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Intravenous Self-Administration: Response Rates,
Effects of Pharmacological Challenges, and Drug Preferences
Robert A. Yokel
Division of Pharmacology and Toxicology
College of Pharmacy
University of Kentucky
Lexington, Kentucky 40536-0053
|Intravenous self-administration preparations, utilizing a chronic indwelling catheter, have been developed for the rat, rhesus monkey, dog, squirrel monkey, pig, baboon, cat, and mouse. A wide variety of psychoactive drugs has been tested in these animal preparations which are considered to be reliable predictors of the abuse potential of drugs. Maintained self-administration is taken as evidence of reinforcing effect, and therefore abuse potential, and has been reported for most of the drugs that humans abuse. Use of the self-administration technique also predicts that some drugs not widely available for human use would be abused if available. Long-term drug access results in drug-intake patterns and drug-induced effects in animals that are similar to those seen in humans. The self-administration technique has been widely used to determine the neurotransmitter basis of the reinforcing effects of drugs. Drug preference and reinforcement magnitude have been estimated by comparing the self-administration of two or more drugs available under various experimental conditions, including choice procedures, progressive-ratio reinforcement schedules, and chain reinforcement schedules.|
Intravenous self-administration in experimental animals can be viewed as an operant behavior. The response, usually a lever press, is followed by a drug injection. In the initial work rats were used as experimental subjects. This required development of techniques which did not necessitate restraint. This was first successfully accomplished by Jim Weeks (1962), who developed a swivel and leash arrangement allowing the intravenous injection of drugs in rats, restrained only by the leash attached to the animal’s back. The method of Weeks has been modified somewhat over the past 20 years (Pickens & Thompson, 1975; Smith & Davis, 1975; Weeks, 1972) and has been applied to the rhesus monkey (Deneau, Yanagita, & Seevers, 1969; Thompson & Schuster, 1964), the squirrel monkey (Goldberg, 1973; Stretch & Gerber, 1970), the pig (Bedford, 1973), the dog (Jones & Prada, 1973), the baboon (Griffiths, Findley, Brady, Dolan-Gutcher, & Robinson, 1975; Lukas, Griffiths, Bradford, Brady, Daley, & Delorenzo, 1982), the cat (Balster, Kilbey, & Ellinwood, 1976), and the mouse (Criswell & Ridings, 1983).
Basically, a silicone rubber catheter, or less commonly a polyvinyl chloride catheter, is implanted into the internal or external jugular vein or into the femoral vein, and sufficient tubing is inserted so that the catheter ends in or near the atrium of the heart. The tubing is usually passed subcutaneously around the shoulder to exit from either the center of the back or from the top of the head (Balster et al., 1976; van Ree, Slangen, & De Wied, 1978). This intravenous catheter is ultimately connected to a pump, which delivers the intravenous fluid injections from its fluid reservoir. [For details on catheter construction and surgical implantation, see Deneau et al., 1969; Jones and Prada, 1973; Pickens and Dougherty, 1972; Smith and Davis, 1975; or Weeks, 1972, who suggests sources of equipment and supplies useful in setting up this technique.] For animals not restrained in a chair during experimental sessions, a chain, parallel with the tubing, is connected to the jugular catheter connecting the animal to a swivel which is mounted either on the top or on the side of the cage. The chain protects the tubing and provides rigidity; as the animal turns in the experimental chamber, it rotates the fluid swivel. The chain is connected to the animal by a harness around its torso, (Weeks, 1972), a subcutaneously implanted anchor on the animal’s back (Pickens & Dougherty, 1972), or an assembly attached to the animal’s skull (Balster et al., 1976). Application of this technique to most species has included the use of a padded leather harness or jacket to facilitate connection of the intravenous cannula to the leash. In dogs and primates a hinged or flexible metal tubing is used as the leash to enclose and to protect the fluid tubing and to provide sufficient rigidity to rotate the fluid swivel. If good catheter materials are used, if the catheter is properly implanted, and if preventive measures are taken against the development of a fibrin clot in the catheter tip, the catheter should remain open for weeks to months in rats and perhaps for a year or more in monkeys and dogs. During prolonged periods between self-administration sessions, hourly or daily programmed injections of vehicle or of heparinized saline help to keep the catheter open (Findley, Robinson, & Peregrino, 1972). The experimental preparation is therefore a chronically intravenous catheterized subject that may be semi-restrained in a chair during a self-administration session (e.g., monkeys) or may be allowed to move freely within the experimental chamber (e.g., rats, cats, and dogs). The technique for intravenous self-administration has been applied to other routes of administration, including the oral, intragastric, and intracranial routes (see Amit, Smith, & Sutherland, this volume; Bozarth, this volume; Meisch & Carroll, this volume.)
Self-administration of a drug is claimed to occur when the operant responding which produces the intravenous drug injection by programming equipment or microprocessor-controlled activation of the fluid pump is initiated and maintained. Generally it is concluded that a drug is self-administered if the rate of drug responding is greater than the response rate on a control lever (which does not result in drug injections), if the rate of drug responding is greater than the saline (or vehicle) response rate, or if the response rate is greater in the subject whose response produces drug injections than its yoked control (Davis & Miller, 1963; Pickens, Meisch, & McGuire, 1967). It can be easily determined if responding is being maintained by drug injection (e.g., if the drug is serving as a reinforcer) by turning off the injection pump or by replacing the drug solution in the pump reservoir with a saline (or vehicle) solution. Extinction (an increase in response rate followed by a cessation of responding) should become evident (Pickens & Harris, 1968; Pickens & Thompson, 1968; Weeks, 1962; Winger & Woods, 1973). If the experimental chamber has two or more response levers with only one producing drug injections, then switching the contingencies between the levers (making the drug lever a control lever and vice versa) should result in appropriate switching of responding. If the response requirement is increased from one response (FR-1 or CRF) to 10 responses per injection (FR-10) then one would expect to see an appropriate increase in the response rate providing the drug dose is an adequate reinforcer (Pickens & Harris, 1968). It has been demonstrated that drug responding under partial reinforcement schedules (e.g., fixed-ratio, fixed-interval, etc.) maintains response patterns consistent with the reinforcement schedule—similar to those obtained with traditional reinforcers like food and water (Pickens, Meisch, & Thompson, 1978; Pickens & Thompson, 1972; Spealman & Goldberg, 1978). In fact, by selecting the proper amounts of reinforcers and the appropriate reinforcement schedule, such as a second order schedule, the rate and pattern of responding by squirrel monkeys for food and cocaine are the same (Goldberg, 1973; Goldberg & Kelleher, 1976). However, when barbiturates or phencyclidine are the reinforcers, increasing the response requirement for drug injection results in reduction of the drug consumed--appropriate increases in responding do not result.
If an experimentally naive animal is prepared with a chronic intravenous catheter and drug injections are made available by allowing access to the lever programmed to deliver drug injections, the subject may eventually initiate self-administration of the drug. If the rate exceeds control lever or saline responding, the drug is probably reinforcing. Less stringent demonstrations that a drug can serve as a reinforcer are obtained: (a) when the experimental subject is first made physically dependent on the drug by programmed drug delivery and then allowed to respond for drug injections after the programmed delivery is terminated (Weeks, 1962); (b) when the subject is trained to respond for a traditional reinforcer (e.g., food) before making the drug injection a consequence of the response (Talley & Rosenblum, 1972); (c) when responding is first established with another reinforcing drug before making the drug of study a consequence of the response (i.e., the substitution technique where the drug under investigation is substituted for the training drug either during the same session [Yokel & Wise, 1978] or during a subsequent session [Winger & Woods, 1973; Yokel & Pickens, 1973]); (d) when shock avoidance is used to encourage drug responding (Findley et al., 1972); (e) when the subject is enticed to respond for the study drug by placing food on the response lever to increase the probability of the first few responses (Johanson & Schuster, 1975); (f) when drugs are injected noncontingently as the study drug is first made available for self-administration (Lyness, Friedle, & Moore, 1980); or (g) when the use of partial food deprivation and prior experience with lever pressing for food presentation encourage drug intake (Lang, Latiff, McQueen, & Singer, 1977).
Using the above approaches, a wide variety of compounds has been demonstrated to maintain intravenous self-administration, as listed in Table 1. These compounds are all centrally acting. It is their central action that is responsible for their reinforcement effects (Yokel & Pickens, 1973; Koob, Pettit, Ettenberg, & Bloom, 1984; Woolverton, Goldberg, & Ginos, 1984).
Drugs that humans abuse are not the only compounds that are
by animals, as listed in Table 1. Although the self-administration
does have good predictive value and has been used to predict abuse
(Brady, Griffiths, Hienz, Ator, Lukas, &
this volume; Clineschmidt, Hanson, Pflueger, & McGuffin, 1977;
Schuster, Aigner, Johanson, & Gieske, 1982; Weeks
& Collins, this volume; Yanagita, this
volume; Yanagita & Takahashi, 1973; Yokel & Pickens, 1973),
it seems likely that some of the drugs reported to be self-administered
by animals (ACTH, clonidine, and haloperidol) will not be abused by
although many of these drugs have positive and negative reinforcing
depending on the circumstances (Wise, Yokel, & de Wit, 1976).
|Acetaldehyde||rat||Myers et al., 1982|
|Moreton et al., 1976
Harrigan & Downs, 1978
|nor-l-a-Acetylmethadol||rat||Young et al., 1979|
|dinor-l-a-Acetylmethadol||rat||Young et al., 1979|
|ACTH||rat||Jouhaneau-Bowers & Le Magnen, 1979|
|Griffiths et al., 1981
Davis & Miller, 1963
Winger et al., 1975
|Griffiths et al., 1975
Risner & Jones, 1975
Deneau et al., 1969
Stretch & Gerber, 1970
Yokel & Pickens, 1973
Balster & Schuster, 1973
|Baxter et al., 1974
Woolverton et al., 1984
Gill et al., 1973
|Barbital||rhesus monkey||Winger et al., 1975|
|Bromocriptine||rhesus monkey||Woolverton et al., 1984|
|Buprenorphine||rhesus monkey||Lukas et al., 1984|
|Bupropion||rhesus monkey||Woods, 1983|
|Butorphanol||rat||Steinfels et al., 1982|
|d-N-Butylamphetamine||rhesus monkey||Woolverton et al., 1980|
|Atkinson & Enslen, 1976
Deneau et al., 1969
|Cathinone||rhesus monkey||Johanson & Schuster, 1979|
|Chlordiazepoxide*||rhesus monkey||Yanagita & Takahashi, 1973|
|Chloroprocaine||rhesus monkey||Woolverton & Balster, 1982|
|Griffiths et al., 1975
Baxter et al., 1973
|Clonidine||rat||Shearman et al., 1977|
|Clortermine||baboon||Griffiths et al., 1975|
|Griffiths et al., 1975
Balster et al., 1976
Deneau et al., 1969
|Collins & Weeks, 1965
Deneau et al., 1969
|Diazepam*||rhesus monkey||Yanagita & Takahashi, 1973|
|Griffiths et al., 1975
Baxter et al., 1973
Johanson et al., 1976a
Gill et al., 1973
|Dimethocaine||rhesus monkey||Woolverton & Balster, 1982|
|Dimethylprocaine||rhesus monkey||Woolverton & Balster, 1982|
|Dynorphin-[1-13]||rat||Khazan et al., 1983|
|D-ala2-Dynorphin-[1-11]||rat||Khazan et al., 1983|
|D-Enkephalin||rat||Tortella & Moreton, 1980|
|rhesus monkey||Mello & Mendelson, 1978|
|Smith & Davis, 1974
Deneau et al., 1969
|d-N-Ethylamphetamine*||rhesus monkey||Woolverton et al., 1980|
|Ethyl ketocyclazocine||rat||Young & Khazan, 1983|
|Etonitazene||rat||Carroll et al., 1979|
|Cone & Risner, 1983
Estrada et al., 1967
|Fenetylline||rhesus monkey||Hoffmeister, 1980|
|Fentanyl||rat||Shearman et al., 1977|
|Flurazepam*||rat||Collins et al., 1984|
|Haloperidol*||rat||Glick & Cox, 1975a|
|Blakesley et al., 1972
Harrigan & Downs, 1978
|Hexobarbital||rat||Davis et al., 1968|
|rat||Collins & Weeks, 1965|
|Lukas et al., 1984b
Moreton et al., 1977
|Ketocyclazocine||rat||Young & Khazan, 1983|
|Risner & Silcox, 1979
Wilson & Schuster, 1976
|Meperidine||rat||Collins & Weeks, 1965|
|Collins & Weeks, 1965
Harrigan & Downs, 1978
|Table 1 continues . . .|
|Balster et al., 1976
Pickens et al., 1967
Deneau et al., 1969
Gill et al., 1973
|l-Methamphetamine*||rat||Yokel & Pickens, 1973|
|Pickens et al., 1981
Winger et al., 1975
|baboon||Griffiths et al., 1975|
|Griffiths et al., 1975
Risner & Jones, 1975
Wilson et al., 1971
|Jones & Prada, 1973
Criswell & Ridings, 1983
Thompson & Schuster, 1964
Goldberg et al., 1979
|Nalbuphine||rat||Steinfels et al., 1982|
|Nalorphine*||rat||Collins et al., 1984|
|Ator & Griffiths, 1983
Risner & Goldberg, 1981
Lang et al., 1977
Deneau & Inoki, 1967
Goldberg et al., 1981
|Norcocaine||dog||Risner & Jones, 1980|
|Oxymorphone||rhesus monkey||Aigner & Balster, 1979|
|Steinfels et al., 1982
Hoffmeister & Schlichting, 1972
|Griffiths et al., 1981
Collins et al., 1984
Deneau et al., 1969
|Lukas et al., 1984
Carroll et al., 1979
Balster et al., 1973
|Lukas et al., 1984b
|b-Phenethylamine||dog||Risner & Jones, 1977|
|Griffiths et al., 1975
Risner & Jones, 1975
Baxter et al., 1973
Wilson et al., 1971
|Phentermine||baboon||Griffiths et al., 1976|
|Pipradrol||rhesus monkey||Wilson et al., 1971|
|Piribedil (ET 495)||rat
|Davis & Smith, 1977
Woolverton et al., 1984
|Collins et al., 1984
Ford & Balster, 1977
|Propiram||rhesus monkey||Hoffmeister & Schlichting, 1972|
|Collins et al., 1984
Hoffmeister & Schlichting, 1972
|d-N-Propylamphetamine||rhesus monkey||Woolverton et al., 1980|
|Propylbutyldopamine||rhesus monkey||Woolverton et al., 1984|
|Griffiths et al., 1975
Findley et al., 1972
|rhesus monkey||Estrada et al., 1967|
|Tetracaine||rhesus monkey||Woolverton & Balster, 1979|
|D 9 THC*||rat
|Takahashi & Singer, 1979
Pickens et al., 1973
|Thiamylal*||rhesus monkey||Winger et al., 1975|
|Wy 13,828||rat||Baxter et al., 1973|
|*Compounds with equivocal reinforcing properties listed in both Tables 1 and 2.|
Although it is not possible to demonstrate that a drug will not be
(i.e., not serve as a reinforcer) under any condition in any species,
studies have failed to obtain drug self-administration after employing
several techniques which should elicit drug self-administration (see
2). For example, Harris, Waters, and McLendon (1974) failed to obtain
self-administration (a) in experimentally naive rhesus monkeys, (b) in
drug self-administration experienced monkeys, (c) in monkeys that had
repeated THC injections, and (d) in monkeys that had THC paired with a
reinforcing drug (cocaine). The latter two procedures assured that the
subjects had experience with THC. However, Deneau and Kaymakcalan
obtained THC self-administration in some of the rhesus monkeys tested
repeated programmed injections and after induction of dependence. THC
was also obtained after replacing the phencyclidine that monkeys were
with THC, although substitution of cocaine by THC did not result in THC
self-administration (Pickens, Thompson, & Muchow, 1973). Van Ree et
al. (1978) reported self-administration after four days of THC
Rats maintained at 80% free-feeding weight and trained to work for food
on a fixed interval 1-min schedule have also been reported to
THC (Takahashi & Singer, 1979). Caffeine self-administration has
observed in monkeys by Schuster, Seevers, and Woods (1969) and by
et al. (1969), although not by Hoffmeister and Wuttke (1973) nor by
and Enslen (1976) in rats.
|Aminophenazone||rhesus monkey||Hoffmeister & Wuttke, 1975|
|Amitriptyline||rhesus monkey||Hoffmeister, 1977|
|Aspirin||rhesus monkey||Hoffmeister & Wuttke, 1973|
|Buspirone||rhesus monkey||Balster & Woolverton, 1982|
|Caffeine*||rhesus monkey||Hoffmeister & Wuttke, 1973|
|Chlordiazepoxide*||rhesus monkey||Balster & Woolverton, 1982|
|Chlorphentermine*||rhesus monkey||Yanagita et al., 1969|
|van Ree et al., 1978
Deneau et al., 1969
Gill et al., 1973
|Clonazepam||baboon||Griffith et al., 1981|
|Griffith et al., 1981
Balster & Woolverton, 1982
|Collins et al., 1984
Aigner & Balster, 1979
|Diazepam*||baboon||Griffiths et al., 1981|
|Diethylaminoethanol||rhesus monkey||Woolverton & Balster, 1979|
|rhesus monkey||Woolverton & Balster, 1982|
|Ethanol*||rat||Collins et al., 1984|
|N-Ethylamphetamine*||rhesus monkey||Tessel & Woods, 1975|
|Griffiths et al., 1976
Risner & Silcox, 1981
Baxter et al., 1973
Woods & Tessel, 1974
Gill et al., 1973
|Flurazepam*||baboon||Griffiths et al., 1981|
|d, l-Glaucine.1.5-phosphate||rhesus monkey||Schuster et al., 1982|
|Haloperidol*||rhesus monkey||Hoffmeister, 1977|
|aHHC||rhesus monkey||Aigner & Balster, 1979|
|Imipramine||rhesus monkey||Yanagita et al., 1972|
|Imipramine-N-oxide||rhesus monkey||Yanagita et al., 1972|
|Iprindole||rhesus monkey||Yanagita et al., 1972|
|Levallorphan||rhesus monkey||Aigner & Balster, 1979|
|Lidocaine||rhesus monkey||Woolverton & Balster, 1979|
|Maprotiline||rhesus monkey||Yanagita et al., 1972|
|Mescaline||rhesus monkey||Deneau et al., 1969|
|l-Methamphetamine*||squirrel monkey||Gill et al., 1973|
|Methoxyamine||dog||Risner & Jones, 1976b|
|Medazepam||baboon||Griffiths et al., 1981|
|Midazolam||baboon||Griffiths et al., 1981|
|rat||Clineschmidt et al., 1977|
|Nalorphine*||rhesus monkey||Deneau et al., 1969|
|van Ree et al., 1978
Goldberg et al., 1971a
|Nefopam||rat||Collins et al., 1984|
|Perphenazine||rhesus monkey||Johanson et al., 1976b|
|Phenylbutazone||rhesus monkey||Hoffmeister & Wuttke, 1975|
|Phenobarbital||rat||Collins et al., 1984|
|Phenylpropanolamine||baboon||Griffiths et al., 1978|
|Phenytoin||rat||Collins et al., 1984|
|Pilocarpine||rat||Glick & Cox, 1975b|
|Piperocaine||rhesus monkey||Woolverton & Balster, 1982|
|Procainamide||rhesus monkey||Woolverton & Balster, 1979|
|Propoxycaine||rhesus monkey||Woolverton & Balster, 1982|
|Protriptyline||rhesus monkey||Yanagita et al., 1972|
|Glick & Cox, 1975b
Aigner & Balster, 1979
(a DA agonist)
|rhesus monkey||Woolverton et al., 1984|
|D 9 THC*||rhesus monkey||Harris et al., 1974|
|*Compounds with equivocal reinforcing properties listed in both Tables 1 and 2.|
Patterns of Drug Intake
Once self-administration is initiated a pattern of drug intake often develops. After initiation of stimulant self-administration, drug intake usually continues for a few days before a period of drug abstinence lasting hours or days is self-imposed by the experimental animal. Over weeks or months of unlimited drug access a pattern of alternating drug-intake and drug-abstinence periods is seen. During drug intake periods there is a great increase in the level of behavior (usually stereotypic movements with little locomotion) accompanied by reduced food and water intake and by no sleeping. Food and water intake and sleeping occur during drug abstinence periods. Alternating periods of stimulant drug intake and abstinence have been reported for amphetamine and methamphetamine (Deneau et al., 1969; Pickens & Harris, 1968; Yokel & Pickens, 1973), cocaine (Deneau et al., 1969; Johanson et al., 1976a), caffeine (Deneau et al., 1969), fencamfamin and SPA (Estrada et al., 1967), methylphenidate and phenmetrazine (Risner & Jones, 1975, 1976a), diethylpropion (Johanson et al., 1976b), and mazindol (Risner & Jones, 1980). Humans demonstrate similar periods of drug intake (binges) and abstinence (Kramer, Fischman, & Littlefield, 1967). Stimuli (perhaps internal) normally initiating a period of drug intake are largely unstudied. However, the ability of external stimuli, particularly drugs, to initiate a period of self-administration is a fruitful approach to the evaluation of the stimulus and reinforcing properties of drugs (see Stewart & de Wit, this volume).
Self-administration of freely available ethanol is also characterized by alternating intake and abstinence periods. Withdrawal symptoms, including convulsions, often appear during the self-imposed drug abstinence periods (Winger & Woods, 1973). Pentobarbital self-administration is characterized by a lack of abstinence periods—monkeys consume the maximum amount of drug they seem to be able to physically obtain (Deneau et al., 1969; Yanagita & Takahashi, 1970). Intravenous opioid self-administration of unlimited drug results in a more uniform pattern with fairly constant daily intake mainly during the light phase (daytime) with less drug intake during the evening. Animals, like humans, do not exhibit voluntary opioid abstinence periods (Deneau et al., 1969; Harrigan & Downs, 1978). Self-administration of phencyclidine, when freely available, results in periods of severe intoxication sufficient to interfere with further drug responding, alternating with periods of mild intoxication during which eating and drinking occur. Withdrawal signs are seen upon drug discontinuation (Balster et al., 1973; Balster & Woolverton, 1980).
Nearly all intravenously self-administered drugs present the risk of being consumed by the experimental animal to the point of acute toxicity or death during periods of unlimited access. Convulsions and self-mutilation have been seen from stimulants (Deneau et al., 1969; Yokel & Pickens, 1973); severe intoxication and respiratory depression have been seen from ethanol, barbiturates, and opioids (Deneau et al., 1969; Harrigan & Downs, 1978; Winger & Woods, 1973); and convulsions have been seen from codeine (Deneau et al., 1969). Unlimited access results in a high incidence of fatality when stimulants are self-administered—most rats and monkeys die within a few weeks after initiation of drug intake—and a lower but significant incidence of fatality from depressants.
Due to the fluctuations in drug intake over time and the risk of acute and chronic toxicity when the self-administered drug is freely available, experimenters place restrictions on drug availability. Typically, drug is made available for self-administration for only a few (1 to 6) hours during daily sessions or during less frequent sessions when long acting drugs are being evaluated. In addition, response requirements for drug injections are often increased beyond a single response.
Regulation of Response Rate
When drug availability is limited to a daily session of several
drug intake is usually quite stable from session to session. After a
sessions experimental subjects learn to initiate drug responding as
as drug becomes available. The stability of the rate of
can be seen from a plot of the number of injections, of the amount of
consumed, or of the number of responses per session across sessions.
reported data are often the total drug intake or the number of
during an experimental session. Some investigators report their data in
successive 1 hour time periods, which is beneficial when response rate
is not uniform throughout the session. For example, with the stimulants
amphetamine and cocaine, there is a period at the beginning of the
session where several injections are earned in rapid succession before
response rate stabilizes in the second or third hour (e.g., see Figure
1). Resolution of results into 1 hour time blocks is useful to see
in drug response rate caused by manipulations such as pharmacological
particularly when the pharmacological probe may have an onset or
of action that would not produce uniform pharmacological effects
the self-administration session (e.g., see Figures 5 and 6). For drugs
that produce very uniform response rates, like cocaine and apomorphine,
the use of inter-response times can be a sensitive measure of changes
self-administration rate (Dougherty & Pickens, 1973; Griffiths,
& Brady, 1979).
|Figure 1: Representative event records from 6 hour sessions of drug lever responding (upper record) and control lever responding (lower record) for several doses of the two optical isomers of amphetamine or methamphetamine. Reprinted with permission from Yokel and Pickens, 1973. Copyright 1973 by the American Society for Pharmacology and Experimental Therapeutics.|
Producing a stable response rate by limiting drug access allows
of variables relevant to the reinforcing effects of the drug. For
if different doses of the drug are available for injection during
sessions, it becomes apparent that below a certain dose the drug will
be self-administered, perhaps being too weak of a reinforcing stimulus.
Above a certain dose the drug will not maintain self-administration,
due to aversive properties. The resulting function between the number
responses per session and the dose of the drug injected becomes an
To the right of the peak of this inverted U-shaped dose response curve
(on the descending limb), response rate decreases as the injection dose
increases, as shown in Figure 2. If the amount of drug consumed is
against the drug dose, then one usually sees a slight increase in drug
intake as the drug dose greatly increases. For example, a 50 fold
in the injection dose of cocaine resulted in only a 5 fold increase in
intake (Wilson et al., 1971); an 8 fold increase in d-amphetamine,
phenmetrazine and methylphenidate produced no more than a 2.5 fold
in intake (Risner & Jones, 1975); procaine intake increased 10 fold
over a 30 fold increase in dose (Ford & Balster, 1977); sodium
methohexital, pentobarbital, and thiopental intake increased less than
2 fold over an 8 fold increase in dose (Goldberg, Hoffmeister,
& Wuttke, 1971b; Winger et al., 1975); and a 30 fold increase in
dose produced only a 3 fold increase in intake (Smith, Werner, &
1976; Weeks & Collins, 1964). Therefore, the increase in drug
is only 10 to 25% of the increase in injection dose. These results have
been taken as evidence that drug intake is being regulated by the
to produce, over a fairly broad range of doses, a fairly uniform
|Figure 2: Mean injections per hour and drug intake per hour for intravenous injection of amphetamine and methamphetamine isomers as a function of injection dose. All values are means ± SEM (vertical lines) in micromoles per kilogram of base. SEM in some cases is less than point height. Reprinted with permission from Yokel and Pickens, 1973. Copyright 1973 by the American Society for Pharmacology and Experimental Therapeutics.|
Several mechanisms have been hypothesized to account for this
of drug intake, including an adjustment of response rate to maintain a
fairly constant drug level in the animal, a suppression of ongoing
by each drug injection in a dose-dependent manner, and a production of
aversive effects by the drug injection in a dose dependent manner
further intake (Wilson et al., 1971). Support for the maintenance of a
minimal drug level as the mechanism regulating drug intake was provided
from calculations of whole body amphetamine levels during
in rats. The calculations indicated that the trough levels were always
about the same (see Figure 3). That is, rats responded for subsequent
injections when metabolism had reduced their drug level to a fairly
critical level. Obviously, peak drug levels were much greater after
than smaller drug injections; thus, peak levels were not uniform. When
was compared to l-amphetamine, the former being about 3 times
potent in maintaining self-administration in the rat (Yokel &
1973), it was found that the calculated drug level at the time of
for a subsequent injection was three times higher with
than d-amphetamine. This supports the notion of maintenance of
minimal effect (Yokel & Pickens, 1974). Furthermore, consideration
of the first order kinetics of amphetamine metabolism explained the
increase in intake as drug dose was increased. That is, the larger
doses merely resulted in more drug being metabolized between drug
while the minimal drug level, which perhaps served as a stimulus for
responding, was maintained. Analysis of amphetamine levels in blood of
rats self-administering d-or l-amphetamine demonstrated
across a 4 fold range of injection doses blood amphetamine levels were
constant at the time of responding for drug injection and that the
were about three times higher with the l-isomer, which was 1/3
potent as the d-isomer (see Figure 4). Cone, Risner, and
(1978) found in the dog that plasma b-phenethylamine
levels were relatively constant when a drug response was made.
|Figure 3: Calculated d-amphetamine whole body drug level during self-administration in a rat. Each point represents the drug level at the time of responding for drug injection. Reprinted with permission from Yokel and Pickens, 1974. Copyright 1974 by Springer-Verlag.|
|Figure 4: Mean ± SEM of measured blood levels of amphetamine isomers in rats at approximately 2, 4, and 6 hours into a 6 hour session of self-administration of those isomers. * = no replication. Reprinted with permission from Yokel and Pickens, 1974. Copyright 1974 by Springer-Verlag.|
The Effects of Pharmacological Challenges
As previously noted, a stable response rate allows manipulation of variables that influence the reinforcing effects of drugs. One approach is the use of pharmacological agents. For example, if the reinforcing drug which the animal is self-administering is given noncontingently before or during a drug self-administration session, there is a suppression of responding (Weeks & Collins, 1964). Unfortunately, a suppression of responding can also be obtained with drugs producing nonspecific behavioral disruption. For example, Wilson and Schuster (1973) found that administration of imipramine, morphine, pentobarbital, d-amphetamine, and phenmetrazine all produced similar decreases in the self-administration of cocaine. However, upon observation, monkeys receiving d-amphetamine, phenmetrazine, and imipramine looked the same as they did during control cocaine self-administration sessions, whereas monkeys receiving morphine or pentobarbital showed gross evidence of depression (e.g., decreased grooming, locomotion, and absence of cocaine-induced stereotypic behaviors). Additionally, d-amphetamine and phenmetrazine produced dose-dependent durations of suppression of cocaine intake. One can conclude from these observations that manipulations increasing or substituting for the reinforcing properties of the drug being self-administered maintain other behaviors but suppress drug responding for a period of time commensurate with the duration of action of the manipulation. By comparison, manipulations which reduce the reinforcing properties of the drug may result in an increased drug intake to compensate for the reduced drug effectiveness, while other behaviors (nondrug responding) remain unchanged. This is well illustrated by demonstrations that increasing doses of nalorphine, naloxone, and naltrexone will initially increase then decrease the rate of morphine and heroin intake in rats and rhesus monkeys (Downs & Woods, 1975; Ettenberg, Pettit, Bloom, & Koob, 1982; Glick, Cox, & Crane, 1975; Goldberg, Hoffmeister, Schlichting, & Wuttke, 1971a; Thompson & Schuster, 1964; Weeks & Collins, 1964). Likewise, antibodies to morphine produce an increase in heroin intake (Killian, Bonese, Rothberg, Wainer, & Schuster, 1978). Although an increased drug intake following a pharmacological challenge may reflect a reduced reinforcement magnitude of the drug, alternative interpretations may need to be ruled out. The pharmacological challenge may increase drug intake by antagonizing an aversive, behaviorally disruptive or toxic action of the self-administered drug or by alteration of the absorption, distribution, biotransformation, or excretion of the self-administered drug (Wilson & Schuster, 1973).
Pharmacological probes that reduce the function of neurotransmitter systems mediating the reinforcing effects of a self-administered drug produce the expected increase in drug intake in the absence of observable changes in nondrug responding behaviors. Amphetamine’s pharmacological actions, although many, are all believed to be dependent on catecholaminergic function. Treatment of rats or rhesus monkeys self-administering an amphetamine or cocaine with an inhibitor of catecholamine synthesis (alpha-methyl-para-tyrosine: ampt) resulted in a temporary increase in drug intake (Baxter, Gluckman, & Scerni, 1976; Pickens, Meisch, & Dougherty, 1968; Wilson & Schuster, 1974). With increases in the dose of a mpt there was a further increase in response rate until a dose of a mpt was reached which produced termination of responding. These results can be interpreted as partial blockade of drug reinforcement effects from doses of a mpt which produced increased drug intake progressing to complete blockade of reinforcement effects from a mpt doses that result in cessation of responding. The results suggest that the animal is able to overcome the blockade of reinforcement effect only to a certain dose of blocking drug; after this dose the blockade cannot be overcome with increases in drug intake, and extinction results. The advantage of using this technique to evaluate the mechanisms of drug reinforcement is that a decrease in reinforcement results in an increase in drug responding and argues against nonspecific disruption of drug responding. With most techniques the response rate reflects reinforcement. When a decreased response rate is seen the experimenter faces the nagging question whether the effect is due to reinforcement reduction or to an effect other than reinforcement reduction. One way to clarify the interpretation of changes in response rate following treatment with a potential reinforcement blocking drug is reviewed by Davis and Smith (this volume).
Further work with more specific pharmacological agents supported the
above interpretation that blockade of catecholaminergic function
amphetamine’s reinforcing effects. Administration of a fairly specific
dopaminergic blocking agent, pimozide, in doses of 0.0625 to 0.25 mg/kg
produced a dose-dependent increase in amphetamine intake similar to
produced by a mpt while the characteristic
behavior of amphetamine self-administration continued. Further
in the pimozide dose above 0.25 mg/kg produced cessation of responding
with loss of amphetamine stereotypic behavior (see Figures 5 and 6).
|Figure 5: Responding from a representative rat after various manipulations. Each vertical line represents a lever press; arrows mark the experimental manipulations. Manipulations were injections of (A) saline (intraperitoneal), (B) 0.0625 mg/kg of pimozide, (C) 0.125 mg/kg of pimozide, (D) 0.25 mg/kg of pimozide, (E) 0.5 mg/kg of pimozide, and (F) substitution of intravenous saline injections for amphetamine. Reprinted with permission from Yokel and Wise, 1975. Copyright 1975 by the American Association for the Advancement of Science.|
Utilization of a dopamine blocker with stereoisomers, one having
blocking activity (+ butaclamol), and the other not (-butaclamol),
partial and then complete extinction of amphetamine responding with the
+ isomer only (Yokel & Wise, 1976). An increase in drug responding
after lower doses of pimozide and other dopamine blockers (e.g.,
chlorpromazine, a-flupenthixol, and
and a decrease in responding after higher doses have been observed in
self-administering amphetamine, cocaine, phenmetrazine,
pipradrol, SPA, phenethylamine, and mazindol (de Wit & Wise, 1977;
Ettenberg et al., 1982; Herling & Woods, 1980; Johanson et al.,
Risner & Jones, 1976b; Risner & Jones, 1977; Risner &
1980; Risner & Silcox, 1979; Stretch, 1977; Wilson & Schuster,
1968, 1972, 1973) and in animals self-administering morphine (Davis
Smith, 1974a; Hanson & Cimini-Venema, 1972), but not heroin
et al., 1982). The dose-dependent increase, then decrease, in cocaine
following injection of dopamine-receptor blocking drugs has been
as a screening method for potential antipsychotic drugs, which
block dopamine receptors (Roberts & Vickers, 1984).
|Figure 6: Median response rate for d-amphetamine after intraperitoneal injections of various doses of pimozide, phentolamine, and l-propranolol, expressed in mg/kg body weight. Reproduced with permission from Yokel and Wise, 1975. Copyright 1975 by the American Association for the Advancement of Science.|
In comparison, the alpha-and beta-adrenergic blocking drugs phentolamine, phenoxybenzamine, and l-propranolol failed to significantly influence amphetamine, cocaine, or SPA self-administration in the rat (de Wit & Wise, 1977; Yokel & Wise, 1976), dog (Risner & Jones, 1976b; 1980), or rhesus monkey (Wilson & Schuster, 1968; 1974) suggesting that the noradrenergic system was not mediating the reinforcement effects of these stimulants. Neither phenoxybenzamine nor pimozide increased the rate of b -phenethylamine intake (although chlorpromazine did), suggesting a nonadrenergic, nondopaminergic reinforcement mechanism (Risner & Jones, 1977). A role for cholinergic systems in cocaine and amphetamine self-administration was suggested by Wilson and Schuster (1973) and by Davis and Smith (1974b), who found an increase in cocaine and d-amphetamine self-administration after atropine but not methylatropine administration. De La Garza and Johanson (1982) found an increase in cocaine intake after physostigmine, further supporting this notion. Whether the effects of cholinergic blockade and blockade of acetylcholine metabolism correspond to decreases and increases, respectively, in the reinforcing effects of these stimulants or to other factors regulating drug responding is unclear. A role for a serotonergic mechanism was suggested by Lyness et al. (1980) and by Lyness and Moore (1983) who found that destruction of serotonergic neurons by 5,7-DHT or by injection of metergoline, a serotonergic antagonist, increased the rate of d-amphetamine intake.
The results of studies using drugs as probes could be interpreted several ways. A decrease in response rate produced by the probe could be due to an increase in reinforcement effects of the drug self-administered or to an inhibition of motor behavior interfering with the animal’s ability to respond. An increase in response rate produced by the probe may be due to a decrease in reinforcement effects of the drug self-administered, to a reduction in aversive effects of the drug self-administered, or to an increase in motor behavior. One way to rule out the interference effect of changes in motor behavior is to record responding on a control lever or to use a reinforcement schedule requiring concurrent responding for another reinforcer. Another approach is to verify your interpretation of the results by using another behavioral procedure; such methods are discussed in this volume by Davis and Smith and by van der Kooy. Another approach is the study of concurrent self-administration and self-stimulation, which provides simultaneous data from two methods commonly used to evaluate drug reinforcing effects (Bozarth, Gerber, & Wise, 1980; Wise, Yokel, Hansson, & Gerber, 1977). Ultimately, humans could be used as subjects to verify the results obtained from experimental animals. In fact, many of the methods used in animal self-administration have been applied to human self-administration studies, as discussed by Henningfield, Jasinski, and Johnson (this volume) and Mello and Mendelson (this volume). The role of dopaminergic systems and the lack of a role of adrenergic systems in amphetamine reinforcement as demonstrated in animal studies reviewed above were supported by results obtained in human amphetamine abusers. The volunteers rated their subjective euphoria produced by intravenous amphetamine injections. Alpha-methyl-para-tyrosine, chlorpromazine, and pimozide reduced the euphoria, whereas phentolamine and phenoxybenzamine had little effect (Jonsson, 1972; Jonsson, Anggard, & Gunne, 1971; Jonsson, Gunne, & Anggard, 1969).
The influence of neurotransmitter system blockers on the rate of responding for reinforcing drugs suggested another pharmacological approach—the administration of neurotransmitter agonists. As noncontingent injections of amphetamine temporarily decrease amphetamine intake, would another drug having similar neurotransmitter actions produce the same effect without markedly influencing behaviors other than amphetamine responding? Administration of the dopamine agonists apomorphine and piribedil to rats self-administering d-amphetamine resulted in a temporary cessation in amphetamine responding, with larger doses of dopaminergic agonists producing a longer temporary response cessation (Yokel & Wise, 1978). Administration of the noradrenergic agonists methoxamine and clonidine failed to influence amphetamine intake in the dog and rat (Risner & Jones, 1976b; Yokel & Wise, 1978). Apomorphine, bromocriptine, piribedil, and propylbutyldopamine, all DA receptor agonists, are self-administered, whereas SKF 38393, a DA agonist, is not (Baxter et al., 1974; Davis & Smith, 1977; Gill et al., 1973; Woolverton et al., 1984; Yokel & Wise, 1978). These results suggest that DA receptor activation, rather than DA or noradrenergic activation mediates the reinforcing effects of psychomotor stimulants.
A further approach to the manipulation of neurotransmitter function in elucidating the reinforcement mechanisms of abused drugs is to manipulate the neurotransmitter systems directly. This can be accomplished by stimulation of specific pathways or nuclei of a particular neurotransmitter system or by ablation, either surgically or chemically, as discussed by Roberts and Zito (this volume).
Clearly then, response rate alone cannot be used to predict reinforcement magnitude or drug preference. To compare two or more doses of the same drug or two or more drugs for their relative reinforcement magnitude (e.g., to ask the simple question whether one is preferred over the other) requires methods more complex than merely looking at response rate. When Deneau et al. (1969) made cocaine and morphine simultaneously available to rhesus monkeys via a double lumen catheter, they found a predominance of cocaine intake during the day and morphine intake at night. Findley et al. (1972) produced a forced choice between two simultaneously available injections by shocking monkeys that failed to self-administer one of the two choices. When secobarbital and saline were choices, secobarbital was preferred. Chlordiazepoxide was preferred over saline, but secobarbital was preferred over chlordiazepoxide when these were the two choices.
One method to compare reinforcers for their relative reinforcement
is to use the discrete trial choice procedure. In the simplest case the
animal can select between two levers, either of which, when pressed,
in an injection of the drug paired with the lever. To assure experience
with each drug contingency prior to the choice session, training
can be conducted prior to the choice session with only one of the
available in each session. Using this procedure, rats were allowed to
either 0.5 or 1.5 mg/kg cocaine for 6 hours by pressing one of two
in an operant chamber (the other lever being covered). The following
6 hours of self-administration of the other dose of cocaine was allowed
by pressing the other lever. On the third day both levers were
allowing the choice between the two levers (two cocaine doses) for 6
of self-administration. Using a counterbalanced design, this procedure
was repeated three times so that the four choice sessions represented
four dose presentation orders and the dose/lever combinations. Figure 7
shows that there was no consistent preference for the larger or smaller
dose of cocaine over the other. Further stimulus cues were added during
the experiment to facilitate the distinction between the two doses. A
comparison of 0.5 mg/kg d- vs. 0.5 mg/kg l-amphetamine
comparable results (i.e., no preference; Yokel & Pickens,
observations). Johanson and Schuster (1975) used a similar discrete
choice procedure to compare cocaine, methylphenidate, and saline in the
rhesus monkey. Both cocaine and methylphenidate were preferred over
Higher doses of cocaine were preferred over lower doses. Higher doses
methylphenidate were also preferred over lower doses, although the
was not as strong as seen between the higher and lower cocaine doses.
cocaine was compared to methylphenidate, the higher dose was always
over the lower dose, regardless of the drug.
|Figure 7: Mean percentage of injections for each of two cocaine doses presented during four 6-hour choice trials in each rat. Additional stimuli were paired with drug injections for rats 29 and 39, as noted on the bottom of the figure. Yokel and Pickens, unpublished observations.|
Similar results were obtained using a concurrent schedule involving two response levers and two doses of cocaine where rhesus monkeys could choose between the two doses. Under independent (Iglauer & Woods, 1974) or dependent variable-interval schedules (where the first response on one lever inactivated the second lever until the first lever’s schedule was completed; Llewellyn, Iglauer, & Woods, 1976), the higher of two cocaine doses was consistently preferred. Utilizing several different reinforcement schedules, Shannon and Risner (1984) found that cocaine maintained higher response rates than d-amphetamine in the dog, suggesting that cocaine is more reinforcing.
Use of the progressive ratio as a means of evaluating the magnitude
of the reinforcement effect of intravenously self-administered drugs
suggested by Yanagita in 1972. The breaking point, or first ratio where
responding is not maintained, is considered to reflect reinforcement
The reinforcing drug injection producing the higher breaking point of
two compared is considered to be the more reinforcing of the pair.
and Pickens (unpublished observations) used an arithmetic
(PR) schedule to compare the breaking points of d- and l-amphetamine.
On an arithmetic PR-1 schedule, each response for successive injections
increases by 1 (FR-1, FR-2, FR-3, etc.), whereas on a PR-5 schedule
increment is 5 (FR-5, FR-10, FR-15, etc.). By presenting d-and l-amphetamine
in a counterbalanced sequence and by incrementing the PR schedule by 1
after each pair of d- and l-amphetamine
sessions until the breaking point was reached within 12 hours for one
both drugs, we were able to compare the two amphetamine isomers for
relative reinforcement magnitudes. Comparison of breaking points
that l-amphetamine was as reinforcing as d-amphetamine
the rat whether equal doses (Figure 8, left side) or equipotent doses
8, right side and Figure 9) were used.
|Figure 8: Maximum fixed-ratio completed as a function of progressive ratio value. Left side: equal injection doses. Right side: injection doses chosen to produce equal inter-injection times. (Note: These results were obtained after equal injection dose data had been obtained). Injection doses of d-amphetamine sulfate were 0.5 mg/kg. All injection doses of l-amphetamine sulfate were 0.5 mg/kg (left side) and 1.1 mg/kg for Rat 124 and 1.4 mg/kg for Rat 125 (right side). Yokel and Pickens, unpublished observations.|
Griffiths et al. (1975, 1978) have utilized the breaking point
by increasing the fixed-ratio requirement weekly to compare the
magnitudes of several stimulants in the baboon. Cocaine and
produced comparable breaking points. Lower breaking points
magnitude) were produced by diethylpropion and chlorphentermine.
was not self-administered. Comparison of cocaine, d-amphetamine,
mazindol, and fenfluramine for their relative reinforcement magnitude
the dog as evidenced by breaking point demonstrated that higher doses
more reinforcing than lower doses and that cocaine was the most
followed by amphetamine and then mazindol. Fenfluramine did not
self-administration (Risner & Silcox, 1981). The breaking point for
cocaine seems to increase as the injection dose increases to a point
which further increases in dose fail to produce any further increase in
the breaking point (Bedford, Bailey, & Wilson, 1978; Griffiths et
1979). Breaking points obtained with the progressive-ratio schedule
similar to those obtained with a fixed-ratio schedule (Griffiths et
|Figure 9: Maximum fixed-ratio completed as a function of progressive-ratio value for injections of d-and l-amphetamine. All injection doses of d-amphetamine were 0.5 mg/kg. Injection doses of l-amphetamine were 2.0 mg/kg for Rat 124 and 1.5 mg/kg for Rats 129 and 132. Yokel and Pickens, unpublished observations.|
Comparison of the reinforcement magnitude of opioids using a progressive-ratio schedule demonstrated that higher injection doses produced higher breaking points with codeine and heroin (Hoffmeister, 1979; Lukas et al., 1984). However, with d-propoxyphene, pentazocine and buprenorphine, the increase in breaking point with increased injection dose was less robust. Beyond a point increases in injection dose resulted in decreased breaking points presumably because toxicity results from these higher doses. For codeine the breaking point increased as the dose increased 16,000 times above the minimally effective reinforcing dose. For heroin the breaking point increased up to 500 times the minimally effective dose, but for pentazocine and d-propoxyphene the breaking point increased as the dose increased only to 50 or 70 times the minimally effective injection dose, suggesting a lower reinforcement potential (Hoffmeister, 1979). Applications of the progressive-ratio method of measuring the relative reinforcement magnitude of two drugs may require equipotent drug doses to obtain meaningful results.
A novel method to compare the reinforcement magnitude of two drugs was developed by Hoffmeister (1980) where drug responding occurs at the end of a chain of reinforcement schedules in which food is earned in the first two of the three components of the chain. This procedure allows the analysis of any influence of previous drug injection on schedule of nondrug (e.g., food) responding. With this procedure cocaine, d-amphetamine, and phenmetrazine were found to be better reinforcers than fenetylline, which had only weak reinforcing properties.
Since the initial observation that rats would lever press for intravenous injections of morphine, the technique of intravenous drug self-administration has been widely applied and tested. Modifications of Weeks’ original technique have been applied to at least seven other species, four of which (rhesus and squirrel monkey, dog and baboon) have been extensively used to evaluate the reinforcing potential, and therefore abuse potential, of over 100 psychoactive compounds. Self-administration techniques are considered useful in predicting drug abuse potential due to the strong concordance between human and animal drug self-administration.
When allowed unlimited drug access, animals develop patterns of drug intake that produce toxicity similar to that seen in humans. Limited drug access (short daily sessions) is required to obtain the stable drug intake rate desired to study the mechanisms of drug reinforcement. The use of pharmacological challenges has received considerable attention, in attempts to elucidate the mechanisms responsible for the reinforcing effects of abused drugs. The use of behavioral approaches to estimate the magnitude of the reinforcing effect, and therefore the preference of one drug over another, has received less attention.
The self-administration technique seems to be the procedure most clearly modeling the human drug abuser. As with any experimental approach, the results obtained from self-administration studies need to be interpreted cautiously to avoid arriving at the wrong conclusion.
I thank Elisabeth Bascom for her skillful typing of this review.
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