Oral drug self-administration: an overview of laboratory animal studies

Alcohol 24 (2001) 117 – 128

Oral drug self-administration: an overview of laboratory animal studies Richard A. Meisch* Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center at Houston, 1300 Moursund, Houston, TX 77030-3497, USA Received 31 October 2000; received in revised form 20 February 2001; accepted 25 February 2001

Abstract Many abused drugs can be established as orally delivered reinforcers for rhesus monkeys and other animals. Benzodiazepines, barbiturates, opioids, psychomotor stimulants, dissociative anesthetics, and ethanol can come to serve as reinforcers when taken by mouth. The principal problems in establishing drugs as reinforcers by the oral route of administration are (1) aversive taste, (2) delay in onset of central nervous system effects, and (3) consumption of low volumes of drug solution. Strategies have been devised to successfully overcome these problems, and orally delivered drugs can be established as effective reinforcers. Reinforcing actions are demonstrated by consumption of greater volumes of drug solution than volumes of the water vehicle, and supporting evidence for reinforcing effects consists of the maintenance of behavior under intermittent schedules of reinforcement and the generation of orderly dose-response functions. This article presents an overview of studies of behavior reinforced by oral drug reinforcement. Factors that control oral drug intake include dose, schedule of reinforcement, food restriction, and alternative reinforcers. Many drugs, administered by the experimenter, can alter oral drug reinforcement. Relative reinforcing effects can be assessed by choice procedures and by persistence of behavior across increases in schedule size. In general, reinforcing effects increase directly with dose. Rhesus monkeys prefer combinations of reinforcing drugs to the component drugs. The taste of drug solutions may act as a conditioned reinforcer and a discriminative stimulus. Consequences of drug intake include tolerance and physiological dependence. Findings with orally self-administered drugs are similar to many findings with other positive reinforcers, including intravenously self-administered drugs. D 2001 Elsevier Science Inc. All rights reserved. Keywords: Drug self-administration; Drug reinforcement; Overview; Dose; Schedule of reinforcement; Taste; Food restriction; Acquisition; Choice; Relative reinforcing effects; Oral route

1. Introduction Substantial progress has been made in the study of orally delivered drugs as reinforcers. This article presents an overview of oral drug-reinforcement studies. Several species have been studied, but the most progress has been made with rhesus monkeys. Consequently, the emphasis here is on studies with this species. This overview is also limited to results of studies that have demonstrated drug reinforcement, as opposed to simple self-administration, and it also focuses on studies that have used operant-conditioning methods whereby an arbitrary response such as a lever press is reinforced by drug delivery. These limitations are imposed to select studies that were conducted in an analo* Tel.: +1-713-500-2863; fax: +1-713-500-2849. E-mail address: [email protected] (R.A. Meisch). Editor: T.R. Jerrells

gous manner to intravenous drug self-administration studies. Intravenous drug self-administration studies also use operant-conditioning methods and can reliably demonstrate drug reinforcement or its absence. One important portion of the literature that is not reviewed in the present article is alcohol-reinforcement studies that use operant-conditioning methods and rodents as subjects. There are many studies in this area, and portions of this literature have been frequently reviewed (e.g., Koob, 2000; Samson, 2000; Samson & Hodge, 1996). 1.1. Problems with the oral route of administration Self-administration studies that use the oral route of administration are far fewer in number than intravenous self-administration studies. Lack of use of the oral route of administration is due to difficulties in getting animals to take drugs by mouth. Three problems can be identified. First, most

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drug solutions have an aversive taste, and animals will prefer to drink water if they have a choice. Restriction of access to a single liquid containing a drug can result in drug ingestion (e.g., see Mello & Mendelson, 1966). However, restriction to a drug solution generally does not lead to the establishment of the drug as a reinforcer. Second, when inexperienced animals do drink a drug solution, they often consume small volumes and thus ingest too little drug to result in pharmacological effects. Finally, the interval between drinking a drug solution and the subsequent onset of central nervous system (CNS) effects is more than 5 min—an interval thought to be too long for operant conditioning to occur. 1.2. Origins of oral drug reinforcement In the 1960s, several laboratories used operant-conditioning procedures to study alcohol self-administration (Mello & Mendelson, 1964; Myers & Carey, 1961). However, only low concentrations were preferred to water, and evidence for pharmacological effects was absent. None of the investigators persisted in using operant methods in oral studies with animals. In 1966, as a graduate student I started an experiment to examine the effects of intraperitoneally administered pentobarbital on variable-interval, food-reinforced responding (Meisch, 1969b). To capture both onset and offset of drug action, I used 6-h sessions, and to prevent disruption of food-reinforced behavior due to lack of water, I attached a water bottle to the operant-conditioning chamber. I gradually became aware that rats were consuming very large volumes of water, sometimes as much as 250 ml. I thought that this high water intake would make possible oral drug self-administration, and so instead of giving an intraperitoneal injection of pentobarbital, I placed the pentobarbital in the water of the bottle attached to the chamber. The result was that on days when the pentobarbital solution was present, the rats showed large changes in the rate of foodreinforced responding. Clearly the rats were ingesting sufficient pentobarbital to produce pharmacological effects. Subsequently it was possible to show that rats would press a lever when the consequence was presentation of a dipper containing the pentobarbital solution (Meisch, 1969b). My thesis advisor, Travis Thompson, told me that this high intake of water had been reported by John Falk (1961) and was termed schedule-induced polydipsia. To make preparation of the drinking solutions easier, I switched from pentobarbital to ethanol, and I also continued to use a liquid dipper that was activated by a lever press. It was possible to induce rats to consume ethanol solutions as high as 32% (wt./vol.), and the presence of pharmacological effects was suggested by large decreases in the rate of foodreinforced lever pressing (Meisch et al., 1970; Meisch & Thompson, 1972). When I discontinued the schedule of food reinforcement, water drinking fell to low levels. However, ethanol drinking persisted, and concentrations as high as 32% (wt./vol.) functioned as reinforcers (Meisch, 1969a;

Meisch & Thompson, 1971). Subsequently, I applied this general strategy to obtain orally delivered etonitazene as a reinforcer for rats (Meisch & Stark, 1977) and ethanol and other drugs as reinforcers for rhesus monkeys (Carroll & Meisch, 1978, 1980; Meisch & Henningfield, 1977; Meisch et al., 1975, 1981). A small number of laboratories have contributed most of the literature on oral drug reinforcement. The largest number of studies has been done with rhesus monkeys in two laboratories: those of Carroll and Meisch. Woods and coworkers, as well as Foltin and Evans (1997, 1999), have conducted operant oral self-administration studies with rhesus monkeys. Importantly, it has been possible to establish many drugs as orally delivered reinforcers for rhesus monkeys (see Section 5), and with the exception of ethanol, most oral drug-reinforcement studies have been conducted with this species. The selection of one species over another depends on the questions being asked and on pragmatic considerations. Nevertheless, the use of rhesus monkeys has many advantages. In addition to a relatively long life span, rhesus monkeys are similar to human beings in their DNA, behavior, anatomy, and physiology, and like human beings, rhesus monkeys have a complex social structure (Higley et al., 1994). Thus, findings with rhesus monkeys have a high probability of being relevant to human beings.

2. Methods The general methods used in the oral drug self-administration studies with monkeys are similar to those used in Carroll’s laboratory and in my laboratory. Each monkey is individually housed 24 h a day in a stainless steel primate cage that also serves as the experimental chamber. A liquiddelivery apparatus panel is attached to the outside of one side wall, with two spouts and stimulus lights protruding into the cage through holes cut in that wall. The spouts serve as operanda or devices for recording operant responses. The operant response, a lip contact with either spout, is detected by completion of a drinkometer circuit. The lip contact response is usually reinforced according to an intermittent schedule of reinforcement. The liquid-delivery apparatus has been described extensively elsewhere (Henningfield & Meisch, 1976a; Meisch & Lemaire, 1993). The programming of experimental events and the recording of data are accomplished with computers located in a room near the experimental chambers. Experimental sessions are 3 h long and are conducted 7 days per week. The stimulus lights above each spout either blink at a rate of 10 Hz or are steadily illuminated, depending on experimental conditions. Each lip contact with a spout illuminates a green-lensed pair of spout lights for the duration of the response if drug is present, or the lip contact illuminates a white-lensed pair of spout lights if water is present. The final response in the schedule requirement initiates flow

R.A. Meisch / Alcohol 24 (2001) 117–128

of approximately 0.67 ml of liquid. To reduce the possible differential responding that might be caused by a monkey’s preference for a particular spout or side of a chamber, the drug solution is alternated between spouts each session. Another liquid, usually the drug vehicle, is available from the second spout under the same schedule conditions that are present with the drug solution. Between sessions, water is available under a fixed-ratio 1 schedule. In certain experiments, changes have been made in some of the conditions described above. Methods used in drug self-administration, including studies with the oral route of administration, have been reviewed (Meisch & Lemaire, 1993).

3. Acquisition procedures A number of acquisition procedures have been developed to establish oral drug reinforcement. These procedures are necessary because without them monkeys do not drink most drug solutions in volumes that exceed vehicle intake (Meisch et al., 1990, 1993; Stewart et al., 1994, 1996b; Vivian et al., 1999b). One approach is to use procedures to induce drinking, such as schedule-induced polydipsia (Carroll & Meisch, 1978, 1980; Meisch et al., 1975; Meisch & Henningfield, 1977) or post-prandial drinking (Lemaire & Meisch, 1985; Meisch, 1975; Meisch & Henningfield, 1977; Meisch et al., 1981). The inducing conditions make it likely that the animal will drink the drug solution. Usually a low drug concentration is used initially, and the concentration is gradually increased across sessions. Subsequently, the inducing condition is terminated either abruptly or in steps, and if the establishment procedure was successful, the animal continues to drink the drug solution in the absence of the inducing conditions. Another approach is to use fading procedures. For example, rhesus monkeys will drink low concentrations of ethanol, such as 1% or 2% (wt./vol.), without any training history (Macenski & Meisch, 1992). Once drinking of a low ethanol concentration has been reliably established, a low concentration of the target drug is added to the ethanol solution, and the concentration is gradually increased across sessions until the desired concentration is reached (Meisch, 1995; Meisch et al., 1981, 1993). Subsequently, the concentration of ethanol is gradually decreased across sessions to zero. Usually, drinking of the target drug persists. In some cases, a monkey will show a high baseline level of water drinking during experimental sessions, and it has been possible to establish a drug as a reinforcer by simply placing the drug in water at a moderate concentration (Carroll, 1982c; Meisch, 1995) or by gradually increasing the drug concentration from low initial levels (Lemaire & Meisch, 1984). An important and efficient method that has been shown to be feasible by Carroll is to simply substitute a new drug for one that is already functioning as a reinforcer (Carroll, 1982a). The establishment of orally delivered drugs as

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reinforcers is facilitated by the use of food restriction (Carroll, 1982c). Once drug reinforcement is established, the subsequent pattern and amount of drug intake appear to be independent of the acquisition procedure (Meisch, 1975). Acquisition of behavior reinforced by oral drug delivery has been discussed in several publications (Carroll et al., 1990; Macenski & Meisch, 1992, 1995; Meisch & Carroll, 1981, 1987; Meisch & Lemaire, 1993). Reviews of the acquisition or establishment of drug- and ethanol-reinforced behavior have been published (Campbell & Carroll, 2000b; Meisch, 1977, 1984; Meisch & Lemaire, 1993). Self-administration of a drug is not equivalent to drug reinforcement. This is especially true with the oral route of administration, because factors other than the drug may account for intake of the drug solution. For example, liquid-deprived animals will consume a drug solution when alternative sources of liquid are not present. Addition of a sweet-tasting substance to the drug solution may also promote drinking of the liquid. A common feature of such extraneous factors is that intake of the drug solution is not due to reinforcing effects of the drug, because intake of the drug solution above vehicle levels does not continue when the extraneous factor is removed.

4. Criterion for drug reinforcement To demonstrate drug reinforcement, it is necessary to show that response-contingent presentation of the drug maintains higher response rates than those achieved with response-contingent presentation of the drug vehicle. The vehicle may be studied during sequential blocks of sessions, such that a block of drug sessions is followed by a block of vehicle sessions. Alternatively, the vehicle and drug solution may be concurrently present, and measures of preference can assess the reinforcing actions of the drug (DeNoble et al., 1982a, 1982b; Henningfield & Meisch, 1979). Important supporting evidence for drug reinforcement is an orderly dose-response function and maintenance of patterns of responding that are characteristic of behavior that occurs under intermittent schedules of reinforcement (Henningfield & Meisch, 1976b, 1978; Meisch & Stewart, 1999).

5. Drugs that serve as positive reinforcers With rhesus monkeys, many drugs have been established as orally delivered reinforcers. Table 1 lists these drugs; they are from among four major pharmacological classes: psychomotor stimulants, opioids, dissociative anesthetics, and CNS depressants. Studies of ethanol self-administration with nonhuman primates have been reviewed (Meisch & Stewart, 1994). A recent finding is that groups of rhesus monkeys can differ in their ethanol intake (Vivian et al., 1999a). One drug that is not abused has been studied for possible reinforcing effects, and this is quinine. It did not act

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Table 1 Drugs that can serve as reinforcers by the oral route of administration in rhesus monkeysa

Table 2 Oral drug-reinforcement studies conducted with subjects other than rhesus monkeysa

Drug

Investigators

Drug

Species

Investigators

alprazolam cocaine d-amphetamine diazepam ethanol etonitazene ketamine methadone methohexital midazolam + N-allylnormetazocine pentobarbital phencyclidine phencyclidine analogs triazolam

Meisch et al., 1996a Meisch et al., 1990 Carroll & Stotz, 1983 Stewart et al., 1994 Meisch et al., 1975 Carroll & Meisch, 1978 Carroll & Stotz, 1983 Stewart et al., 1996b Carroll et al., 1984 Stewart et al., 1994 Carroll, 1988 Meisch et al., 1981 Carroll & Meisch, 1980 Carroll, 1982a, 1982b Meisch et al., 1996a

amphetamine cocaine cocaine diazepam ethanol ethanol ethanol ethanol ethanol

Baboons Mice Baboons Baboons Baboons Baboons Baboons Mice Rats

etonitazene fentanyl fentanyl methohexital triazolam triazolam

Rats Rats Rats Baboons Baboons Baboons

Foltin, 1997 George et al., 1991 Foltin, 1999 Ator & Griffiths, 1992 Ator & Griffiths, 1992 Foltin, 1998 Henningfield et al., 1981 Elmer et al., 1986 Meisch, 1969a; Meisch et al., 1970; Meisch & Thompson, 1971, 1973 Meisch & Stark, 1977 Carroll & Meisch, 1984 Shaham et al., 1993 Ator & Griffiths, 1983 Ator & Griffiths, 1992 Kautz & Ator, 1995

a

Note that only the initial study or studies for each drug are listed.

a

as a reinforcer (Carroll, 1982a; Vivian et al., 1999b). Nicotine and cannabinoids have not been studied. When established as reinforcers, orally delivered drugs can maintain high consistent rates of responding over a broad range of doses under appropriate schedule conditions. Orally delivered drugs can also maintain responding under large schedule requirements, even as high as fixed ratio 1024 (Lemaire & Meisch, 1985). Thus, drugs can serve as strong reinforcers when delivered orally.

Note that for rats and mice only the initial studies demonstrating reinforcement are listed.

male rhesus monkeys also have higher intakes than their female counterparts (Grant & Johanson, 1988). In contrast, in a study of phencyclidine self-administration there were multiple differences in drinking between male and female rhesus monkeys, and these findings led to the conclusion that female rhesus monkeys are more likely than male rhesus monkeys to acquire drug-reinforced behavior (Carroll et al., 2000b).

6. Organismic factors 6.3. Food restriction 6.1. Species Drugs can act as reinforcers by the oral route of administration for mice, rats, and baboons (Table 2). However, with the exception of ethanol, far fewer studies have been conducted with these species, relative to the number of studies with rhesus monkeys. With mice, ethanol (Elmer et al., 1986), etonitazene (Elmer et al., 1995), and cocaine (George et al., 1991) can be established as reinforcers. One disappointment has been that with rats only ethanol and potent opioids have been demonstrated to serve as reinforcers. Attempts to establish pentobarbital (unpublished observations, K.L. Shelton, 1998), phencyclidine (Bell et al., 1991), and cocaine (Bell et al., 1993, 1995) as reinforcers have failed. With baboons, ethanol (Henningfield et al., 1981), methohexital (Ator & Griffiths, 1983), and triazolam (Ator & Griffiths, 1992) can serve as reinforcers. 6.2. Gender Juvenile, male rhesus monkeys have higher ethanol intakes than their female counterparts at concentrations of 4%, 8%, and 16% (wt./vol.) (Pakarinen et al., 1999). Adult,

Food restriction increases drug self-administration and lowers the threshold for the reinforcing effects of electrical brain self-stimulation (Carr, 1996). Table 3 lists studies of

Table 3 Food restriction Drug

Schedule

Investigators

cocaine ethanol ethanol ethanol ethanol ethanol methohexital pentobarbital phencyclidine phencyclidine phencyclidine phencyclidine phencyclidine phencyclidine phencyclidine

Fixed-ratio Fixed-ratio Fixed-ratio Fixed-ratio Fixed-ratio Progressive-ratio Fixed-ratio Fixed-ratio Fixed-interval Fixed-ratio Fixed-ratio Fixed-ratio Progressive-ratio Second-order Tandem

Macenski & Meisch, 1999 Henningfield & Meisch, 1981 Meisch & Lemaire, 1991 Pakarinen et al., 1999 Rodefer et al., 1996 Rodefer & Carroll, 1996 Carroll et al., 1984 Kliner & Meisch, 1982, 1989 Carroll, 1985b Carroll & Stotz, 1984 Carroll et al., 2000a Rodefer et al., 1996 Rodefer & Carroll, 1996 Carroll, 1985b Carroll, 1985b

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the effects of food restriction on drug-reinforced responding and intake. Food restriction effects on drug self-administration occur across species, routes of administration, and drug classes (Carroll & Meisch, 1984). The behavioral mechanism of action is an increase in drug-reinforcing effects. (For a discussion of the evidence supporting this mechanism of action, see Carroll [1999] and Kliner & Meisch [1989].) The increases are not uniform across all concentrations but, rather, are greatest at low concentrations, particularly concentrations that during the food-satiated state are too low to sustain responding (Kliner & Meisch, 1989). Food restriction is not always necessary, because some drugs, such as ethanol (Stewart et al., 1996a) and phencyclidine (Carroll, 1982c), can also serve as reinforcers in monkeys that are not food restricted.

7. Pharmacological factors 7.1. Dose A fundamental determinant of drug effects is dose. In oral self-administration studies, the dose can be varied either by changing the concentration and holding the volume constant or by varying the volume and keeping the concentration constant. Both methods have been used, but changing the dose is usually done by varying the drug concentration. When dose is varied in oral drug-reinforcement studies, two findings emerge: (1) Responses and liquid deliveries are an inverted U-shaped function of dose (failure to find an inverted U-shaped function is usually due to the use of too narrow a range of doses) and (2) across the same range of doses that yield such inverted U-shaped functions, drug intake increases with increases in dose (Carroll & Meisch, 1978, 1980; Henningfield & Meisch, 1978; Meisch, 1980). Drug intake is usually expressed in terms of milligrams of drug consumed per kilogram of body weight per session.

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7.3. Relative reinforcing effects of different doses A valid interpretation of drug self-administration studies depends on understanding the relation between drug dose and magnitude of reinforcing effects. One method for analyzing this relation is the use of choice or preference procedures. Table 4 lists studies that examined preferences between pairs of drug concentrations or pairs of drug volumes. It is generally acknowledged that doses on the ascending limb of the dose-response curve are more reinforcing than lower doses. However, there is controversy regarding interpretation of the descending limb, and satiation, aversive effects, and disruption of behavior have been mentioned as possible explanations (Katz, 1989). Nevertheless, over a broad dose range, reinforcing effects clearly increase with increases in dose. Results of multiple studies have shown that higher drug doses are preferred to lower doses. This is the case for pentobarbital (Meisch & Lemaire, 1988, 1990; Meisch & Spiga, 1998), methadone (Meisch et al., 1996b), cocaine (Meisch & Stewart, 1995), ethanol (unpublished observations, R. B. Stewart, N. S. Wang, A. A. Bass, & R. A. Meisch, 1996), and phencyclidine (Rodefer & Carroll, 1999). The relative reinforcing effects of benzodiazepines also increase with increases in concentration (Meisch et al., 1996a). With pentobarbital, when concentration is held constant, larger volumes are preferred to smaller volumes (Meisch & Lemaire, 1989). Importantly, these findings of preferences for larger doses are consistent with results of earlier studies with the intravenous route of administration (e.g., Iglauer & Woods, 1974; Johanson & Schuster, 1975). An unexpected finding is that the size of the reinforcement schedule may be a determinant of choice, because preference for the larger reinforcer may not be present consistently at low schedule values (Meisch & Lemaire, 1990; Shelton et al., 1998; Wang et al., in press).

7.2. Time course of drug intake A repeated finding with all drug classes is that when access to the drug is limited to 3 h each day, the highest rate of responding is at the beginning of the session. After an initial bout of drug drinking, there is usually a pause in responding that is followed by one or more shorter bouts. The time course of drinking is important, because the effects of self-administered drugs depend on both the time course of drinking and the amount of drug ingested. Carroll (1982c) has described an interesting exception to this time course. When monkeys are food satiated during the acquisition phase, phencyclidine self-administration is delayed until later portions of the session. This delay in responding may reflect a decrease in the reinforcing value of the drug (Carroll, 1982c). When the monkeys were subsequently food restricted, there was a typical sustained bout of drinking at the beginning of the session.

Table 4 Choice procedures Drug

Concurrent schedule

Investigators

cocaine methadone methadone

Fixed-ratio Fixed-ratio Mutually exclusive fixed-interval Nonindependent variable-ratio Signaled differentialreinforcementof-low-rate Fixed-ratio

Meisch & Stewart, 1995 Meisch et al., 1996b Meisch et al., 1996b

pentobarbital pentobarbital

pentobarbital phencyclidine phencyclidine and ethanol phencyclidine

Meisch & Spiga, 1998 Meisch et al., 1992

Fixed-ratio Fixed-ratio

Meisch & Lemaire, 1988, 1989 Carroll, 1987a Carroll, 1987c

Progressive-ratio

Rodefer & Carroll, 1999

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7.4. Drug effects on drug-reinforced behavior Table 5 lists drugs that have been studied for their effects on drug-reinforced behavior. There is no simple generalization that summarizes the diverse findings. Nevertheless, it should be noted that because monkeys can serve as subjects for many years in oral self-administration experiments, extended studies of treatment drug effects are possible, and the screening of multiple drugs with the use of the same monkeys is feasible. 7.5. Drug combinations and polydrug abuse Polydrug abuse is more common than abuse of a single drug (Chan, 1991). There are several experimental arrangements that can be employed to study polydrug abuse. One procedure is to place one drug in one reservoir and another drug in another reservoir (Carroll, 1987c). However, the most common arrangement is to place both drugs in the same reservoir (or the same infusion pump, in studies with the intravenous route of administration). Combinations of pentobarbital plus ethanol (Meisch & Lemaire, 1990), methadone plus ethanol (Shelton et al., 1998), and methadone plus cocaine (Wang et al., in press) have been examined. When these drug combinations are concurrently present along with the liquid vehicle, the monkeys show a strong preference for the drug combinations. Thus, these combinations serve as reinforcers. The combinations can also be presented concurrently with one of the component drugs. Under these conditions, there is also a strong preference for the drug combinations, and thus they are stronger reinforcers than is each individual drug. However, when the individual drugs are studied in sequential blocks of sessions and the drug combination is studied in another sequential block of sessions, the response rates maintained by the

Table 5 Drug pretreatment studies Pretreatment drug

Reinforcing drug

Investigators

buprenorphine buprenorphine buprenorphine d-amphetamine dizocilpine naloxone naltrexone naltrexone naltrexone naltrexone naltrexone naltrexone

phencyclidine ethanol phencyclidine phencyclidine phencyclidine methadone ethanol ethanol ethanol ethanol ethanol ethanol

naltrexone naltrexone pentobarbital quadazocine quadazocine

phencyclidine phencyclidine phencyclidine ethanol phencyclidine

Carroll et al., 1992, 1994 Carroll et al., 1992 Rawleigh et al., 1996 Carroll, 1984b Carroll et al., 1994 Wang et al., 1999 Boyle et al., 1998 Carroll et al., 2000a Rodefer et al., 1999 Williams et al., 1998 Williams et al., 1999 Williams & Woods, 1998, 1999 Carroll et al., 2000a Rodefer et al., 1999 Carroll, 1984b Williams et al., 1999 Williams et al., 1999

component drugs and by the drug combination are often similar (Wang et al., in press). These results show that sequential measures of response rates may not correspond with concurrent measures of rate. Therefore, sequential measures can give misleading information regarding the reinforcing effects of drug combinations relative to their component drugs. 7.6. Consequences of drug intake Both drug tolerance and behavioral dependence can develop when drugs are taken by mouth. Carroll and coworkers have shown that chronic self-administration of phencyclidine produces tolerance and dependence (Carroll, 1982b, 1982d; Carroll et al., 1988). Dependence can be detected when termination of drug access results in disruption of food-reinforced responding (Carroll, 1987b, 1988; Carroll and Carmona, 1991; Carroll et al., 1988). In my laboratory, we have seen tolerance to the effects of selfadministered alcohol and have observed abstinence syndromes after termination of chronic 24-h access to pentobarbital (unpublished observations, R. A. Meisch & G. A. Lemaire, 1987).

8. Environmental factors 8.1. Schedules of reinforcement Schedules of reinforcement are another fundamental determinant of drug-reinforced behavior. A wide variety of schedules have been successfully used in oral drug selfadministration studies. Table 6 lists examples of the many schedules used. The patterns of responding are similar to those seen with other reinforcers under the same schedules, except in cases in which direct drug effects disrupt the pattern of behavior. Such disruption can be avoided by scheduling all drug reinforcers for delivery at the end of the session, contingent on completion of a response requirement (Meisch & Thompson, 1974). A consistent finding is that if a sufficiently broad range of schedule sizes is used, rates of responding initially increase and then subsequently decrease as schedule size increases. Drug deliveries initially remain constant as schedule size is increased to moderate values. However, with further increases in schedule size, drug deliveries progressively decrease. 8.2. Relative persistence of behavior across increases in schedule size Use of the oral route of administration makes possible long-term parametric studies. Interactions between the two fundamental variables of dose and schedule size have been examined (Lemaire & Meisch, 1984, 1985, 1991; Macenski & Meisch, 1998). Progressive increases in schedule size generally result in decreases in reinforcer deliveries. How-

R.A. Meisch / Alcohol 24 (2001) 117–128 Table 6 Schedules of reinforcement

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Table 7 Alternative reinforcers

Schedule

Drug

Investigators

Alternative reinforcer

Reinforcing drug

Investigators

Concurrent fixed-interval Concurrent fixed-ratio Concurrent progressive-ratio Concurrent-signaled differentialreinforcementof-low-rate Fixed-interval Fixed-ratio

methadone

Meisch et al., 1996b

ethanol

Henningfield & Meisch, 1979 Rodefer & Carroll, 1999 Meisch et al., 1992

food food food saccharin saccharin saccharin saccharin saccharin saccharin saccharin

cocaine d-amphetamine ethanol ethanol pentobarbital phencyclidine phencyclidine phencyclidine phencyclidine phencyclidine

Foltin, 1999 Foltin, 1997 Foltin, 1998 Carroll et al., 1995 Macenski et al., 1993 Carroll, 1985a Campbell & Carroll, 2000a Campbell et al., 1998 Rawleigh et al., 1996 Rodefer & Carroll, 1997

Second-order Tandem

phencyclidine phencyclidine

phencyclidine pentobarbital

phencyclidine ethanol

Carroll, 1985b Henningfield & Meisch, 1976b Carroll, 1984a, 1985b Carroll, 1985b

ever, the decreases are not equal across doses. The decreases are often least at the highest drug dose and become progressively greater as the dose decreases. Because different numbers of deliveries occur across doses at the baseline or lowest schedule value, each dose has its own baseline value. To calculate the relative persistence of behavior, at each dose the number of deliveries at higher schedule values is expressed as a percentage of deliveries at the baseline schedule value at the same dose (Meisch, 2000a). A review of studies in this area reveals that relative reinforcing effects increase with increases in reinforcer magnitude and that the relative persistence of behavior is a fundamental measure of relative reinforcing effects (Meisch, 2000a, 2000b). Significantly, the findings of relative persistence of behavior correspond directly with the findings of preference for higher drug doses (Meisch, 2000a, 2000b). Thus, two independent procedures converge in assigning greater relative reinforcing effects to larger reinforcer magnitudes. 8.3. Effects of alternative reinforcers on drug-reinforced behavior Any reinforcer in the environment, in addition to the drug reinforcer, might be conceptualized as an alternative reinforcer. In the present article, however, an alternative reinforcer is defined as a nondrug reinforcer that is explicitly made concurrently available with the drug reinforcer. Table 7 lists studies of alternative reinforcers. Alternative reinforcers more effectively decrease drug-reinforced behavior when their delivery is mutually exclusive with delivery of the drug reinforcer (Macenski et al., 1993). When a pentobarbital solution (4 mg/ml) was concurrently available with saccharin under a schedule of differential reinforcement of low rates, the number of pentobarbital deliveries decreased as the saccharin concentration increased (Macenski et al., 1993). Increases in saccharin concentration presumably increase the reinforcing effects of saccharin and make it a

more effective alternative to pentobarbital. These findings indicate that orderly and predictable decreases in drug intake can be arranged by use of mutually exclusive reinforcers. Alternative reinforcers are widely used in the behavioral treatment of drug abuse. 8.4. Behavioral economics Behavioral economics concerns factors that control the allocation of behavior among available reinforcers (Hursh, 1993). In behavioral economics, a primary dependent variable is the level of consumption of available commodities as a function of the level and allocation of responding (Hursh, 1993). Analysis of consumption is particularly appropriate in the study of drug abuse because the consequences of drug intake are often closely related to the quantity consumed. In a series of studies, Carroll and coworkers have used behavioral economics to analyze oral drug-taking behavior (see Table 8). The oral route of administration is appropriate for use in these studies because subjects can participate in studies over long periods. Also, this makes possible extensive parametric manipulations that are important in a behavioral economic analysis. Other

Table 8 Behavioral economic studies Commodity

Commodity

Investigators

cocaine cocaine d-amphetamine ethanol ethanol ethanol ethanol ethanol ethanol phencyclidine phencyclidine phencyclidine phencyclidine phencyclidine phencyclidine phencyclidine

Food None Food Saccharin Saccharin Food None None Water Saccharin Saccharin Saccharin Saccharin None None Saccharin

Foltin, 1999 Macenski & Meisch, 1998 Foltin, 1997 Carroll et al., 1995 Carroll et al., 2000a Foltin, 1998 Rodefer et al., 1996 Rodefer & Carroll, 1996 Williams & Woods, 2000 Carroll, 1993 Carroll et al., 1991 Carroll & Rodefer, 1993 Carroll et al., 2000a Rodefer et al., 1996 Rodefer & Carroll, 1996 Rodefer & Carroll, 1997

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investigators have also used concepts from behavioral economics to analyze behavior reinforced by oral drug delivery (Table 8). 8.5. Role of taste Drug solutions at concentrations that have CNS pharmacological effects are initially aversive in taste. Animals will avoid them and prefer water. Taste effects, however, are important in another capacity. As a result of acquisition procedures, the taste of drug solutions comes to function as a conditioned reinforcer of drug drinking and as a discriminative stimulus for further drinking (Carroll, 1982a; Carroll & Meisch, 1979). Surprisingly, perhaps, orally delivered drugs maintain behavior at lower doses than are used in most studies with intravenously delivered drugs; in contrast, high doses must be used when drugs are taken intragastrically (see Meisch & Lemaire, 1993). With the intragastric route of administration, onset of action is delayed, and there is no immediate feedback due to stimuli such as taste. Thus, although taste is often initially an impediment to the establishment of oral drug-reinforced behavior, it provides important stimulus functions for the experienced animal and probably does the same with human alcohol drinkers.

10. Advantages and disadvantages of the oral route All routes of administration, including the oral route, have a profile of positive and negative features. Which route is most appropriate for a particular study depends on the questions being addressed. A pertinent aspect of the oral route of administration is that those who abuse drugs (including alcohol) frequently do so orally. In studies with laboratory animals, use of the oral route of administration permits long-term studies that are not feasible with the intravenous route of administration. The problems of surgery, infections, and occluded or dislodged catheters are not present. With the oral route of administration, rhesus monkeys can participate in studies for many years. The principal problem with the oral route of administration is that in some cases extended training lasting many months may be necessary to establish a particular drug as a reinforcer. In other cases, however, a new drug may immediately substitute for a drug already functioning as a reinforcer. An important feature is that in spite of the delay of onset of drug action and aversive taste, many drugs can be robust reinforcers when taken by mouth and maintain high response rates over a range of conditions. Thus, the oral route of administration can be used to investigate many aspects of drug-reinforced behavior.

9. Relation to studies with human beings 11. Summary Two studies of oral drug self-administration have been conducted with human beings with methods similar to those used in studies with rhesus monkeys (Spiga et al., 1996, 1997). The sessions were limited to several hours each day. An identical pair of drinking devices was used, so that the human subjects had a choice of taking liquid from one device or the other device, or both devices, or neither device. An operant response was required, in this case a button press. The liquids were available under concurrent fixed-ratio fixed-ratio schedules, and a discrete amount of liquid was delivered on schedule completion. (In these studies, 10 ml was the volume.) The locations of drug (ethanol or methadone) and water were alternated each session to balance for possible side biases. Drug concentration and fixed-ratio size were varied. The ethanol and methadone solutions functioned as orally delivered positive reinforcers. The findings were very similar to those with rhesus monkeys. The drug solutions were markedly preferred to their vehicles and maintained characteristic fixedratio performance. As in the animal studies, the highest response rate was at the beginning of the session. Significantly, the relative persistence of behavior across increases in fixed-ratio size was greatest at the highest dose and least at the lowest dose. These results show that when studied under comparable conditions, the behavior of human subjects and laboratory animals can be strikingly similar (Meisch, 1980, 2000a).

In spite of the problems of aversive taste and delay in onset of CNS effects, orally delivered drugs can serve as effective reinforcers. Responding is well maintained over a broad range of doses and under intermittent schedules of reinforcement. The magnitude of reinforcing effects increases with increases in dose, and the relative persistence of behavior across increases in schedule size also becomes greater with increases in dose. The taste of drug solutions may come to function as a conditioned reinforcer and a discriminative stimulus. Food restriction increases oral drug self-administration, as well as intravenous drug self-administration. Tolerance and physiological dependence can occur as a consequence of oral drug self-administration. Alternative reinforcers can decrease oral drug self-administration. Drug combinations are generally preferred to individual drugs. Rhesus monkeys can serve as subjects in oral selfadministration studies for more than 20 years. This time span provides an unique opportunity to examine the behavior of drug taking and its consequences over an interval that is closer to drug-taking periods observed with human beings and longer than that provided when other routes of administration and animals are studied. More generally, findings with orally self-administered drugs are similar to many findings with intravenously self-administered drugs, and they are also consistent with results obtained with other reinforcers such as food.

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Acknowledgments Research from the my laboratory was supported by NIDA grants DA04972, DA08913, and DA12651 and by NIAAA grant AA10498. I am the recipient of Research Scientist Award DA00159. I thank Dr. Gregory A. Lemaire for his helpful comments on the manuscript.

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