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Reprinted from R.A. Meisch and M.E. Carroll (1987), Oral drug self-administration: Drugs as reinforcers. In M.A. Bozarth (Ed.), Methods of assessing the reinforcing properties of abused drugs (pp. 143-160). New York: Springer-Verlag.
 
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Chapter 7

Oral Drug Self-Administration: Drugs as Reinforcers
 

Richard A. Meisch and Marilyn E. Carroll

Department of Psychiatry
University of Minnesota
Minneapolis, Minnesota 55455


Abstract
Drugs from the four major classes of abused drugs can serve as reinforcers when taken orally. In studies from several laboratories rats, rhesus monkeys, and baboons have served as subjects. Surprisingly, behavior reinforced by orally delivered drugs appears quite strong despite the long delay between ingestion and onset of drug effects. Drug delivery, if appropriately scheduled, can maintain high rates of responding over long periods of time. The rate and pattern of drug reinforced behavior vary in an orderly way according to a number of variables such as drug concentration, reinforcement schedule, and feeding conditions (e.g., food deprivation vs. food satiation). The significance of these findings is that an animal model of oral drug (including alcohol) abuse now exists. This is important because the oral route is the most common route of drug abuse in humans. Furthermore, unlike the intravenous route where short catheter life limits experiments, the oral route permits complex sequential experiments that span many years.

 

Introduction

In the 1960s techniques were developed so that animals could inject themselves with drugs (Deneau, Yanagita, & Seevers, 1969; Thompson & Schuster, 1964; Weeks, 1962). These techniques have now been used in many studies (for reviews see Griffiths, Bigelow, & Henningfield, 1980; Johanson, 1978; Johanson & Schuster, 1981; Pickens, Meisch, & Thompson, 1978; Spealman & Goldberg, 1978). Two major conclusions emerging from these studies are that the drugs that serve as reinforcers for animals are the same drugs that humans abuse (Griffiths & Balster, 1979; Johanson & Balster, 1978) and that drug taking behavior is a specific instance of operant behavior—behavior controlled by its consequences.

Self-Administration of Orally Delivered Drugs
vs. Behavior Reinforced by Orally Delivered Drugs

There are many ways to obtain drug self-administration. Animals can be restricted to a liquid solution containing the drug. Extrinsic reinforcement can be used, such as making food pellet delivery or escape from electric shock contingent upon drinking. If one’s objective is simply to get the animal to self-dose, then these are good methods. However, oral drug self-administration must not be confused with behavior reinforced by orally delivered drugs. This paper is concerned with the latter topic. With drug reinforced behavior, intake of the drug is not secondary to induced intake of the vehicle or to extrinsic reinforcement of drinking. To demonstrate that a drug is serving as a positive reinforcer, it is generally accepted that one should document three findings. First, drug presentation must be shown to maintain characteristic patterns of intermittently reinforced behavior. Second, rates of drug maintained behavior must exceed rates of vehicle maintained behavior when the vehicle is presented either sequentially or concurrently with the drug. Finally, orderly concentration response curves must be demonstrated.

Techniques are now available so that drug-reinforced behavior can be studied when drugs serve as reinforcers under conditions where they are taken intragastrically (Altshuler, Weaver, & Phillips, 1975; Yanagita & Takahashi, 1973), intramuscularly (Goldberg, Morse, & Goldberg, 1976; Katz, 1979), and by inhalation (Wood, Grubman, & Weiss, 1977; Yanagita, Takahashi, Ishida, & Funamoto, 1970).

Establishment of Orally Delivered Drugs as Reinforcers

Over the last 15 years, techniques have been developed at the University of Minnesota that permit the establishment of orally delivered drugs as reinforcers for both rats and rhesus monkeys. The general strategy is to food deprive the animals and then to give them their ration of food during daily 3-hour sessions. Water drinking reliably follows eating. Next, low drug concentrations are substituted for water, and across sessions the drug concentration is gradually increased. Once an intermediate concentration is reached, the time of feeding is shifted from within the session to after the session so that drinking is no longer induced by presentation of food. If the drug has come to function as a reinforcer, then drinking persists even when it is no longer induced by food. To confirm that the drug is functioning as a reinforcer, several tests are performed. Delivery of the drug is intermittently scheduled, and response rates maintained by the drug and the vehicle are compared. Often a concentration response function is obtained. These steps are illustrated below by results of a study done with rhesus monkeys and ethanol (Henningfield & Meisch, 1977).

In this study ethanol was established as a reinforcer for four ethanol-naive rhesus monkeys. The monkeys lived in their experimental chambers. Sessions were 3 hours in duration and were conducted daily at a regular starting time. Each session was preceded and followed by a 1-hour time-out when responding had no consequences and data were recorded and solutions changed. Water was continuously available during the 19-hour intersession periods.

The monkeys were reduced to and maintained at 80% of their free-feeding weights. Liquids were delivered through a spout that had an electronic sensing device for detecting lip-contacts. Each lip contact resulted in an illumination of a feed-back light above the spout and operation of a solenoid-controlled valve that permitted the delivery of 0.5 ml of liquid. Details of the apparatus and drinking device have been reported (Henningfield & Meisch, 1976a; Meisch & Henningfield, 1977).

During the initial phase, the baseline rate of water drinking was determined. Figure 1 shows that in general little drinking occurred. An exception was monkey M-B who showed a high rate of water intake. In the next phase drinking was induced by giving the monkeys access to their daily ration of food within instead of after the session. Food access began at the second hour of the 3-hour session. Figure 1 shows that a high rate of water drinking promptly followed eating.
 

 
Cumulative records of liquid deliveries
Figure 1: Cumulative means (n = 5) of liquid deliveries at 10-minute intervals during 3-hour sessions. Filled circles indicate water deliveries during sessions when food pellets were available. Unfilled circles indicate water deliveries during sessions when food was not concurrently available. Brackets show the standard error of the mean. Absence of brackets indicates that the standard error value fell within the area occupied by the plotted point. Arrows mark the first interval when food pellets were available. Reprinted with permission from Henningfield and Meisch, 1977.
 

In the next phase a series of increasing ethanol concentrations (0.5, 1, 2, 4, 5.6, and 8% w/v) was substituted for water. Each concentration was present for at least five sessions and until behavior stabilized. Figure 2 shows that during this induced drinking phase the number of liquid deliveries was an inverted U-shaped function of ethanol concentration. Although the number of deliveries decreased at the higher concentrations, the quantity of ethanol consumed (g per kg of body weight) went up with increases in the concentration. At concentrations of 0.5, 1, 2, 4, 5.6, and 8%, the monkeys drank 0.31, 0.74, 1.42, 2.18, 2.84, and 3.14 g/kg/3-hour session, respectively.

Once behavior was stable at 8%, the time of feeding was permanently switched from within the session to 1 hour after the end of the session. The figure shows that for three of the four monkeys ethanol drinking persisted at levels close to the induced drinking levels. The fourth monkey, M-L, showed the highest intake during the induced drinking phase, 5.76 g/kg/3-hour session. This monkey’s drinking declined the most and reached a level of 0.99 g/kg/3-hour session. Nevertheless, he continued to consume the ethanol solution and as subsequent tests showed, ethanol had been established as a reinforcer for all monkeys.
 

 
Mean liquid deliveries as a function of ethanol dose
Figure 2: Mean liquid deliveries (n = 5) per 3-hour session as a function of ethanol concentration. Filled circles indicate that food was available during the sessions (food-induced drinking procedure). Open circles indicate that food was available after the termination of the session, and only liquid was available during the session. Brackets show the standard error of the mean. Note the different scales of the ordinates. Reprinted with permission from Henningfield and Meisch, 1977. 
 

In the next phase the number of responses required per ethanol delivery, that is the fixed-ratio (FR) schedule of reinforcement, was increased in the following steps: 1, 2, 4, 8, 16. Figure 3 shows that as the response requirement was increased, the number of responses increased directly with the response requirement, whereas the number of liquid deliveries remained relatively constant. At FR-16 the mean intake was 1.96 g/kg/3-hour session. Liquid deliveries were distributed in a negatively accelerated pattern; that is, the highest rate was at the beginning of the session. The large initial burst was followed by a pause and then by smaller bouts in the latter part of the session. Responding, when it occurred, was characteristic of FR responding maintained by other reinforcers.

In the last phase water was substituted for 8% ethanol. After behavior was stable for five sessions, the ethanol was reintroduced. Responding was maintained at substantially higher rates by the ethanol solution than by water (see Figure 4). Thus, ethanol was serving as a positive reinforcer. Note that the data for monkey M-B are from sessions at FR-32 rather than at FR-16. For this monkey when water was substituted for 8% ethanol at FR-16, his response rate increased in the presence of water; thus, the FR value was increased to FR-32. With other monkeys it has been occasionally noted that at low FR values, vehicle maintained responding may equal or exceed that maintained by drug (Henningfield & Meisch, 1976b). However, clear differences in response rates emerged when the magnitude of the response requirement was increased.
 

 
Mean responses and ethanol deliveries as a function of fixed-ratio size
Figure 3: Mean responses and 8% ethanol deliveries (n = 5) as a function of fixed-ratio size. Brackets show the standard error of the mean. Absence of brackets indicates that standard error values fell within an area occupied by the plotted point. Reprinted with permission from Henningfield and Meisch, 1977.
 

Procedures Used to Establish Orally Delivered
Drugs as Reinforcers

A number of techniques have been used to establish orally delivered drugs as reinforcers. In one study several of these techniques were compared. With rats three different strategies were successfully used to obtain ethanol reinforced responding (Meisch, 1975). In the first procedure food-induced drinking was used in a manner similar to that described above for rhesus monkeys. In the second procedure schedule-induced polydipsia was used to generate high levels of water drinking; and once water intake was stable, the water was replaced by 8% (w/v) ethanol. Schedule-induced polydipsia refers to the excessive water intake that occurs when food deprived animals receive small pellets of food at the rate of approximately one pellet per minute (Falk, 1961, 1971). After five sessions of schedule-induced ethanol drinking, the food schedule was terminated, and water drinking dropped to low values; whereas, ethanol drinking persisted at values significantly greater than water values. Schedule-induced polydipsia has also been used to establish etonitazene as a reinforcer for rats (Leander & McMillan, 1975; McMillan & Leander, 1976; Meisch & Stark, 1977a), and it has been used to establish ethanol (Meisch, Henningfield, & Thompson, 1975), phencyclidine (Carroll & Meisch, 1980b), and etonitazene (Carroll & Meisch, 1978) as reinforcers for rhesus monkeys. With the third procedure rats were food deprived and ethanol was simply made available in the liquid reservoir (Meisch, 1975). This procedure was also effective. Importantly, once ethanol reinforced responding was stable and no longer induced, the pattern of responding was similar regardless of the acquisition procedure used.
 

 
Mean liquid deliveries when ethanol or water was available
Figure 4: Mean liquid deliveries (n = 5) per 3-hour session when either 8% ethanol (striped bars) or water (open bars) was present. Brackets show the standard error of the mean. Liquid deliveries for monkey M-B were contingent on FR-32 whereas liquid deliveries for the other three monkeys were contingent on FR-16. Reprinted with permission from Henningfield and Meisch, 1977.
 

Two additional procedures have been used in recent studies to establish orally delivered drugs as reinforcers for rhesus monkeys. With the first procedure the drug solution was simply made available to food-satiated rhesus monkeys for 3 hours daily (Carroll, 1982b). Another group received the same treatment but was food deprived. Phencyclidine was rapidly established as a reinforcer in both groups. A second procedure, that has been tested recently, involves drug substitution. This procedure parallels intravenous drug self-administration research (cf. Johanson & Balster, 1978). d-Amphetamine, ketamine (Carroll & Stotz, 1983), methohexital (Carroll, Stotz, Kliner, & Meisch, 1984) and phencyclidine analogs (Carroll, 1982a) have been established as reinforcers for rhesus monkeys by substituting these drugs for pentobarbital or phencyclidine. Drug history appears to be an important determinant of the success of these substitution procedures (Carroll et al., 1984). Despite the existence of these and other procedures for establishing orally delivered drugs as reinforcers, there is still no standard procedure that is uniformly effective with all drugs. Table 1 lists drugs that have been established as reinforcers when taken orally, and the reader is referred to the references listed for details of how particular drugs came to function as reinforcers. Note that more drugs have been established as reinforcers for rhesus monkeys than for rats.
 

Table 1
Establishment of Orally Delivered Drugs as Reinforcers
Rats
codeine Suzuki et al., 1982


ethanol Marcucella et al., 1984; Meisch, 1969, 1975; Meisch & Thompson, 1971, 1974b; Poling & Thompson, 1977a; Roehrs & Samson, 1981; Samson & Falk, 1974


etonitazene Beardsley & Meisch, 1981; Carroll & Meisch, 1979a, 1979b; Leander & McMillan, 1975; Lewis et al., 1975; McMillan & Leander, 1976; Meisch & Kliner, 1979; Meisch & Stark, 1977a


fentanyl Carroll & Meisch, 1984


morphine Suzuki et al., 1982


Rhesus monkeys
d-amphetamine Carroll & Stotz, 1983


ethanol Henningfield & Meisch, 1977; Meisch et al., 1975; Meisch & Henningfield, 1977


etonitazene Carroll & Meisch, 1978


ketamine Carroll & Stotz, 1983


methohexital Carroll et al., 1984


PCE 
(N-ethyl-l-phencyclohexylamine)
Carroll, 1982a


pentobarbital DeNoble et al., 1982; Meisch et al.,1981


phencyclidine Carroll, 1982a, 1982b, 1982c, 1984a, 1984b, 1985a, 1985b; Carroll & Meisch, 1980b


TCP 
{1-[1-(2-thienyl) cyclohexyl] piperidine
Carroll, 1982a


Baboons
ethanol Henningfield et al., 1981
methohexital Ator & Griffiths, 1983
 

  Factors Controlling Behavior Reinforced
by Orally Delivered Drugs

Drug Concentration

Generally, drug-reinforced responding is an inverted U-shaped function of drug concentration (e.g., Figure 5). Table 2 lists studies in which concentration was varied. In contrast to rate of responding, drug intake (mg of drug/kg of body weight/session) increases as drug concentration is increased (see Figure 5). Varying drug concentration is one way to vary amount of drug per response sequence. Another way is to hold concentration constant but vary the volume delivered. This procedure has been used in one study (Henningfield & Meisch, 1975), and the results were consistent with those obtained when concentration was varied.

Schedules of Reinforcement

Orally delivered drugs can maintain responding that is intermittently reinforced. The most frequently studied schedule in both oral and intravenous studies is the fixed-ratio (FR) schedule (Spealman & Goldberg, 1978). Under such a schedule delivery of the drug is contingent upon emission of a fixed number of responses. Two results are reliably observed when FR size is increased: (1) response rate first increases and then decreases and (2) liquid deliveries initially remain constant and then systematically decrease (Meisch & Thompson, 1973). Figure 3 shows these functions for FRs of 16 and lower. Table 3 lists studies of FR responding maintained by oral drug delivery. In intravenous studies as animals become more experienced, responding can be maintained at lower drug doses and at higher FRs (Goldberg, 1973). It is our impression that when the oral route is used behavior can be maintained under a broader range of conditions as the animals become more experienced.

Orally delivered drugs can also maintain behavior reinforced under interval schedules (Anderson & Thompson, 1974; Beardsley, Lemaire, & Meisch, 1983; Carroll, 1985b; Treibergs & Meisch, 1979). A special case of interval schedules occurs when drugs are delivered only at the end of the session (Carroll, 1984b; 1985b; Meisch & Thompson, 1974a). This method of scheduling drug delivery permits the antecedent behavior to be reinforced by drug delivery, but responding is not disrupted by the effects (e.g., intoxication) that follow drug intake (Goldberg et al., 1976; see also Katz & Goldberg, this volume).

Second-Order Schedules as a Means of Reducing
the Effects of Drug Intake on Drug-Reinforced Behavior

Second-order schedules have been extensively used to study behavior maintained by intravenously delivered drugs (e.g., Goldberg, Kelleher, & Morse, 1975; Katz & Goldberg, this volume), and they have recently been applied to behavior maintained by orally delivered drugs (Carroll, 1984b, 1985b). Under a second-order schedule, behavioral requirements specified by one schedule are considered as a unitary response that is reinforced according to a second schedule (Kelleher, 1966a, 1966b). These schedules can be used to generate high rates and long sequences of behavior, to increase low rates of responding for certain drugs such as nicotine (Goldberg, Spealman, & Goldberg, 1981), to provide a complex behavioral baseline upon which to compare reinforcers, and to prevent intoxication or overdose by scheduling long intervals between drug infusions or by providing all drug at the end of the session.
 

Table 2
Studies of Drug Concentration on Behavior Reinforced by 
Oral Delivery of Drugs
Rats
ethanol Beardsley et al., 1978; Meisch, 1975; Meisch & Beardsley, 1975; Meisch & Thompson, 1971, 1974b, 1974c; Poling & Thompson, 1977b


etonitazene Carroll & Meisch, 1979a; Meisch & Stark, 1977a


Rhesus monkeys
d-amphetamine Carroll & Stotz, 1983


ethanol Henningfield & Meisch, 1977, 1978, 1979; Meisch et al., 1975; Meisch & Henningfield, 1977


etonitazene Carroll & Meisch, 1978


ketamine Carroll & Stotz, 1983


methohexital Carroll et al., 1984


PCE 
(N-ethyl-l-phencyclohexylamine)
Carroll, 1982a 


pentobarbital DeNoble et al., 1982; Lemaire & Meisch, 1984; Meisch et al., 1981


phencyclidine Carroll, 1984a, 1985a; Carroll & Meisch, 1980b; Carroll & Stotz, 1983


TCP {1-[1-(2-thienyl) cyclohexyl] 
piperidine}
Carroll, 1982a


Baboons
ethanol Henningfield et al., 1981


methohexital Ator & Griffiths, 1983
 

A recent study was conducted in our laboratory to compare the effects of food satiation and food deprivation on behavior maintained by a second-order schedule. In one study three rhesus monkeys responded under a second-order fixed interval (FI) 60-minute (FR-16:S) schedule for either 300 or an unlimited number of phencyclidine (0.25 mg/ml) deliveries (0.55 ml each) while food satiated or food deprived (Carroll, 1985b). The stimulus (S) presented after each 16 responses was a brief auditory and visual stimulus and delivery of a small amount of water (0.02 ml) for 20 milliseconds. During food deprivation the second-order schedule produced high, steady rates of responding (e.g., 74.4 to 156.6 responses/minute) throughout the 60-minute interval. However, during food satiation, response rates declined to a range of 21 to 67.8, and the pattern of responding became more sporadic. Schedule-maintained responding during the 60-minute interval was not altered by the number of liquid deliveries available at the end of the session (300 vs. an unlimited number, approximately 750 to 1350). To evaluate the importance of brief stimulus presentations to the persistence of high rates of responding, brief stimulus presentations were removed; thus, the schedule was a tandem FI 60-minute/FR-16. The monkeys were also tested under a simple FI 60-minute schedule. Response rates decreased to a maximum of 33.6 and 7.8 responses/minute under the tandem and FI schedules, respectively, and these response rates decreased again by about one half when the monkeys were food satiated. These results showed that long sequences of behavior could be maintained by time-based schedules with all drug delivered orally at the end of the session. Response rates were markedly increased by food deprivation even when the amount of drug delivered at the end of the session was fixed at 300 deliveries indicating that increases in response rate due to food deprivation can occur independently of increases in drug intake.
 

 
Drug deliveries and intake as a function of phencyclamine and ketamine doses
Figure 5: Mean liquid deliveries and drug intake (mg/kg) are presented as a function of phencyclidine (PCP) or ketamine concentration for monkeys M-B2, M-P1, and M-G1. Concentrations were presented in the following order--PCP: 0.25, 0.5, 1, 2, 4, and 0.5 mg/ml; ketamine: 0.25, 0.125, and 0.5 mg/ml. The FR schedule parameters for liquid deliveries are indicated in parentheses. Upper frames: filled triangles, PCP deliveries, and open triangles, water deliveries under a concurrent FR-16 schedule. Open circles, food deprivation sessions; filled circles, food satiation sessions; solid lines, ketamine deliveries; dashed lines, concurrent water deliveries. Lower frames: PCP intake (mg/kg) is indicated by triangles. Open circles, ketamine intake during food deprivation sessions; filled circles, ketamine intake during food satiation sessions. Each point refers to a mean (± SEM) of the last five sessions of stable behavior at each condition. Reprinted with permission from Carroll and Stotz, 1983. Copyright 1983 by the American Society for Pharmacology and Experimental Therapeutics.
 

 
Table 3
Studies of Fixed-Ratio Responding Maintained by Oral Drug Delivery
Rats
codeine Suzuki et al., 1982


ethanol Meisch & Thompson, 1973; Roehrs & Samson, 1981


etonitazene Meisch & Stark, 1977a, 1977b


morphine Suzuki et al., 1982


Rhesus monkeys
ethanol Henningfield & Meisch, 1976b; Henningfield & Meisch, 1977


etonitazene Carroll & Meisch, 1978


pentobarbital DeNoble et al., 1982; Lemaire & Meisch, 1984; Meisch et al., 1981


phencyclidine Carroll, 1982b; Carroll & Meisch, 1980b
 

In another study with six monkeys, a second-order FR-240 (FR-20:S) schedule was used to generate high rates of responding in monkeys that had been performing under concurrent FR-16 schedules for 300 deliveries of phencyclidine 0.25 mg/ml (Carroll, 1984b). According to this schedule a brief stimulus was presented each time 20 lip-contact responses were completed. The stimulus consisted of a brief auditory and visual signal and the delivery of 0.02 ml of liquid. After 240 brief stimuli had been delivered, 300 phencyclidine deliveries were available from another drinking spout under an FR-1 schedule. After 10 sessions under the second-order schedule, the monkeys were returned to the concurrent FR-16 schedules. Phencyclidine-maintained responding increased by 42% after second-order schedule training, and this increase appeared to be irreversible. A control group received the same second-order schedule training with a saccharin solution rather than phencyclidine, and another control group received the same amount of phencyclidine (under an FR-1 schedule) as the initial group did during training, except they were not trained under a second-order schedule. Neither of these groups showed a change in concurrent FR-16 performance. Thus, drug-reinforced behavior was markedly influenced by a combination of brief behavioral and drug histories.

Food Deprivation Effects on Drug-Reinforced Behavior

Food deprivation increases drug intake and drug reinforced behavior (for a review see Carroll & Meisch, 1984). The increases occur with drugs from four pharmacological classes: general depressants, opioids, psychomotor stimulants, and the dissociative anesthetics. These increases are found with both the oral and intravenous routes and with both rats and rhesus monkeys. Figure 5 illustrates that over a range of ketamine concentrations, more ketamine deliveries were obtained when monkeys were food deprived than when they were food satiated (Carroll & Stotz, 1983). Figure 6 shows results from another experiment (Kliner & Meisch, 1982a). Food satiation produced an abrupt decrease in pentobarbital deliveries for four monkeys that had been maintained at 70 to 75% of their free-feeding body weights. These decreases lasted throughout the entire 30-day food satiation phase. When the monkeys were again food deprived, pentobarbital deliveries gradually increased to their former levels. Table 4 lists studies published since 1970 that have reported such increases when the oral route is used. Prior to 1970 many investigators noted that food deprivation increases ethanol intake, and these increases were attributed to the caloric property of ethanol (for a review see Meisch, 1977). Some possible explanations for the increased drug intake have been ruled out. For example, the greater drug intake during food deprivation is not due to a nonspecific increase in activity or to increased intake of the vehicle. Food deprivation appears to act by enhancing the reinforcing efficacy of the drugs, but the mechanism is not known. The increases in drug intake due to food deprivation may be a specific case of a more general phenomenon, for increased intravenous drug self-administration has been reported to occur during water deprivation (Carroll & Boe, 1982).
 

 
Liquid deliveries as a function of food condition
Figure 6: Liquid deliveries of 1 mg/ml pentobarbital (filled points) or water (open points) are plotted as a function of food condition: deprivation (sessions 1 to 10), satiation (sessions 11 to 40), and redeprivation (sessions > 41). Numbers and arrows above data points refer to the body weights of monkeys (in kilograms) and the respective days on which they were obtained. Note that the FR size differed for each of the four monkeys tested. Reprinted with permission from Kliner and Meisch, 1982a. Copyright 1982 by Ankho International, Inc.
 

 
Table 4
Studies of Food Deprivation and Food Satiation
on Behavior Reinforced by Oral Drug Delivery
Rats
ethanol Beardsley et al., 1978; Meisch & Thompson, 1973, 1974b; Roehrs & Samson, 1982


etonitazene Carroll et al., 1979; Carroll & Meisch, 1979b, 1980a, 1981; Meisch & Kliner, 1979; Meisch & Stark, 1977b


fentanyl Carroll & Meisch, 1984


Rhesus monkeys
d-amphetamine Carroll & Stotz, 1983


ethanol Kliner & Meisch, unpublished data


ketamine Carroll & Stotz, 1983


methohexital Carroll et al.,1984


pentobarbital Kliner & Meisch, 1982a, 1982b


phencyclidine Carroll, 1982b, 1985b; Carroll & Meisch, 1980b; Carroll & Stotz, 1983
 

 Conclusions

Drugs from the four major classes of abused drugs—opioids, psychomotor stimulants, dissociative anesthetics, and general depressants—can function as effective reinforcers when taken by mouth. The subjects used in these studies have included rats, rhesus monkeys, and baboons. Several different procedures can be used to establish drugs as reinforcers. Work in our laboratory has shown that some acquisition procedures can effectively establish some drugs as reinforcers in only a few weeks. However, no one procedure is uniformly effective for all drugs and subjects.

There are many advantages to using the oral route. Long sequential experiments can be conducted, and invasive surgical procedures and sterile conditions are not necessary. Importantly, the oral route is the most common route of drug abuse in humans. However, there are several limitations to the oral procedure. For example, the aversive taste of drug solutions may limit the range of concentrations that can be tested, and it often takes longer with the oral route than with the intravenous route to establish drugs as reinforcers. It appears to be more difficult to establish orally delivered drugs as reinforcers for rats than it is for rhesus monkeys. Monkeys are more expensive than rats, but their experimental life is longer than that of rats.

Acquisition procedures and their results vary considerably with drugs and species, but once drug reinforced behavior has been established, the amount and pattern of responding seem to be independent of the particular training procedure used. The stabilized pattern of responding is characterized by a negatively accelerated time course; that is, the highest rate of responding is at the beginning of the session. Number of drug deliveries is an inverted U-shaped function of drug concentration; whereas, drug intake (mg of drug/kg of body weight/hour) is a direct function of drug concentration. High persistent rates of responding can be maintained under intermittent schedules of reinforcement. Under many conditions food deprivation increases drug reinforced behavior. Findings obtained with the oral route confirm and extend findings obtained with the intravenous route. These findings also demonstrate the feasibility of using the oral route in studies of drug reinforced behavior.

Acknowledgments

Preparation of this manuscript was supported by NIAAA Grant AA 00299, NIDA Grant DA 00944, and Research Scientist Development Award DA 00007 to R. A. M. and by Grants DA 02486 and DA 03240 to M. E. C.

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