained by opiates.Roberts and Bennett (1993) showed that pretreatmentwith the non-selective opioid antagonist naloxone de-

creased breaking points maintained by heroin, an out-come which parallels the findings generally obtainedwith dopamine receptor antagonist pretreatment on co-caine reinforcement. Hubner and Koob (1990) found thatlesioning the ventral pallidum with ibotenic acid resultedin decreased heroin-maintained breaking points. Since inthis study similar lesions also disrupted cocaine rein-forcement, these data suggest that the ventral pallidumplays a general role in mediating the reinforcing effectsof psychostimulant and opioid drugs.

Physical dependence on the self-administered drug

Yanagita (1973) used PR schedules to assess the effectsof physical dependence on breaking points. The perfor-mance of monkeys that had received “programmed ad-ministration” (p. 59) of morphine or cocaine, which pu-tatively produced physical dependence, was comparedwith their performances in a non-dependent state. Withmorphine, physical dependence produced larger breakingpoints, but this effect was absent with cocaine. These re-sults support the contention that physical dependence ona drug is associated with an increased reinforcing effica-cy of that drug, and it demonstrates that the likelihoodthat this phenomenon will occur differs across abuseddrugs.

Time since last exposure to the self-administered drug

Two experiments have used human smokers as subjectsto assess the effects of restricting access to tobacco onPR responding maintained by puffs on a cigarette. Will-ner et al. (1995) observed a straightforward effect of cig-arette deprivation – subjects instructed not to smoke for4 h prior to the experimental session reached higherbreaking points than they did in other sessions withoutsuch instructions. In a similar vein, Epstein et al. (1991)showed that during cigarette deprivation, subjects chosemoney and cigarette puffs about equally according to aconcurrent PR schedule; in a non-deprived condition,subjects strongly preferred money. Both of these experi-ments demonstrate that PR performance is sensitive tochanges in level of drug deprivation, an outcome consis-tent with the interpretation of breaking points as an indexof the reinforcing efficacy of the self-administered drug.

Repeated non-contingent exposure to a drug

Li et al. (1994) assessed the effects of repeated exposureto cocaine (three injections per day for 7 days) on the re-sponding maintained by a PR schedule of cocaine deliv-ery in rats. In four of seven subjects, this treatment re-sulted in a rightward shift of the breaking-point dose-ef-fect function. That is, tolerance to the reinforcing effectsof cocaine was observed. Further, when repeated expo-sure to cocaine was discontinued, the dose-effect func-

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tion returned to pre-repeated-administration form overthe course of the next 15 days (i.e. tolerance was “lost”).Peltier et al. (1996) reported similar tolerance to co-caine’s reinforcing effects following repeated once-dailyadministration of a relatively large dose of d-amphet-amine or methamphetamine, and, when the repeated ad-ministration regimen was discontinued, tolerance disap-peared over the next 10 days.

Extinction of self-administration and reinstatementof responding

Three early papers (Stretch et al. 1971; Stretch and Gerber1973; Gerber and Stretch 1975) assessed the effects of dis-continuing drug infusions after establishing reliable pat-terns of PR-maintained behavior – that is, extinguishingself-administration – and then administering a drug priorto sessions in which responses continued to be extin-guished to assess “reinstatement” of responding. Breakingpoints maintained by d-amphetamine or cocaine were de-creased by substitution of saline for either drug. Baselinepatterns of responding could be reinstated by pre-sessioninjections of d-amphetamine or cocaine, but not by injec-tions of pentobarbital or chlorpromazine. Interestingly,this reinstatement effect could be eliminated by removinganother discriminative stimulus (masking noise) that hadbeen paired previously with drug availability.

Organismic factors

Gender of subject

A report by Roberts et al. (1989a) indicated that femaleand male rats performed differently on a PR schedule ofcocaine delivery. More specifically, cocaine maintainedgreater breaking points among female rats than amongmale rats, and breaking points reached by female rats dur-ing estrus were significantly greater than breaking pointsobserved during other stages of the estrous cycle. So faras we know, the variables responsible for these interest-ing outcomes have not received further attention.

Strain of subject

In two experiments, contrary to expectations, rats thathad been selectively bred to prefer ethanol in two-bottlechoice tests reached breaking points on a PR schedule ofethanol delivery that were comparable to those reachedby rats selectively bred to avoid ethanol (Ritz et al. 1994;Hyytiä et al. 1996). This outcome is intriguing consider-ing that both the two-bottle choice tests and the PRschedule are thought to produce measures of relative re-inforcing efficacy, and the failure to observe a correla-tion between them deserves further scrutiny. Ward et al.(1996) compared the breaking points reached by Fischer344, ACI, and Brown Norway rats on a PR schedule of

cocaine self-administration. They found that Fischer 344rats reached significantly greater breaking points over arange of doses than did ACI and Brown Norway rats; inaddition, the strains were differentially affected by pre-treatment with the selective dopamine antagonists SCH23390 and eticlopride. The observation that Fischer 344rats reach relatively large breaking points on a PR sched-ule of cocaine reinforcement is somewhat surprising,since others have shown that these rats do not exhibit ro-bust levels of cocaine-induced conditioned place prefer-ence (Kosten et al. 1994), and acquire intravenous co-caine self-administration at a relatively slow pace (Kostenet al. 1998). It is unknown whether these different out-comes with Fischer 344 rats are due to the methodologi-cal differences between studies or to other factors.

Behavioral factors

Degree of food restriction

Breaking points maintained by a PR schedule of cocaine(Comer et al. 1995) or PCP (Rodefer and Carroll 1996)delivery were increased by restricting subjects’ access tofood. These data demonstrate how states of deprivationfor a non-drug reinforcer (i.e. food) may influence thereinforcing efficacy of a self-administered drug. Thisclearly illustrates that the reinforcing efficacy of a drugcan be modified by behavioral/environmental variables,rather than it being a fixed, physical property of thedrug. That food deprivation increases the reinforcing ef-ficacy of food is not surprising, but the observation thatthe reinforcing efficacy of self-administered drugs issimilarly affected deserves further scrutiny. Continuedinvestigations that explore “cross-reinforcer” effects ofthis sort might lead to refinement of current proposals re-garding the neuropharmacological substrates of rein-forcement in general.

Exposure to electric shock

Shaham et al. (1993) demonstrated that exposure to a se-ries of electric shocks resulted in increased breakingpoints maintained by a PR schedule of fentanyl delivery.A similar outcome was reported by Shaham and Stewart(1994), in which breaking points maintained by relative-ly large doses of heroin were significantly greater forsubjects exposed to shock compared with breakingpoints observed in a control group; breaking pointsmaintained by relatively small doses of heroin, however,were not different from those reached by the control sub-jects. The neuropharmacological basis for these resultsis presently unclear. In general, increasing attention hasbeen directed at describing interactions between expo-sure to physical and social stressors and subsequent self-administration of drugs under other schedules of rein-forcement (e.g. Piazza et al. 1989, 1990, 1994; Miczekand Mutschler 1996; Goeders 1997; Tidey and Miczek1997).

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Summary

Although the data that have been obtained using PRschedules of drug delivery are in most cases suggestive,insofar as the lack of systematic replications leaves theirgenerality unknown, a few over-arching themes haveemerged. It appears that of all the drugs tested in self-ad-ministration procedures, cocaine usually maintains thelargest relative breaking points (but see Richardson andRoberts, Fig. 5), supporting the widely held view that co-caine’s reinforcing efficacy is particularly high. But, asnoted by Katz (1990), cocaine has received much moreattention from experimenters studying self-administrationthan the attention paid to other drugs (see Table 2). Fur-thermore, there have been few attempts to directly com-pare the breaking points maintained across drugs of abusefrom different pharmacological classes (see Table 1).

Several reports have indicated that pretreatments withdopamine antagonists decrease cocaine-maintainedbreaking points, and that this outcome can be markedlyinfluenced by the location into which the specific antag-onist is administered (see Table 2). These data, in con-junction with those obtained in lesioning studies, supportthe proposal that the mesolimbic, mesocortical, and me-sopallidal dopaminergic systems play a significant rolein mediating the reinforcing effects of cocaine. Continu-ing research of this type will provide data crucial to acritical evaluation of the proposal that all drugs of abuseinteract with this neuropharmacological pathway (Boz-arth 1986; Di Chiara and Imperato 1988; Koob and LeMoal 1997). Progressive-ratio schedules could providevaluable data relevant to this general contention, but upto this point, drugs other than cocaine have received lit-tle attention.

Behavioral and organismic factors have been shownto have effects on breaking points maintained by co-caine, ethanol, PCP, fentanyl, and heroin, but reports inthis area are relatively infrequent and general relationshave not yet been established. A recent study by Ward etal. (1996) demonstrated that the effects of dopaminergicantagonists on breaking points were influenced by strainof subject. Although the generality of this outcome re-mains to be determined, in our view, it is likely that theeffects of many, if not all, drug treatments can be strong-ly influenced by behavioral and organismic factors (forother examples see Caine and Koob 1994; Comer et al.1996; Rodefer et al. 1997). The neuropharmacologicalmechanisms by which behavioral or organismic factorsexert their effects on the reinforcing efficacy of drugs oralter the consequences of drug pretreatments are also alargely unexamined but potentially significant issue.Richardson and Roberts (1996) indicated that there are“qualitative differences between psychostimulant andopiate self-administration” under PR schedules of rein-forcement (pp. 8–9). Whether the effects of pharmaco-logical, behavioral, or organismic factors on breakingpoints maintained by a given drug can be replicatedwhen responding produces drugs from other pharmaco-logical classes stands as a major challenge for future re-

search. For example, would exposure to electric shockresult in increased breaking points maintained by non-opiate reinforcers? Would females reach greater breakingpoints than males under PR schedules delivering drugsother than cocaine? Would repeated non-contingenttreatment with non-psychostimulant drugs result in toler-ance to their reinforcing effects? In our view, answeringquestions like these with PR schedules of self-adminis-tration would help to build a more solid foundation forcritical thinking regarding the concept of reinforcing ef-ficacy and the variables that influence it.

Procedural issues

The algorithm for ratio progression

The manner in which PR schedules of drug deliveryhave been programmed has varied substantially acrosslaboratories. In the earliest descriptions of PR schedules(Hodos 1961; Hodos and Kalman 1963), subjects couldearn access to sweetened condensed milk by completingresponse requirements that increased from one ratio tothe next within each experimental session. In these ex-periments, the response requirements increased accord-ing to an arithmetic progression (i.e. a fixed number ofresponses were added to each succeeding ratio – for ex-ample, one series of ratio values was 5, 10, 15, 20, 25,30, etc.). When a subject failed to respond for 15 consec-utive minutes, the session was terminated, and the lastratio completed by the subject was considered the break-ing point. Although a very similar procedure continuesto be used in research with non-drug reinforcers (e.g.Thomas 1974; Baron et al. 1992; Jones et al. 1995), PRschedules of drug delivery have been modified in a num-ber of ways.

A large number of experiments that use PR schedulesof drug delivery have favored an exponential or logarith-mic progression, in which response requirements typical-ly escalate much more rapidly from one ratio to the next(e.g. the exponential progression used by Roberts et al.(1996) required one response for the first drug infusion,then 2, 4, 6, 9, 12, 15, 20, 25, 32, 40, 50, 62, 77, 95, 118,145 responses, and so on). To our knowledge, no investi-gator has provided a specific rationale for favoring expo-nential or logarithmic progressions over arithmetic ones,although several reports have outlined positive aspects ofthe former types of progression. Roberts et al. (1989b)remarked that their quasi-logarithmic progression en-sured that breaking points would be reached within afive-hour experimental session. Limiting session lengthappears to be a particularly pertinent concern when theeffects of relatively short-acting pharmacological treat-ments are to be assessed on the drug-maintained behav-ioral baseline. Depoortere et al. (1993) favored exponen-tial progressions because the breaking-point data theygenerated could be logarithmically transformed withease, which led to data that did not violate statistical as-sumptions of variance. It is also possible that the more

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rapidly increasing response requirements arranged bylogarithmic or exponential progressions could help tolimit a subject’s overall exposure to the drug. That is,relatively fewer ratios might be completed by the sub-jects on exponential progressions than on arithmetic pro-gressions. If so, complications arising from the develop-ment of tolerance or sensitization as a result of repeateddelivery of the self-administered drug might be mini-mized by the choice of an exponential or logarithmicprogression. Roberts and Bennett (1993) outlined a mod-ified PR procedure using an exponential progression thatwas specifically designed to minimize the probabilitythat tolerance or sensitization to the reinforcing effects ofheroin would develop. According to this procedure, theinitial response requirements in each session were deter-mined by performance observed in the immediately pre-vious session; more specifically, the starting response re-quirement was set at two “steps” below the breakingpoint observed during the previous session, rather than atthe minimum response requirement. Stable breakingpoints were obtained using this procedure while the sub-jects’ overall contact with heroin was minimized.

The breaking-point criterion

The “breaking-point criterion” has varied substantiallyacross laboratories studying the self-administration ofdrugs. Early experiments using PR schedules with non-drug reinforcers allowed sessions to continue until a pe-riod of time (e.g. 15 min) passed in which the subjectmade no responses, but only a few drug self-administra-tion experiments have followed this lead (e.g. Gerberand Stretch 1975; Kantak et al. 1991; Willner et al.1995). Many reports have instead employed breaking-point criteria that allow the subject a fixed amount oftime to complete each ratio; this period of time has var-ied from 12 min (Woolverton 1995) to 48 h (Yanagita1973). In some cases, reinforcer deliveries have alsobeen followed by a TO from the schedule. The intendedpurpose of these procedural modifications appears to bequite simple; drug delivery itself is often followed by aperiod of time in which subjects’ response rates are re-duced to zero. The purpose of a breaking-point criterionis to identify the response requirements that are simplytoo large to maintain responding, and a time-without-a-response criterion may not always be capable of accom-plishing this function when a drug is serving as a rein-forcer. As Markou et al. (1993) put it, “the reliability ofthe breaking point measure, and more specifically theconsistency of the measure between subjects and labora-tories, depends partly on the criterion period of time se-lected to define the breaking point” (p. 167). Rowlett etal. (1996) examined the effects of different TO durations(15 or 30 min) and different breaking-point criteria (12or 24 min to complete each ratio) on behavior main-tained by a PR schedule of cocaine delivery. Five trialswere scheduled per day (each trial consisted of four op-portunities to earn cocaine according to an FR schedule),

and the ratio requirements increased from one trial to thenext. They determined that the combination of the longerTO and break-point criterion often resulted in monotoni-cally increasing dose-effect functions, whereas the com-bination of the shorter TO and breaking-point criterionoften produced an inverted U-shaped dose-effect func-tion. As noted in a previous section, the authors conclud-ed that the longer TO and breaking-point criterion helpedto minimize direct, operant-behavior-disrupting effectsof large doses of cocaine.

Ratio progression: within and across-session increases

Although many experiments have arranged increasing re-sponse requirements within each experimental session,other reports have arranged for response requirements toincrease across sessions (e.g. Yanagita 1973; Griffiths etal. 1975, 1978, 1979, 1989; Hoffmeister 1979; Risner andSilcox 1981; McLeod and Griffiths 1983; Risner andGoldberg 1983; Risner and Cone 1986; Mello et al.1988). Across-session progressions have typically ar-ranged a fixed number of trials – each separated from thenext by a lengthy TO – per day, in which a constant num-ber of responses per trial is required to produce exposureto the drug. If an individual subject were observed tocomplete most or all of the trials in a day, the ratio re-quirements would be increased for the next day, and thisprocess continued until performance dropped below apre-determined criterion level. This procedure obviouslydiffers markedly from the more typical within-session re-sponse-requirement progression, in which subjects areexposed to a range of ratio sizes during each session.Whether the across-day progressions should be called PRschedules is open to debate; more recent reports usingsomewhat similar methods have not termed themselves assuch (Ranaldi and Roberts 1996).

Significant limitations or problemswithin the PR schedule of drug-delivery literature

Lack of food-reinforcement control conditions

Although many recent experiments have tested the ef-fects of pharmacological pretreatments on behaviormaintained by PR schedules of drug delivery, the degreeto which these effects are behaviorally specific is rela-tively unknown. One way to determine whether a pre-treatment exerts a behaviorally specific effect is to exam-ine its effects on responding maintained by another rein-forcer, such as food. A pretreatment that reduces behav-ior maintained by a drug and, at the same doses, also re-duces behavior maintained by food would seem to havelittle potential for clinical development as a specific,non-sedative pharmacotherapy for human drug abusers.In our view, assessing the behavioral specificity of theeffect of a pretreatment may be as important as assessingwhether the pretreatment has an effect at all. Even so,

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only a few experiments testing the effects of pharmaco-logical pretreatments on behavior maintained by a PRschedule of drug delivery have included control condi-tions in which subjects earn food reinforcers (e.g. Mc-Gregor et al. 1993; Roberts et al. 1994, 1996; Smith etal. 1995; LeSage et al. 1997). One would hope that futureinvestigations in this area would include either a controlgroup or condition in which behavior is maintained byfood or another reinforcer in an attempt to determine thespecificity of effects of a pretreatment.

While suggesting that a pretreatment ought to be test-ed on both drug- and food-maintained PR responding,one might as easily point out that such comparisonsought to be carried out using food magnitudes and drugdoses that are shown to maintain roughly equivalentbreaking points. The purpose of including a food-controlcondition could be subterfuged if no attention were paidto balancing reinforcing efficacies for the food and drugconditions. Consistent with this notion, there are sugges-tions in the literature that self-administration maintainedby more reinforcing doses of drugs is less affected bypharmacological pretreatments than that maintained byless reinforcing doses (e.g. Ward et al. 1996).

Missing unit-dose-effect data

Experiments designed to assess the effects of pharmaco-logical pretreatments on drug self-administration havetypically tested several doses of the pretreatment agent,but very few of them have tested the effects of a treat-ment agent on different unit doses of the maintainingdrug (e.g. McGregor et al. 1994, 1996; Caine and Koob1995; Ranaldi et al. 1996; Roberts et al. 1996; Ward etal. 1996). Obtaining unit-dose-effect data allows an in-vestigator to determine the extent to which the effects ofa particular pretreatment depend upon the dose of drugmaintaining a subject’s behavior. Without such data, onecannot evaluate whether the pretreatment results in ashift of the unit-dose-effect function or is unique to theunit dose tested.

Lack of assessments of vehicle-maintained responding

For a drug to be judged as reinforcing, according to thePR procedure, breaking points maintained by the drugmust significantly exceed the breaking points maintainedby the drug vehicle (e.g. saline). Surprisingly few experi-ments in this area, however, have bothered to measureperformance maintained by the drug vehicle. Further,several of the experiments that have measured such per-formance have observed that the vehicle often maintainsa breaking point substantially greater than zero (e.g.Gerber and Stretch 1975; Hoffmeister 1979; Spear andKatz 1991). Data from other reports indicate that the vehi-cle maintains little or no responding (e.g. Risner and Cone1986; Depoortere et al. 1993; Woolverton 1995; Rowlettet al. 1996). So far as we know, the variables responsible

for these different outcomes remain unspecified and un-explored, which is surprising, since establishing a cleardifferentiation between vehicle- and drug-maintained re-sponding would seem to be a fundamental requirement ofall drug self-administration experiments. One would hopethat subsequent research using PR schedules of drug de-livery will not only include conditions in which subjects’responding produces vehicle infusions, but also in thosesituations in which vehicle infusions maintain breakingpoints significantly greater than zero, some effort is ex-pended to determine the variables responsible for it.

Infrequent analysis of within-session response patterns

Dynamic patterns of behavior are maintained by PRschedules of drug delivery. These response patterns re-flect not only the influence of ratio size but also the ef-fects of increasing blood and brain concentrations of theself-administered drug, which can impact operant behav-ior by producing motor-behavior disruption or stimula-tion, temporary satiation, or other effects. The influenceof accumulating blood levels of drug may be particularlysubstantial at the beginning of a session and soon there-after, when several small-sized ratios can be completedin rapid succession. Unfortunately, a systematic analysisof the role of rapid drug accumulation in subsequent re-sponse patterning is currently lacking. Increased atten-tion to within-session patterns of responding could alsoimprove the interpretation of effects produced by phar-macological, behavioral, and organismic treatments onPR responding. It is possible that different treatmentswhich change breaking points similarly could be distin-guished on the basis of the response-patterning altera-tions they produce. Distinctions of this sort would re-present a significant refinement in the analysis of treat-ment-induced effects on PR-maintained self-administra-tion responding.

Future directions

The use of PR procedures has been accelerating (see Fig.1). In the previous section, we attempted to pinpoint anumber of methodological issues which, if subjected toexperimental scrutiny, could lead to a refinement of ex-isting PR procedures. In this section our primary intentwill be to offer further, non-methodological, suggestionsfor future research.

First, the uses of PR schedules of drug delivery in hu-man drug-abuse research could be expanded. Up to thispoint, there have been only a few examples of humanperformance maintained by a PR schedule of drug deliv-ery (e.g. McLeod and Griffiths 1983; Griffiths et al.1989; Epstein et al. 1991; Willner et al. 1995). These da-ta suggest that this procedure can generate stable andsensitive behavioral baselines in humans. Although non-human subjects are necessary to address some experi-mental topics (e.g. assessing the effects of lesioning neu-

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ronal tissue), many other topics can only be exploredwith human subjects (e.g. the effects of instructions onperformance). Further, the use of human subjects wouldallow some assessment of the degree to which conclu-sions drawn from non-human research using PR sched-ules of drug delivery are applicable to human concerns.

Second, data produced by PR schedules of drug deliv-ery may have particular relevance to the area of behav-ioral economics, especially to the concept of a demandcurve (Hursh 1984). In general, a demand curve de-scribes the relation between the price of a commodity(i.e. a reinforcer) and consumption of that commodity.Price may be operationalized as the number of responsesrequired for the presentation of the reinforcer and FRschedules of reinforcement are often employed. A rangeof prices may be studied across conditions by varyingthe FR response requirements (e.g. different conditionsmight arrange the following schedules: FR 1, FR 10, FR100, FR 1000). Consumption may be measured in termsof the average number of reinforcers earned at a givenprice. Numerous reports in the behavioral-economic lit-erature have shown that a demand-curve assessment mayyield interesting and useful data, especially measures ofintensity and elasticity of demand (e.g. Hursh 1984;Bickel et al. 1990, 1991; Hursh and Winger 1995). Typi-cally, a demand curve can identify the price at which to-tal behavioral output for a reinforcer “peaks” (pmax),which, in our view, appears conceptually related to thebreaking-point measure produced under a PR schedule.

Unfortunately, generating a demand curve using FRschedules requires a considerable amount of time and ef-fort, because each experimental condition (i.e. each FRschedule) can produce consumption data for only oneprice (i.e. the FR response requirement); hence, a de-mand curve representing consumption at n different pric-es would require n different conditions. Progressive-ratioschedules of drug delivery may offer an efficient alterna-tive to the FR methodology, because they appear capableof assessing relations between a range of prices and con-sumption within a single experimental session.

At least two recent papers have examined potentiallinkages between PR schedules of drug delivery and con-cepts employed in the field of behavioral economics (En-glish et al. 1995; Rodefer and Carroll 1996). In additionto reporting the average breaking points they observed ineach condition, Rodefer and Carroll (1996) also present-ed the data plotted as demand functions. Consumption ofdrug was found to decrease with increases in unit pricein a manner generally similar to that observed using FRschedules of drug delivery (see their Fig. 4). For un-known reasons, however, the PR-based demand curvefell to the left of the FR-based demand curve. That is,consumption of drug declined at lower unit prices in thePR schedule. Future research could be designed to ex-plore further the potential benefits of using PR proce-dures to help answer behavioral-economic questions.

Third, PR schedules of drug delivery could be valu-able instruments for measuring the changes taking placein the reinforcing efficacies of drugs during periods of

withdrawal. Breaking points for cigarette puffs in hu-mans have, in fact, been shown to be elevated followinga period of restricted access to smoking (Willner et al.1995). Further scrutiny of this general phenomenoncould help to guide research aimed at developing effec-tive pharmacotherapies for the treatment of drug abuse,especially by identifying the time course of changes inthe reinforcing efficacies of drugs as withdrawal pro-ceeds. The periods of time during which the drug is mostefficacious as a reinforcer for the withdrawing subject,and, hence, when relapse would be most expected, mightrequire a different intervention strategy, and possibly adifferent pharmacotherapy, than that employed duringother portions of withdrawal. The use of PR schedules ofdrug delivery might also be helpful in analyzing thechanges taking place in drug “craving” (Markou et al.1993) during withdrawal periods. That is, when stimulihave been repeatedly associated with drug availabilityand consumption, they may subsequently help generatedrug-seeking behavior, and specifying the manner inwhich exposure to these stimuli during withdrawal peri-ods alters the reinforcing efficacy of the relevant drugcould add valuable information to an analysis of the vari-ables controlling drug self-administration in general.Given the widespread interest in drug craving, relapse,and the development of treatments to combat such re-lapse, the practical relevance of such research appearsparticularly clear.

Fourth, PR schedules of drug delivery may be usedproductively in conjunction with rapidly advancing tech-nologies in molecular biology, such as transgenic expres-sion, knockout mutations, and antisense exposure (Gold1996), in which the expression of a particular gene maybe enhanced or disrupted in an otherwise normally func-tioning organism. Each of these techniques can be valu-able tools in determining the relative contributions of thegene product in the reinforcing effects of a given drug,and PR schedules may be particularly useful in providinga reliable index of treatment-induced alterations in thatdrug’s reinforcing efficacy. Research of this type has, infact, recently been reported (Rocha et al. 1997). In thisstudy, mice that lacked 5-HT1B receptors (i.e. 5-HT1Bknockout mice) reached significantly greater breakingpoints across several unit doses of cocaine than did wild-type mice. The authors concluded that, to some degree,the presence of 5-HT1B receptors in wild-type mice di-minished the reinforcing efficacy of cocaine. The combi-nation of PR schedules of drug delivery and molecularbiological techniques of this sort seems to have enor-mous potential in dealing with some of the most basicquestions in drug self-administration. For example, theunderstanding of the acquisition of drug-taking might beimproved markedly by determining whether the over- orunder-expression of a specific gene product promotes orretards the normal course of acquisition. The understand-ing of long-term drug exposure could be similarly im-proved: Would over- or under-expression of a certaingene alter the typical behavioral and neuropharmacologi-cal consequences of long-term drug use? In our opinion,

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issues in withdrawal, relapse, and craving could alsobenefit from a similar conjunction of PR schedules ofdrug delivery and these molecular biological techniques.

Fifth, and finally, PR schedules could serve as valu-able instruments in investigating whether there are pre-dictable relations between the reinforcing and the phar-macological efficacies of novel and known-to-be-abuseddrugs. As mentioned at the outset of this paper, this is arelatively unexplored topic, but we feel that it could beas significant as the demonstration of a strong correla-tion between reinforcing and pharmacological potenciesof several psychostimulant reinforcers at the dopaminetransporter (Ritz et al. 1987). Among a group of drugswith primary actions at specific neuropharmacologicalsites of action, it is possible that those that maintaingreater breaking points on PR schedules also exhibit rel-atively greater pharmacological efficacies at the relevantreceptor(s). Data related to this issue have been collectedwith FR schedules of cocaine delivery (Wise et al. 1995).In that study, larger doses of self-administered cocaine,which usually maintain greater breaking points on PRschedules, were found to produce larger and more pro-longed increases in extracellular levels of dopamine inthe nucleus accumbens through an in vivo microdialysisprocedure in which samples were collected at 1-min in-tervals. Similar analyses using PR schedules of cocainedelivery or PR schedules in which drugs of abuse thathave primary actions at other receptor systems are self-administered could substantiate the contention that thereinforcing and pharmacological efficacies of drugs aredirectly correlated. In sum, the PR schedule’s demon-strated ability to generate a reliable index of relative re-inforcing efficacy may be useful in providing a frame-work in which the neuropharmacological substrates ofdrug reinforcement may be investigated and interpreted.

Acknowledgements Preparation of this manuscript was support-ed by the National Institute on Drug Abuse (DA 09820). The au-thors would like to thank Drs. Marc N. Branch and David W.Schaal and three anonymous reviewers for their helpful commentson previous versions of the manuscript.

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