Discussion of Symposium on Conditioning and Addiction

Crr,~_~LES R. Scausrma

Departments of Psychiatry and Pharmacological and Physiological Sciences, The University of Chicago, Pritzker School of Medicine,

Chicago, Illinois

BEFORE I BEGIN my discussion of the papers presented today I would like to take this opportunity to acknowledge my intellectual indebtedness to the chairperson of today's meeting, Dr. Abraham Wilder. His research and theories regarding the interactive role of Pavlovian and operant conditioning in the phenomenon of drug dependence have stimulated much of my own research as well as many others inelud_ing today's speakers. I believe that today's presentations amply attest to the fertility and importance of the study of the dynamic interactions of drugs and behavior. Such interactions achieve special importance in the area of drug de- pendence because the repetitive nature of drug-seeking and con- summatory behaviors are ideal conditions for the conditioning of drug effects. Today's papers have presented compelling evidence demonstrating the significance of stimuli associated with drug ad- ministration in the analysis of the factors maintaining drug-seeking behavior. Such an analysis is essential ff we are to gather the data necessary to understand the behavioral variables responsible for drug dependence. Rational therapy for drug dependent humans, as well as preventive measures are more likely to evolve when both pharmacological and behavioral variables controlling drug-seeking behavior have been isolated and parametrically explored. The need for further development in the area of therapy for heroin addiction is most strikingly shown by noting that even with the best treatment available, i.e., methadone maintenance, the success rate is depressingly low.

In my discussion I will briefly summarize what I consider to be some of the high points of today's presentations and the ques- tions and thoughts that these have generated in me.

Dr. Goldberg presented the results of research carried out in part in my laboratory while I was at the University of Michigan. i believe his research confirms and extends the work of Wikler (1967) in showing that stimuli associated with administration of an opiate antagonist to opiate dependent animals can acquire the

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ability to elicit certain of the autonomic and behavioral signs of withdrawal. Two of his findings impress me as having special im- portance: 1) I was extremely impressed with the speed with which conditioned changes were produced by stimuli associated with nalorphine elicited withdrawal. The durability of these responses further demonstrates the strength of this conditioning. The fact that these conditioned responses remain even after animals are no longer physically dependent upon opiates offers support for Wilder's contention that conditioned withdrawal signs lead to a return to heroin use in the detoxified addict (Wilder, 1965). This durability of conditioned withdrawal signs in the monkeys is, how- ever, in marked contrast to the data presented by Dr. O'Brien, using human subjects, in Dr. O'Brien's studies in which stimuli were associated with naloxone-elicited withdrawal, conditioning was demonstrated but was very rapidly extinguished. The differ- ence between the speed of extinction in these two studies may be related to the different narcotic antagonists used to elicit with- drawal. Nalorphine, used in Dr. Goldberg's studies, is a mixed agonist-antagonist whereas naloxone, used by Dr. O'Brien, is a more "pure" antagonist. In addition the intensity of the withdrawal signs elicited in the monkey experiments was much greater than it was ethieally possible for Dr. O'Brien to use. Only further para- metric studies can resolve this issue.

2) The fact that responding for morphine reinforcement was increased by the presentation of stimuli previously associated with nalorphine induced withdrawal. This correlates well with Dr. O'Brien's findings that under similar experimental circumstances human addicts report a craving for heroin. Clearly both these find- ings lend additional eredenee to the importance of conditioned withdrawal in the maintenance of drug-seeking behavior.

One question which Dr. Goldberg's and Dr. O'Brien's data raised for me is what is being conditioned. I noticed that Dr. Gold- berg avoided saying that he had conditioned the opiate withdrawal syndrome. Wisely, I believe, he stated that he has conditioned certain behavioral and autonomically mediated responses. The question is, are these responses being individually conditioned o r

is some central state being conditioned which gives rise to these behavioral and autonomic signs? We cannot answer this question at this point; however, it is of some importance both theoretically and practically and deserves further attention. A related question has to do with the interaction between Pavlovian conditioning and operant conditioning. In Dr. Goldberg's experiments a tone pre- ceding the injection of nalorphine causes the suppression of the monkey's lever-press for food reinforcement. Is the operant be-

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havior suppressed because the tone elicits incompatible autonomic responses or is there a direct effect of the aversive properties of the withdrawal syndrome on the operant responding? Frankly, we do not know; and further research is needed to clarify this interaction.

Clearly, most of us working in animal laboratories hope that our data have some relevance for man. Dr. O'Brien's studies of the conditioning of various response components of the opiate with- drawal syndrome in man are therefore of great importance. I was very pleased to see that this work is being carried out with great scientific rigor. The results to date indicate that a variety of the behavioral, subjective and autonomic response components of the withdrawal syndrome can be conditioned in man. This is important in its own right but also gives some validation to the animal re- search in this area.

I was intrigued and puzzled by Dr. O'Brien's observations that the conditioned signs of withdrawal observed in his subjects were of greater intensity than the unconditioned effects elicited by na- loxone. This result was not obtained in Dr. Goldberg's work and I have no ready explanation for this unexpected finding. In addi- tion, Dr. O'Brien was able to show conditioned respiratory effects in man whereas Dr. Goldberg did not see such conditioned effects in the rhesus monkey. Parametric studies may reveal the reasons for these differences. Regardless of these minor differences in results, the work of Dr. O'Brien in man clearly confirms and ex- tends the prior animal research.

The studies of Drs. Goldberg and O'Brien have demonstrated that the effects of opiate antagonists can be conditioned. In the other presentations today the conditioning of opiates' agonistic effects have been impressively demonstrated.

In 1962, Dr. Thompson and I reported that stimuli which had been paired with response~c0ntingent morphine presentations could alleviate behavioral disruptions caused by morphine with- drawal (Thompson and Schuster, 1962). Our interpretation was that the visual stimulus paired with morphine had acquired the ability to produce some of the physiological effects of morphine and thus reverse or alleviate the opiate withdrawal changes.

Dr. LaYs presentation has shown that stimuli associated with morphine can as well alleviate the hypothermia and wet dog shakes seen in rats going through opiate withdrawal. These findings con- firm and extend my previous research. Dr. Lal has as well cor- roborated the findings of Dr. Perez-Cruet on the conditioning of the effects of opiates on dopamine metabolism. These studies have shown that both morphine and stimuli associated with

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morphine cause an increase in turnover rate of dopamine. It is tempting to speculate that the conditioned changes in dopamine metabolism may be the mechanism underlying the conditioned be- havioral changes. There is reason, however, to question the direc- tion of causality in this interpretation. The work of Selden has amply shown that central monoamine metabolism may be as much a function of behavioral change as a cause of it (Seiden, et al., 1975). Nonetheless, Doctors Lal and Perez-Cruet's presentations indicate that stimuli associated with morphine can produce mor- phine-like physiological changes through Pavlovian conditioning. This may be the basis for the ability of stimuli associated with morphine to act as conditioned reinforcers. Several years ago Dr. Woods and I demonstrated that visual stimuli previously paired with response-contingent morphine could maintain high rates of responding for significant periods of time. Further, the condi- tioned reinforcing properties of the visual stimuli could be demon- strated even after the monkeys had been withdrawn from morphine (Woods and Schuster, 1968). The impressive work presented by Dr. Davis today is remarkable in the ease of the development of drug related conditioned reinforcers. This is extremely important work and should be further investigated.

To summarize, the presentations today clearly demonstrate the importance of the analysis of the dynamic interaction of the en- vironment and drugs in order to explicate the phenomenon of drng- seeking behavior. Clearly, non-pharmacologic variables affecting drug-seeking behavior must be isolated and studied if we are ever to establish procedures designed to aid hurnans in regulating their dmg intake.

References

Selden, L. S., MacPhail, R. C., and Oglesby, M. W.: Catecholamines in drug behavior interactions. Fed. Proc., $4:1823-1831, 1975.

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

Wilder, A.: In D. M. Wilner and Kassebaum, G. G. (Eds.), Conditioning Factors in Opiate Addiction and Relapse, Narcotics. New York, Me- Craw-Hill, 1965.

Wilder, A. and Pescor, F. T.: Classical conditioninng of a morphine ab- stinence phenomenon, reinforcement of opioid-drinking behavior and "relapse" in morphine-addicted rats. Psychopharmacologia, 10:255-284, 1967.

Woods, J. H. and Schuster, C. R.: Reinforcement properties of morphine, cocaine, and SPA as a function of unit dose. Intern. I. Addict., S:231- 237, 1968.