A summary of the results of a drug self-administration study using substitution procedures in rhesus monkeys

Sections

Method
Results
Discussion
TABLE 7 References
Acknowledgements
Bibliography

Details

Author: Chris E. JOHANSON , Robert L. BALSTER
Pages: 43 to 54
Creation Date: 1978/01/01

A summary of the results of a drug self-administration study using substitution procedures in rhesus monkeys

Chris E. JOHANSON Department of Psychiatry, The University of Chicago Pritzker School of Medicine,950 East 59th Street, Chicago, Illinois 60637, U.S.A.
Robert L. BALSTER
Department of Pharmacology, Medical College of Virginia, Virginia Commonwealth University Richmond, Virginia 23298, U.S.A.

In the early 1960s, several investigators demonstrated that opiate dependent rats and monkeys would repeatedly make responses that resulted in the intravenous delivery of morphine (Weeks, 1962; Thompson and Schuster, 1964). Subsequent research over the last 15 years has shown that non-dependent animals self-administer not only morphine but also a wide variety of other drugs, including psychomotor stimulants, barbiturates, ethanol and other opiates. Several reviews summarizing the rapidly expanding literature in this field indicate that drugs are similar to other positive reinforcers in their ability to maintain responding leading to their delivery (Schuster and Thompson, 1969; Schuster and Johanson, 1973, 1974; Goldberg, 1977; Johanson, 1978). Of particular interest is the observation that drugs which are self-administered by animals are usually considered drugs of abuse for humans. If this correlation is valid, it might be possible to use animals as a model for studying pharmacological and behavioural factors which contribute to excessive drug use in humans. One application of this model would be to use drug self-administration procedures in infra-human organisms as part of a battery for the preclinical assessment of the abuse liability of new agents.

The reinforcing efficacy or capacity of a drug can be considered one of its pharmacological properties. Like other pharmacological properties such as analgesia, however, the evaluation of reinforcing efficacy is dependent to some extent on the specific test situation, particularly when an attempt is made to quantify the property in order to compare different drugs. Researchers interested in developing a methodology for screening new compounds for their reinforcing properties are well aware of this problem. Nevertheless, it is generally believed that over a wide variety of procedures, similar qualitative results have been obtained with the drugs tested. However, in order to test this idea, an organization of interested researchers, the International Study Group Investigating Drugs as Reinforcers (ISGIDAR), sought to determine whether the results using a variety of self-administration procedures are comparable and whether these procedures can potentially be used to screen compounds for their abuse liability. The present report summarizes the findings of this group and represents the combined efforts of all the members of the organization.

One procedure which has been used extensively to measure the reinforcing properties of drugs is substitution. Animals are trained to respond on a manipulandum for drugs known to maintain responding, such as cocaine. When responding becomes stable, a dose of a test compound or vehicle (usually saline) is substituted. If saline is substituted, responding tends to decline to relatively low rates. On the other hand, when a test compound is substituted, responding may be maintained by the compound at some level above that of saline. If this occurs at any dose of a test drug, the drug is classified as a positive reinforcer. On the other hand, responding can fail to be maintained by the particular drug in a manner similar to saline, i.e. a gradual decline in response rate over several sessions. It should be emphasized that differences in the rate of responding for various drugs may be a function of many variables, only one of which is the reinforcing efficacy of the drug under study. Therefore, it is not possible using this procedure to rank drugs along a continuum of relative abuse liability. The procedure simply indicates in a qualitative manner whether or not a drug is a positive reinforcer. For instance, responding is maintained using the substitution procedure by both cocaine and diethylpropion (Johanson and Schuster, 1977). Both of these psychomotor stimulant drugs are abused by man but the incidence of cocaine use is generally recognized to be greater. However, fenfluramine, an anorexic not abused by man, does not maintain responding in animals with the substitution procedure (Tessel and Woods, 1975). Despite the qualitative nature of the data, dose-response functions do indicate differences in potency. However, these differences are not necessarily related to abuse liability.

The purpose of the present report is to summarize data generated using substitution procedures in order to assess the reliability of the results across a variety of experimental protocols, and to indicate where additional data are needed so that an evaluation of the procedure as a predictor of abuse potential can be made. For instance, if, despite differences in parameters and test situation, the results with a particular drug are consistent from laboratory to laboratory, and if these results indicate that drugs which are abused by man are self-administered by animals and drugs not abused by man are not, a case can be made for the validity of the animal model.

Method

Because of the enormity of data which could be summarized, this report includes only selected data. The criteria used for this selection are described below. The primary criterion was whether the investigators had submitted a report of their data to ISGIDAR using the form shown in table 8. Occasionally, additional published data are included when appropiate. The failure to include certain data reports does not indicate that the studies are inappropriate, but simply that the data were not made available.

Animals. Data were selected from studies using rhesus monkeys ( Macaca mulatta). Many investigators also used rats (Weeks, 1962), cats (Balster et al., 1976), dogs (Jones and Prada, 1973), squirrel monkeys (Goldberg, 1973), baboons (Griffiths et al., 1975), but data using a substitution procedure with these species are not as extensive. Drugs were delivered intravenously through catheters implanted in one of several veins (e.g. internal jugular, femoral) using a variety of surgical procedures. Animals were restrained either by a primate chair or harness and arm arrangement during experimental sessions. Studies using only one animal were not included.

A drug self-administration study using substitution procedures 45

Procedure. During experimental sessions, which varied in length, responding on a manipulandum was maintained by delivery of drug (termed baseline drug) under a specified schedule of reinforcement. In almost all the reported studies, the schedule was a fixed ratio n ( n responses required for drug delivery). The baseline drug used was known by the investigator from previous studies to maintain responding in most animals (e.g. cocaine or codeine). After responding was stable, the test drug at one dose was substituted for the baseline drug for a particular number of experimental sessions. At some point in the study, the vehicle of the test drug (usually saline) was also substituted for the baseline drug (extinction control). Several additional doses of the test drug were substituted in the same manner. Although there were some exceptions, either the baseline drug or saline was available in between the testing of each dose. Studies which tested only one dose of a test drug were not included. Responding maintained by each dose of a test drug was compared with responding maintained by the vehicle. If more than 50 per cent of the monkeys self-administered more of the test drug than saline at least at one dose, the test drug was considered a positive reinforcer.

Results

Tables 1 to 5 show all test drugs, listed by pharmacological classes, reported to ISGIDAR whose testing met the above criteria. Whether or not the drug was self-administered is indicated in column (2). Column (3) indicates the investi-gator(s) who submitted the data to ISGIDAR. The numbers refer to the investigators listed in table 6. Table 6 also lists the adresses of the investigators. Any information concerning procedural details or results can be obtained by contacting the investigators directly. If the data are available in published form, the reference is indicated in column (4). Table 7 is a list of these references.

Discussion

Using some variation of the substitution procedure, the participating laboratories of ISGIDAR have tested over 90 different compounds. As might have been expected, most of the drugs tested were well recognized drugs of abuse. However, for purposes of validation, many other types of drugs have also been tested. These include drugs presumed to have no abuse liability (e.g. imipramine, scopolamine), as well as compounds not available to the public but structurally related to an abused drug (e.g. propylamphetamine). With few exceptions (e.g., chlordiazepoxide, pentazocine, tilidine), the results obtained from different laboratories testing the same drug were in agreement. It seems therefore, that the substitution test fulfils two very important requirements for the preclinical screening of compounds: (1) many compounds can be rapidly assessed, and (2) the data are reliable across laboratories despite great variations in procedural detail.

The most important question to ask, however, is whether the substitution test is valid-i.e, are drugs which are self-administered by rhesus monkeys the same drugs that humans abuse. One of the problems in determining the answer to this question is that we are not absolutely sure about what drugs humans take in an excessive manner for non-medical purposes. There is a continuum of drugs ranging from those with considerable abuse liability to those with none. Almost everyone would agree about the status of drugs at either end of this continuum but the drugs which lie in the middle are often the subject of great debate. However, for our present purposes, our decision for saying whether or not a drug is abused by humans will be based upon our experience as experts in this area. While the reader may disagree with our decision on individual drugs, this criterion is sufficient for testing the validity of the procedure as a whole.

TABLE 1

Narcotics

Drug (1)

Result (2)

Laboratory (table 6) (3)

Reference (table 7) (4)

Agonists
     
1-Alpha-acetylmethadol
Yes
9  
Azidomorphine
Yes
15  
Codeine
Yes
4, 10, 15, 17 9, 11, 17, 25, 26
Etonitazine
Yes
9  
Etorphine
Yes
15  
Fentanyl
Yes
15  
Heroin
Yes
4, 10, 15 11
Ketobemidone
Yes
15  
Levomethorphan
Yes
15  
Levorphanol
Yes
15  
Meperidine
Yes
15, 17 26
Methadone
Yes
9, 15, 17  
Morphine
Yes
2, 4, 9, 10, 15, 17 7, 8, 9, 17
Oxymorphone
Yes
2  
d-Propoxyphene (hydrochloride)
Yes
4, 10, 15 9, 17, 29
d-Propoxyphene (napsylate)
Yes
5 29
Tilidine
Yes
10  
Tilidine
No
9  
Mixed agonist-antagonists
     
N-Amyl-nor-ketobemidone
Yes
2  
Buprenorphine
Yes
15  
Butorphanol
Yes
15  
α-Etazocine
Yes
2  
GPA-1657
Yes
2, 15 21
Nalbuphine
Yes
15  
Pentazocine
Yes
10, 17 9, 11, 26
Pentazocine
No
2, 15  
d,l-Profadol
Yes
10, 15  
Propiram
Yes
10, 15 9, 11
Antagonists
     
Cyclazocine
No
10, 15 11
Ketocyclazocine
No
15  
Levallorphan
No
9, 15  
Nalorphine
No
1, 9, 10, 15 9, 11
Naloxone
No
15  
Naltrexone
No
15  
Others
     
Dextromethorphan
Yes
17 28
Dextrorphan
No
15  
Ethoheptazine
No
15  
Thebaine
No
15, 17
25

Table 1 is subdivided into narcotic agonists, mixed agonist-antagonists, antagonists and a group of miscellaneous drugs. In general, both the agonists and the mixed agonist-antagonists were positive reinforcers in the substitution procedure. This corresponds well to the general belief that any narcotic with analgesic (i.e. agonistic) properties has some potential for abuse. Except for dextro-methorphan, none of the narcotic antagonists or miscellaneous drugs function as positive reinforcers. This is also true for the non-narcotic analgesics (table 2).

TABLE 2

Non-narcotic analgesics

Drug (1)

Result (2)

Laboratory (table 6) (3)

Reference (table 7) (4)

Acetylsalicylic acid
No
10 10
Aminophenazone
No
10 12
Phenylbutazone
No
10 12
Sodium salicylate
No
4  

TABLE 3

Psychomotor stimulants

Drug (1)

Result (2)

Laboratory (table 6) (3)

Reference (table 7) (4)

d-Amphetamine
Yes
4, 10, 15, 17 2, 7, 8, 16, 22
d,l-Amphetamine
Yes
15 18
l-Amphetamine
Yes
4 2
N-Butylamphetamine
No
16  
Caffeine
No
10, 17 23
Chlorphentermine
No
17 23
Cocaine
Yes
15, 17 21, 22
Diethylpropion
Yes
13 14
d,l-Ephedrine
Yes
15  
N-Ethylamphetamine
Yes
15, 16 18
Fenfluramine
No
16 18, 21
Mazindol
Yes
  19
d-Methamphetamine
Yes
4, 6, 9, 15, 17 2, 3, 22
Methylphenidate
Yes
6, 17 3, 22
Pemoline
No
6 3
Phenmetrazine
Yes
17 22
Pipradrol
Yes
17 22
N-Propylamphetamine
No
16  

TABLE 4

Central nervous system depressants

Drug (1)

Result (2)

Laboratory (table 6) (3)

Reference (table 7) (4)

Amobarbital
Yes
15 20
Barbital
Yes
15 20
Chlordiazepoxide
Yes
8  
Chlordiazepoxide
No
9  
Ethanol
Yes
8  
Flurazepam
Yes
6  
Methohexital
Yes
15 20
Pentobarbital
Yes
6, 8, 9, 10, 15, 17 20
Thiamylal
Yes
9  
Thiopental
Yes
6, 15 20

TABLE 5

Other drugs

Drug (1)

Result (2)

Laboratory (table 6) (3)

Reference (table 7) (4)

Antidepressants
     
Amitryptiline
No
10  
lmipramine
No
10, 17 7, 27
Major tranquillizers
     
Chlorpromazine
No
10, 15 7, 8
Haloperidol
No
10, 15  
Perphenazine
No
10, 11 13
Trazodone
No
9  
Hallucinogens
     
LSD
No
10  
Mescaline
No
10  
STP
No
10, 17  
r9-THC
No
5, 17 6, 29
Miscellaneous
     
Arecoline
No
9  
Chloroprocaine
Yes
11  
Dexoxadrol
No
15  
Diphenhydramine
Yes
9  
Ditran
No
10  
Ketamine
Yes
9 15
Nicotine
No
9, 17 24
Phencyclidine
Yes
3 1
Pilocarpine
No
9  
Procaine
Yes
7, 11, 14 4
Proparacaine
No
11  
Propranalol
No
9, 10  
Pyrilamine
Yes
12  
Scopolamine
No
1  

TABLE 6

Laboratories

1. Aigner and Balster
Robert L. Balster, Ph.D.
 
Pharmacology Department
 
Medical College of Virginia
 
Virginia Commonwealth University
 
Richmond, Virginia 23298
2. Balster and Harris
Same as above.
3. Balster, Johanson and Schuster
Same as above.
4. Balster and Schuster
Same as above.
5. Carney and Balster
Same as above.
6. Dren and Jochimsen
Anthony T. Dren, Ph.D.
 
Department of Pharmacology
 
Abbott Laboratories
 
North Chicago, Illinois 60064
7. Ford and Balster
Same as laboratory No. 1.
8. Gill and Holz
William C. Holz, Ph.D.
 
Smith, Kline & French Laboratories
 
1500 Spring Garden Street, P.O. Box 7929
 
Philadelphia, Pennsylvania 19101
9. Harrigan and McCarthy
S. Harrigan
 
Warner-Lambert/Parke-Davis
 
2800 Plymouth Road
 
Ann Arbor, Michigan 48105
10. Hoffmeister
Dr. F. Hoffmeister
 
Bayer AG
 
56 Wuppertal 1,
 
Friedrich-Ebert-Str. 217
 
Federal Republic of Germany
11. Johanson
Chris E. Johanson, Ph.D.
 
The University of Chicago
 
Department of Psychiatry
 
950 East 59th Street
 
Chicago, Illinois 60637
12. Johanson and Kotzin
Same as above.
13. Johanson and Schuster
Same as above.
14. Mitchell and Hammerbeck
Dr. Clifford Mitchell
 
National Institute of Environmental Health
 
Sciences
 
P.O. Box 12233
 
Research Triangle Park, No. Carolina 27709
15. Woods
James H. Woods, Ph.D.
 
Department of Pharmacology
 
Medical Science Building I
 
M6322
 
University of Michigan
 
Ann Arbor, Michigan 48109
16. Woolverton, Johanson and Schuster
Same as laboratory No. 11.
17. Yanagita
Tomoji Yanagita, M.D.
 
Preclinical Research Laboratories
 
Central Institute for Experimental Animals
 
1433 Nogawa, Kawasaki, Japan 211

TABLE 7 References

  1. R. L. Balster, C. E. Johanson, R. T. Harris and C. R. Schuster, "Phencyclidine self-administration in the rhesus monkey", Pharmac. Biochem. Behav., 1: 167-173, 1973.

  2. R. L. Balster and C. R. Schuster, "A comparison of d-amphetamine, l-amphetamine and methamphetamine self-administration in rhesus monkeys", Pharmac. Biochem. Behav., 1: 67-71, 1973.

  3. A. T. Dren and R. S. Janicki, "Premoline", in: Pharmacological and Biochemical Properties of Drug Substances, M. E. Goldberg (ed.). Washington, D. C.: American Pharmaceutical Association, 1977, pp. 33-65.

  4. R. D. Ford and R. L. Balster, "Reinforcing properties of intravenous procaine in rhesus monkeys", Pharmac. Biochem. Behav., 6: 289-296, 1977.

  5. D. M. Hammerbeck and C. L. Mitchell, "The reinforcing properties of procaine and d-amphetamine compared in rhesus monkeys", J. Pharm. Exp. Ther., 204, 558-569, 1978.

  6. R. T. Harris, W. Waters and D. McLendon, "Evaluation of reinforcing capability of delta-9-tetrahydrocannabinol in rhesus monkeys", Psychopharmacologia, 37: 23-29, 1974.

  7. F. Hoffmeister and S. R. Goldberg, "A comparison of Chlorpromazine, imipramine, morphine and d-amphetamine self-administration in cocaine-dependent rhesus monkeys", J. Pharmac. Exp. Ther., 187 ( 1): 8-14, 1973.

  8. F. Hoffmeister, S. R. Goldberg, U. U. Schlichting and W. Wuttke, "Self-administration of d-amphetamine, morphine and chlorpromazine by cocaine 'dependent' rhesus monkeys", Naunyn-Schmiedeberg's Arch. exp. Path. Pharmak., 266: 359-360, 1970.

  9. F. Hoffmeister and U. U. Schlichting, "Reinforcing properties of some opiates and opioids in rhesus monkeys with histories of cocaine and codeine self-administration", Psychopharmacologia, 23: 55-74, 1972.

  10. F. Hoffmeister and W. Wuttke, "Self-administration of acetylsalicylic acid and combinations with codeine and caffeine in rhesus monkeys", J. Pharm. Exp. Ther., 186 ( 2): 266-275, 1973.

  11. F. Hoffmeister and W. Wuttke, "Self-administration: Positive and negative reinforcing properties of morphine antagonists in rhesus monkeys", In: Narcotic Antagonists ( Advances in Biochemical Psychopharmacology 8), M.C. Braude, E. L. May, J. P. Smith and J. E. Villareal (eds.). New York: Raven Press, 1974, pp. 361-369.

  12. F. Hoffmeister and W. Wuttke, "Further studies on self-administration of antipyretic analgesics and combinations of antipyretic analgesics with codeine in rhesus monkeys", J. Pharm. Exp. Ther., 193 ( 3): 870-875, 1975.

  13. C. E. Johanson, D. A. Kandel and K. Bonese, "The effects of perphenazine on self-administration behavior", Pharmac. Biochem. Behav., 4: 427-433, 1976.

  14. C. E. Johanson and C. R. Schuster, "A comparison of cocaine and diethylpropion under two different schedules of drug presentation", in: Cocaine and Other Stimulants, E. H. Ellinwood, M. M. Kilbey (eds.) New York: Plenum Press, 1977, pp. 545-570.

  15. J. E. Moreton, R. A. Meisch, L. Stark and T. Thompson, "Ketamine self-administration by the rhesus monkey", J. Pharm. Exp. Ther., 203: 303-309, 1977.

  16. U. U. Schlichting, S. R. Goldberg, W. Wuttke and F. Hoffmeister, " d-Ampheta-mine self-administration by rhesus monkeys with different self-administration histories'', Excerpta Medica International Congress Series, 2 ( 220): 62-69, 1971.

  17. C. R. Schuster and R. L. Balster, "Self-administration of agonists", in: Agonists and Antagonist Actions of Narcotic Analgesic Drugs. H. W. Kosterlitz, H. O. J. Collier and J. E. Villarreal (eds.). London: MacMillan Press, 1973, pp. 243-254.

  18. R. E. Tessel and J. H. Woods, "Fenfluramine and n-etlhylamphetamine: Comparison of the reinforcing and rate-decreasing actions in the rhesus monkey", Psychopharmacologia, 43: 239-244, 1975.

  19. M. C. Wilson and C. R. Schuster, "Mazindol self-administration in the rhesus monkey", Pharmac. Biochem. Behav., 4: 207-210, 1976.

  20. G. Winger, M. L. Stitzer and J. H. Woods, "Barbiturate-reinforced responding in rhesus monkeys: Comparisons of drugs with different durations of action", J. Pharm. Exp. Ther., 195 ( 3): 505-514, 1975.

  21. J. H. Woods. "Narcotic-reinforced responding-a rapid screening procedure", Proceedings of the Committee on Problems of Drug Dependence, pp. 420-437, 1977. - and R. E. Tessel, "Fenfluramine: Amphetamine congener that fails to maintain drug-taking behavior in the rhesus monkey", Science 185: 1067-1069, 1974.

  22. T. Yanagita. "An experimental framework for evaluation of dependence liability of various types of drug in monkeys", Bulletin on Narcotics, XXV: 4, 57-64, 1973.

  23. T. Yanagita. "Self-administration studies on various dependence-producing agents in monkeys", The University of Michigan Med. Centr. J., 36(4-2): 216-133, 1970.

  24. T. Yanagita, K. Ando, N. Oinuma and K. Ishida, "Intravenous self-administration of nicotine and an attempt to produce smoking behavior in monkeys", Proceedings of the Committee on Problems of Drug Dependence for 1974, pp. 567-578 (Mar. 1974, Mexico City D.F.).

  25. T. Yanagita, K. Miyasato, N. Oinuma and H. Kiyohara, "Dependence potential of drotebanol, codeine and thebaine in rhesus monkeys", Bulletin on Narcotics, XXIX:1, 33-46, 1977.

  26. T. Yanagita, N. Oinuma and S. Takahashi, "Drug dependence liability of pentazocine evaluated in the rhesus monkey", Preclinic. Rept. of Cent. Instit. for Exptl. Animals, l(1): 51-57, 1975.

  27. T. Yanagita, S. Takahashi and N. Oinuma, "Drug dependence liability of tricyclic antidepressants evaluated in monkeys", Jap. J. of Clinic. Pharmacol., 3(4): 289-294, 1972.

  28. T. Yanagita, S. Takahashi and N. Oinuma, "Drug dependence liability test on AT-17 in the rhesus monkey", Preclinic. Rept. of Cent. lnstit. for Exptl. Animals, 1(1): 35-41, 1975.

  29. J. M. Carney, I. M. Uwaydah and R. L. Balster, "Evaluation of a suspension system for intravenous self-administration studies of water-insoluble compounds in the rhesus monkey", Pharm. Biochem. Behav., 7: 357-364, 1977.

In general, therefore, there is little doubt that the substitution procedure differentiates analgesics and related compounds qualitatively in terms of abuse potential. However, as previously pointed out, it does not rank these drugs in any quantitative manner. For instance, although it is generally recognized that heroin presents a more serious abuse problem than codeine, the results in the substitution procedures are similar for these two drugs.

Most of the psychomotor stimulant drugs which are positive reinforcers (table 3) are relatively similar in structure to the prototype amphetamine. In addition, these compounds are abused by humans. There are, nevertheless, stimulant drugs, such as cocaine and mazindol, which are not related structurally to amphetamine but which function as positive reinforcers. But these drugs, particularly cocaine, are also commonly abused by humans. However, there do exist compounds which are structurally related to amphetamine which are neither abused by humans nor are positive reinforcers in animals. These include chlorphentermine, fenfluramine and certain N-alkylated amphetamine derivatives. Although it is not clear what aspect of their structure is responsible for the alteration in activity, there is correspondance between their abuse and reinforcing properties. Two psychomotor stimulant drugs which are not positive reinforcers are caffeine and pemoline. These two drugs fall into the grey area where their abuse liability is a matter of debate.

Sequence(j) of drug presentation (T = Test drug, C = Control, M = Maintenance); ....., ....., ......, ......, ......, ......, ......, ......, ......, ......, ......, ......,(days) or other time units ..............................

Other than constant sequence(k)-

Were drugs and control values obtained from the Same monkeys? .......................................... Was crossover design used? .....................................

Ethanol, as well as all barbiturates (table 4), are capable of functioning as positive reinforcers. This correlates well with their indisputable abuse potential. The results with the benzodiazepines (e.g. chlordiazepoxide) are not as clear. In fact, the most widely prescribed member of this class, diazepam, has not been tested in the substitution procedure, perhaps due to its water insolubility. Altough it has been tested under unlimited access conditions the results are equivocal (Yanagita and Takahashi, 1973). The abuse potential of this class of compounds is also questionable. Although they are widely prescribed, there is little agreement as to whether this indicates abuse. Clearly, however, more research with this class of drugs is needed.

There is little doubt that the antidepressants and major tranquillizers are neither abused nor function as positive reinforcers (table 5). However, it may be surprising that none of the hallucinogens serve as positive reinforcers (table 5) since it is generally believed that these drugs are highly abused by humans. There are two possible reasons for this discrepancy between the human and animal data. First, LSD and related hallucinogens are usually taken orally by humans and the time between dosings is generally greater than for other abused drugs. In the substitution test, these drugs were delivered intravenously and their rate of intake was compared with that of saline, which is often quite high. Therefore, the parameters of this animal model may simply be inappropriate. The second reason for the discrepancy may be that these drugs are not abused in the same manner as drugs such as cocaine or heroin. Hallucinogens may not be taken because they are positive reinforcers but because of their ability to alter some unique human behaviour such as visual imagery. Such notions, however are speculative. The best that can be said at this point is that more research with both animals and humans is necessary.

Among the miscellaneous drugs listed in table 5, it is no surprise that are-coline, ditran, pilocarpine, propanolol and scopolamine are not positive reinforcers although it is important to verify that the substitution test is capable of differentiating these types of drugs. Likewise, ketamine and particularly phencyclidine, which are known to be highly abused, were found to be positive reinforcers. There were some drugs whose results are puzzling. Nicotine, which possesses abuse potential, did not maintain responding. However, as with the hallucinogens, the intravenous route of administration may be inappropriate for testing. It is most surprising that two structurally related local anesthetics, procaine and chloroprocaine, were found to be positive reinforcers. A third, related compound, proparacaine, was not. Although procaine and chloroprocaine are structurally similar to cocaine, they are not considered drugs of abuse. Similarly, pyrilamine and diphenhydramine, both antihistamines but of different types, are not considered drugs of abuse.

In summary, most drugs which maintain responding in animals (i.e. are positive reinforcers) are considered drugs of abuse in humans. On the other hand, drugs which do not maintain responding are not abused. The only clear exceptions to this relationship are some local anaesthetics and antihistamines. Nevertheless, the high correlation between the animal and human data makes the substitution test an excellent preclinical screening procedure, particularly since it is relatively rapid and the results generated by different laboratories are comparable. While such screening procedures may help us avoid the marketing of extremely dangerous new compounds, the abuse of a drug is only to a limited extent determined by its pharmacological properties. Availability, environmental contingencies, and other complex social variables are equally important and in some circumstances may be entirely responsible for the extent of a drug's non-medical use.

Acknowledgements

The preparation of this manuscript was supported by USPHS DA-00250 (Chris E. Johanson) and NIDA Contract 271-77-3404 (Robert L. Balster).

Bibliography

Balster, R.L., M.M. Kilbey and E.H. Ellinwood (1976). Methamphetamine self-administration in the cat. Psychopharmacologia (Berl.). 46: 229-233.

Goldberg, S.R. (1973). Comparable behavior maintained under fixed-ratio and second-order schedules of food presentation, cocaine injection or d-amphetamine injection in the squirrel monkey. J. Pharm. Exp. Ther. 186(1): 18-30.

- (1977). The behavioral analysis of drug addiction. In: Behavioral Pharmacology. S.D. Glick and J. Goldfarb (eds.). C.V. Mosby.

Griffiths, R.R., J.D. Findley, J.V. Brady, K. Dolan-Gutcher and W.R. Robinson (1975). Comparison of progressive ratio performance maintained by cocaine, methylphenidate and secobarbital. Psychopharmacologia (Berl.). 43: 81-83.

Johanson, C. E. (1978). Drugs as reinforcers, In: Contemporary Research in Bahavioral Pharmacology. D.E. Blackman and D.J. Sanger (eds.). Plenum Press, New York: pp. 325-390.

- and C.R. Schuster (1977). A comparison of cocaine and diethylpropion under two different schedules of drug presentation. In: Cocaine and Other Stimulants. E.H. Ellinwood and M.M. Kilbey (eds.). New York: Plenum Press, pp. 545-570.

Jones, B.E. and J.A. Prada (1973). Relapse to morphine use in dog. Psychopharmacologia. 30: 1-12.

Schuster, C.R. and C.E. Johanson (1973). Behavioral analysis of opiate dependence. In: Opiate Addiction: Origins and Treatment. S. Fisher and A.M. Freedman (eds.). Washington, D.C.: Winston & Sons, pp. 77-92.

- and - (1974). The use of animal models for the study of drug abuse. In: Research Advances in Alcohol and Drug Problems. R.J. Gibbins, Y. Israel, H. Kalant, R.E. Popham, W. Schmidt and R.G. Smart (eds.). New York: John Wiley & Sons, pp. 1-31.

- and T. Thompson (1969). Self-administration of and behavioral dependence on drugs. Annual Review of Pharmacology. 9: 483-502.

Tessel, R.E. and J.H. Woods (1975). Fenfluramine and n-ethylamphetamine: Comparison of the reinforcing and rate-decreasing actions in the rhesus monkey. Psycho. pharmacologia (Berl.). 43: 239-244.

Thompson, T. and C.R. Schuster (1964). Morphine self-administration, food-reinforced and avoidance behaviors in rhesus monkeys. Psychopharmacologia.5: 87-94.

Weeks, J.R. (1962). Experimental morphine addiction: Method for autonomic intravenous injections in unrestrained rats. Science. 138: 143-144.

Yanagita, T. and S. Takahashi (1973). Dependence liability of several sedative-hypnotic agents evaluated in monkeys. J. Pharm. Exp. Ther. 185: 307-316.