BIOBEHAVIORAL BASES OF THE REINFORCING PROPERTIES OF OPIATE DRUGS

BIOBEHAVIORAL BASES OF THE REINFORCING PROPERTIES OF OPIATE DRUGS *

Conan Kornetsky and George Bain

Laboratory of Behavioral Pharmacology Division of Psychiatry

Boston University School of Medicine Boston, Massachusetts 021 18

INTRODUCTION

One thing that is certainly not in short supply in the field of drug abuse is theories. A recent NIDA monograph edited by Lettieri et a1.l gives 43 theories presented by 43 different researchers and commentators. Each of the theories is classified into one of four types of theories: self, others, society, and nature. The editors of the monograph point out that many theories could be classified into more than one category. What the monograph clearly indicates is that there are multiple contributions to initiation, continuation, cessation, and relapse to substance abuse. Despite these multiple factors, the focus of the present essay is that there exists a commonality of central nervous system action of many substances of abuse that for the user is translated into some pleasurable feelings that have been described as the “high.” At the level of the CNS it is translated into an activation of those areas of the brain for which electrical stimulation is rewarding. At a behavioral level in an animal it is translated into abuse substances causing a lowering of the threshold for rewarding brain stimulation. Of interest for the main focus of this meeting, opioids in mental illness, is that the experiments described implicate an important interaction between the catecholaminergic and the endorphinergic systems.

ABUSE

As mentioned, there are multiple reasons why opioids are abused, and many of these reasons are unrelated to the pharmacological action of the drugs. Certainly peer pressure, psychopathology, and, most important, avail- ability of drugs contribute to nonmedical use. However, none of these reasons or the reasons expressed in the NIDA monograph would have any causative factor in drug use if the drugs were not in some way reinforcing. It could be argued that this is a tautology. If the taking of the drugs leads to drug-seeking behavior, then by definition the taking of the drug is reinforcing. However, the question is not really whether the drug is reinforcing, but why and how it is reinforcing? This question may be looked at in various ways. The effects of two aspirin tablets can be reinforcing if we find that as a result of taking these two tablets our headache is relieved. Even though the aspirin-taking

Much of the research and preparation of this paper was supported by Grant DA 02326 from the National Institute of Drug Abuse (NIDA).

24 1 ooi~-a923/a2/039a-o24r $o i . i 5 /0 6 1982 WAS

242 Annals New York Academy of Sciences

behavior is reinforcing, and even if the aspirin is taken every four hours around the clock, it is not considered drug abuse. The person who continually takes a benzodiazepine for the relief of anxiety, fear or tension is also not usually considered a drug abuser.

What is unique in the aspirin or benzodiazepine example is that the drug is used to relieve some discomfort, be it physical or psychological. Both psychological as well as biological theories have emphasized the restorative nature of drug use as the reinforcement of drug use. For example, Beckett poetically stated, “that heroin addiction in some is symptomatic of an under- lying chronic depression in a wounded personality . . .” and that drug use is adaptive. This position is not different from that of Chein et nl. 10 years earlier or Wikler 12 years earlier.“ Many writers have argued that the use of opiates protects the user from feelings of “unmitigated aggression.” Even the more biological theories have studied the adaptive nature of the opiate use. For example, Dole and Nyswander have argued that there is a metabolic deficiency in the narcotic addict, and opiate use is restorative.

These theories have emphasized the negative aspects of the user to explain the reinforcement properties of narcotic use. However, the need to relieve the withdrawal symptoms is also an example of the adaptive nature of drug taking that makes no statement regarding a predisposing psychopathology.

Mello7 has argued that the major effects of opiates and most other abuse substances is unpleasant or negatively reinforcing, and, if this be so, then these aversive effects become positively reinforcing. This hypothesis is based on the finding that electric shock that can maintain escape and avoidance behavior, may under certain conditions be self-administered by the same monkey.s. Although response-produced shock in animals may be a reasonable model for the reinforcing properties of abuse substances for a few individuals, it is not particularly parsimonious, and it makes the assumption that the prepotent effect of the drug is unpleasant even in initial use. This model ignores the fact that abuse substances differ from the non-abuse substances in that all of the former cause some euphoria and well-being in the subject, even in the presence of aversive actions, while none of the latter cause such euphoriant effects. If this were not the case, all substances that had aversive properties would be abused by a significant number of people.

In the NIDA monograph on theories, only 7 of the 43 proffered theories have euphoria as a key variable. For the most part theories have ignored the euphoriant-producing aspects of opiate use. Margaret Mead more than a decade ago at a Congressional hearing on drug abuse characterized society’s attitude toward drug use when she defined the difference between virtue and vice: “Virtue is when you have pain followed by pleasure, while vice is when you have pleasure followed by pain.” Thus, despite the fact that drug use has pharmacologically as well as societally caused pain, it also has a pharmacologically caused pleasure that we believe accounts for much of the reinforcing properties of drug use. Further, a model for this euphoric action is suggested by the effects of opioids, as well as of other abuse substances, on brain- stimulation reward (also referred to as intracranial self-stimulation.) lo* l1

BRAIN STIMULATION Although the phenomenon of intracranial self-stimulation was first described

by Olds and Milner in 1954,12 it was not until 196013 that the effects of

Kornetsky & Bain: Reinforcing Properties of Opiate Drugs 243

opiates on self-stimulation was first described. Although Olds and Travis found that morphine (7.0 mg/kg i.p.) caused significant decrease in response rate in most of their preparations, some facilitation in rate was seen in some animals.

Of interest is that after the 1960 paper by Olds and Travis there was, as far as we could find, not a single publication on the effects of any opiate on intracranial self-stimulation until a paper by Adams et al. in 1972.'" Although Adams and coworkers found that morphine facilitated self-stimulation behavior, the increase in response rate was not seen until three hours after drug administration. The immediate effect was inhibitory. The lack of interest in intracranial self-stimulation as a method for the study of the reinforcing properties of opioids for over 10 years after the Olds and Travis paper in 1960 was probably due to the growth and interest in the intravenous self-administration of drugs by animals first described by Weeks in 1962 l5 as a model for the study of reinforcing properties, and secondly to the fact that the major effect of morphine reported by Olds and Travis In was to inhibit self-stimulation behavior.

In addition to the 1972 Adams et a/. paper," we reported in 1972 l6 on the effects of morphine on the EEG recorded from depth electrodes implanted in areas of the brain that elicit self-stimulation behavior. This work was, in part, based on a 1970 dissertation by Nelsen." In the late 1960s Nelsen became interested in determining if the phenomenon of single dose tolerance to morphine lR. l9 could be demonstrated in the EEG recorded from intracranial sites. As it was wished to emphasize the possible difference between the effects of morphine as an analgesic and as a euphoriant, each animal was prepared with two electrodes, one in a negatively reinforcing site and one in a positively reinforcing site. Since epochs of EEG were simultaneously recorded from the two sites in each animal, the results indicated that morphine could simultaneously cause both depression (increased amplitude) in those areas of the brain for which stimulation is aversive and stimulation (decreased amplitude) in the EEG in those areas of the brain for which stimulation is rewarding.

THRESHOLD MEASURES

The Nelsen findings raised the obvious question of whether or not the results could be functionally demonstrated. That is, is the intensity of stimulation to positively reinforcing sites enhanced by morphine while the intensity of stimulation to negatively reinforcing sites decreased? Since we were primarily interested in whether or not the rewarding value of the stimulation was increased or decreased after morphine, we believed that a direct approach would be to determine the effect of the drug on the threshold for the stimulation rather than the effect on rate of response. There has been sufficient evidence from experiments by Hodos and Valenstein 2o and a review by Valen- stein 21 that rate of response does not necessarily reflect the rewarding value of the stimulation. Also, current work in our laboratory by Payton?' indicates that rate of response for intracranial stimulation does not correlate with the absolute threshold for rewarding brain stimulation. The product moment correlation between rate of response and threshold was 0.02. It is highly possible that a change in rate of response after a drug could be


affecting nonspecific depressant or stimulating effects without altering the value of the reinforcer. Although an individual animal’s response rate will be, within limits, proportional to the intensity of stimulation, a change in response rate after drug taking does not necessarily reflect a change in the reinforc- ment value.

The first experiment in which we looked at the functional manifestation of the Nelsen findings was reported in a 1973 Ph.D. thesis by Marcus2R and published in 1974.2* This was the first published experiment indicating (1) that the effect of morphine on facilitating brain-stimulation reward occurred within the fist 30 minutes after an injection of morphine, and (2) that the drug actually increased the sensitivity of the animal to rewarding brain-stimulation.

In the Marcus experiment, animals were prepared with electrodes in either positive or negative reinforcement sites. FIGURE 1 shows the percent change in threshold after morphine for each of three animals with electrodes in positive sites and three animals with electrodes in negative sites. As can be seen,

-20- 0 4 8 1 2

Dose of Morphine Sulfate (mg/kg Body Weight)

FIGURE 1. Mean percent change in threshold after morphine from three animals stimulated in “negative” reinforcement sites (on the left) and three animals stimulated in “positive” reinforcement sites (on the right). The standard error for approximately 10 threshold determinations after saline ( 0 dose) is indicated for each animal. (After Marcus & Kornetsky.”)


the threshold for rewarding brain-stimulation is lowered by morphine while the threshold for negatively reinforcing brain-stimulation is raised by morphine. These results gave clear functional confirmation to the results obtained by Nelsen.

The double staircase psychophysical methodz5 was used in the Marcus experiment. And in subsequent experiments we have used a modification of the psychophysical method of limits.26 With both psychophysical methods a rate-free discrete trial procedure is used. Also a cylindrical wheel manipu- landum, mounted in one wall of the experimental chamber, is used rather than the usual lever. This is shown in FIGURE 2 from Kornetsky and Bain 2*

along with a schematic of a single trial in which the animal did not respond (labeled I) and one in which the animal did respond (labeled 11).

Generally we find that the absolute threshold in the CDF rat (Charles River, Fisher-derived rat) usually is between 65 and 125 pA at 160 Hz. Morphine at doses from 2-8 mg/kg S.C. lowers the threshold approximately 20 PA. Details of the procedure have been published by Esposito and Kornetsky.28

FIGURE 3 summarizes the mean effects of morphine from a number of our experiments on the threshold for brain-stimulation reward.2T These are per- centage changes based on post-pre difference. Thus negative scores indicate a lowering of the threshold. Of interest is that although 12 mg/kg seems to bring the threshold change back to that seen after saline, higher doses did not cause a raising of the threshold. At higher doses, and for some animals at doses as low as 6 mg/kg, we could not measure the threshold since the animal is incapable of performing the task.

TOLERANCE

Of interest is the failure to find tolerance to either the rate facilitating effect I , 28, 5o or threshold lowering effect of opioids on brain-stimulation reward. In the Adams et al. experiment,14 the effects of five consecutive days of morphine injections were studied. As with most studies they found a significant decrease in rate of response for the first two hours after drug administration on day 1 with significant increases subsequently. However, by day 3 there was complete tolerance to the inhibitory effect on rate with no tolerance to the facilitatory action of the morphine. However, after chronic administration the facilitatory effect appeared earlier after treatment. Other investigators also found that there was no tolerance to the facilitatory effect, only tolerance to the inhibitory 31 Contrary results have been reported by Glick and R a p a p ~ r t . ~ ~ They found tolerance to both the facilitatory and inhibitory effects of morphine on self-stimulation to animals with electrodes in the medial forebrain bundle. This report of tolerance to the facilitatory effect, contrary to the findings of most investigators, is difficult to explain and may, as suggested by Esposito and K o r n e t ~ k y , ~ ~ be due to subtle differences in training or baseline rates of response which were not reported in the Glick and Rapaport study. Using a threshold measure we have found that a relatively high dose, which previously had no effect on threshold, lowered the threshold after a number of days of daily drug administration. FIGURE 4 shows the results of animals from a number of our experiments in which the same


animals were studied after single doses of morphine and after 14-38 days of daily administration. Of interest is that not only d o these results indicate that

FIGURE 2. A schematic representation of the method for determining brain-stimulation reward thresholds. (I) A sequence of a single trial when an animal does not respond. (11) The sequence when the animal makes a response. A trial begins with the delivery of a noncontingent stimulus train (ti1), if the animal fails to respond by turning the wheel within 7.5 sec from the onset of the S, the trial is terminated and 15 sec later the next trial is begun. If the wheel is turned as indicated in example 11, the rat receives a contingent stimulus (S). Intensity of stimulation is varied according to a modification of the method of limits.m A response after the 7.5-sec available response time postpones the presentation of the next stimulus for 15 sec.


I I 0 5 1 2 4 6 8 12

MS (mg/kg)

FIGURE 3. Mean effect of various doses of morphine on the threshold for brain- stimulation reward. Data summarized from a number of experiments in our laboratory (References 24, 28, 29, and some unpublished data). Standard errors are only indicated at doses in which five or more animals were tested. The large standard errors are primarily the result of individual animals obtaining maximum threshold lowering effect at different doses. The curve was U-shaped for all animals.

there is no tolerance to the reward threshold lowering effect of morphine, but that there is an increased effect of morphine. This suggests either a supersensitivity whose functional significance is not evident or that tolerance to the depressant effects allows for a greater manifestation of the threshold lowering effect.

NALOXONE

The facilitation of self-stimulation by opioids has suggested that the critical neurochemical basis for rewarding brain-stimulation may indicate a role for the endorphins or enkephalins.:34* 36 Not only does electrical stimulation of enkephalin-rich regions of the brain serve as a reinforcer, but enkephalins as well, have been reported to serve as reinforcers in self-administration behavior. Belluzzi and Stein 34 have also reported that naloxone will decrease self-stimulation behavior in animals with electrodes in the central gray. Al- though some investigators have also reported inhibition of self-stimulation rate after n a l o x ~ n e , ~ ~ other investigators have found no effect on rate of re- ~ p o n s e . ~ ~ - . ~ ~


In order to determine if naloxone actually changes the rewarding value of the electrical stimulation, we studied the effects of intraperitoneal injections of 2.0 to 16.0 mg/kg of naloxone on the threshold for rewarding brain- stimulation in six animals J2 with electrodes in the medial forebrain bundle or the ventral tegmental area. Subsequently we have tested doses of 0.25, 0.5, and 1.0 mglkg. We have found no evidence of any effect on threshold except an increase in intrasubject variability. The mean effect of naloxone is shown in FIGURE 5 and the effects of 5 consecutive days of 16 mg/kg per day in FIGURE 6.43

Although we have failed to find that naloxone by itself has any effect on the reward threshold, we have found that it will reverse the threshold-lowering effects of other abuse substances, suggesting some commonality that probably is related to the endorphin system. Amphetamine,4* cocaine,4J or phencyclidine lo will lower the threshold for rewarding brain-stimulation. FIGURES 7 and 8 show the results of experiments in which naloxone administered prior to cocaine JB or amphetamine 42 attenuated these drugs’ threshold-lowering action. Preliminary experiments indicate that naloxone will similarily attenuate the effects of PCP.4E What is of interest is that an animal that is given an effective dose of naloxone and cocaine, for example, will show all the increased motor behavior and stereotypy previously exhibited when given cocaine alone despite an attenuation of the threshold-lowering effect. Thus the effect of naloxone seems to specifically attenuate the effect of these compounds on the threshold for reinforcement.

I 0 5 1 2 4 6 8 lo

MS (mg/kg)

FIGURE 4. Mean effect of various doses of morphine reward threshold before and after chronic treatment (14-38 days) in the same animals (N = 9, not all animals tested at all doses).


2 -

0 -

-1

w

8 N

1 -

- IX

NALOXONE

I I I I I 2.0 40 8.0 16.0

DOSE (mg/kg)

FIGURE 5. Mean effect of various doses of naloxone on brain-stimulation reward. Data are presented as Z-scores based on the mean and standard deviation of saline treatments. Vertical bars indicate standard errors. (After Esposito et al.")

German and B ~ w d e n , ~ ~ and Fibiger 50 have all implicated catecholamines in self-stimulation behavior with particular emphasis on a dopaminergic substrate. Our failure to find a direct effect of naloxone on the absolute threshold for self-stimulation and the reported attenuation of

1 2 3 4 5

FIGURE 6. Mean effect of daily intraperitoneal administration ( 5 days) of 16 mg/kg of naloxone. Data are expressed by %scores as previously described. (After Perry et a\.")


2 ........... " ..... ." .I._. "..".." ---. I _..--.. --I___-*-__.- c 1

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WKG COCAINE FIGURE 7. Mean effect of various doses of cocaine and cocaine and naloxone on

the reward threshold. The dose of naloxone was either 2 or 4 mg/kg depending on the animal (N = 4). These doses of naloxone had no effect by themselves in these animals. Data are presented as Z-scores based on the mean and standard deviation of saline treatments. Vertical bars indicate standard errors. (After Kornetsky et ~ 1 . ' ~ )

the threshold-lowering effect of amphetamine, cocaine, and PCP-all indirect dopaminergic agonists-argue against a tonically active endorphinergic system for maintaining self-stimulation behavior as suggested by Belluzzi and Stein.34 However, it does indicate that there may be a strong complementary role between these two systems.

Further evidence for a complementing role of the two systems is given in an experiment in which the effects of naloxone and chlorpromazine on the reward threshold was measured.51* 52 Chlorpromazine, like other neuroleptics, raises the threshold for brain-stimulation reward as well as increases the rate of response for such stimulation. In this experiment, doses of chlorpromazine (0.25-2.0 mg/kg, i.p.) were tested with and immediately after 4.0 mg/kg of naloxone. Animals had electrodes in the medial forebrain bundle or the ventral tegmental area. FIGURE 9 shows that effects of chlorpromazine alone and after naloxone. As can be seen, the naloxone potentiated the threshold-raising effect. This effect was seen in each of the four animals represented in the mean effects in the figure. Also, it has been reported that naloxone will


-*[ &AMPHETAMINE

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FIGURE 8. Mean effect of various doses of naloxone and the maximum threshold lowering dose of d-amphetamine for the individual animals ( N = 6). These doses varied from 1-2 mg/kg. The effect of this dose of d-amphetamine is shown on the left. Data are presented as Z-scores as previously described. (After Esposito et a/.'*)

W U 0 0 v) N DC

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FIGURE 9. Mean effects of various doses of chlorpromazine and chlorpromazine plus 4 mg/kg naloxone of the threshold for rewarding brain stimulation. Effects of naloxone alone are shown on the left. Results are expressed as Z-scores as previously described. Vertical bars indicate standard scores ( N = 4). (After Esposito et aLm)


potentiate the threshold-raising effect of chlorpromazine on the threshold for nociceptive ~ t imula t ion .~~, B4

Although it is difficult to characterize the threshold-raising effect of chlorpromazine on brain stimulation, we do not believe it is due to a simple attenuation of the hedonic effect of stimulation as suggested by Wise.65 Considering the effect of chlorpromazine on attentive the raising of the reward threshold by chlorpromazine is probably a more subtle behavioral disruption on attention and reward.

The naloxone potentiation of the chlorpromazine effect may have relevance for those studies in which schizophrenic patients are treated with naloxone. Several studies have demonstrated a decrease in hallucinations and bizarre thought content after naloxone.6i40 For the most part these studies generally have used larger doses and longer observation periods, and in many cases patients were also receiving neuroleptic medication.

SITE SPECIFICITY OF DRUG ACTION

Since a number of sites within the brain will support brain-stimulation reward, the technique seemed ideally suited for site specificity studies. Morphine will facilitate self-stimulation from a variety of brain These areas include the lateral h y p o t h a l a m ~ s , ~ ~ ~ Ex locus coeruleus,'J2 ventral tegmental area,E3 medial frontal cortex,61 dorsal raphe nucleus,64 and central gray.B5 Some investigators have reported that the effects of opiates on rewarding brain-stimulation is site specific. The earliest study by Olds and Travis suggested a site-specific effect. All of the authors above have presented data suggesting site specificity. However, Schenk et did an intrasubject comparison of the effects of morphine on lateral hypothalamic and central gray stimulation. They concluded from their experiment that there is little evidence for site-specific effects of morphine on rewarding brain-stimulation. They found large intersubject differences in magnitude and time course of the drug effects but little intrasubject variability. This suggested a difference in subjects' sensitivity to the drug's effect rather than a difference caused by electrode placement. Esposito and Kornetsky 33 also concluded that a "pre- cise description of the critical anatomical pathways involved would be a difficult task." They argued that there may exist important individual differences between animals and that differences in baseline rates of response must be considered in interpreting differences in the effect of morphine on stimulation to different brain sites.

In a more recent study,E'J we determined the effects of cocaine on both reward and detection threshold in the same animals from the same stimulating electrodes. In this experiment the effects of cocaine on the threshold for rewarding brain-stimulation was first determined. As expected, cocaine lowered the threshold in all animals. Animals were retrained in a procedure in which stimulation to the animal was used as a discriminative stimulus for receiving a supra-threshold rewarding stimulation. In this procedure the noncofitingent stimulation was varied as described (FIGURE 2) for determination of the reward threshold. However, a response by the animal within 7.5 sec after the discriminative stimulus was followed always by a supra-threshold reinforcing brain stimulation. The intensity of noncontingent stimulus was varied accord-


3- 2 -

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ing to the psychophysical method of limits. In this experiment the absolute threshold for rewarding stimulation was 65-125 p A while in the same animals the detection threshold was 7-22 pA. FIGURE 10 shows the results of this experiment and what can easily be seen is the clear dissociation in effect between detection and rewarding thresholds. This dissociation was evident in every animal. If we assume that the detection threshold represents a functionally significant measure of sensitivity at the site of stimulation, as suggested by Phillips and LePiane O i and Swett and Bourassa,GS then these findings suggest that the action of drugs on reinforcement levels may be mediated at a site(s) other than the locus of stimulation.

COCAINE

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+* REINFORCEMENT ,O

@--a DETECTION I' .' FIGURE 10. Mean effect of various doses of cocaine on the .' threshold for brain-stimulation .' reward (reinforcement) and on

o'--o-- - - - - -0' the threshold for brain-stirnula- tion detection. Data are expressed GS Z-scores based on the *--. respective mean and standard deviation of the effects of saline (N= 4). (After Marcus & Kornetskv.")

.-

I I

2.5 5.0 10.0 20.0

DOSE (mg/kg)

HUMAN DRUG USE

Although it is well established that opioids facilitate intracranial self- stimulation, the question of whether or not this increase in rate of response and the lowering of threshold for self-stimulation is related to the euphoria- producing effect of these drugs is not proven. Human subjects who have received electrical stimulation to areas of the brain that are homologous to those for which animals will self-stimulate, report pleasurable s ens at ion.^^^ io Nelsen li pointed out the similarity between these reports and the reports of narcotic users describing their opiate-induced euphoria. Implicit, if not ex- plicit, in most of the experiments in which there is facilitation of responding for rewarding brain-stimulation is the hypothesis that continued opiate-seeking behavior in many may be due to the drug causing an increase in the activity of central reward pathways.

This hypothesis implicating the reward system in opiate abuse was ex- plicitly made by Marcus and Kornetsky ? ' based on the results of their experiments showing that morphine lowered the threshold for rewarding brain- stimulation. Earlier, Collier i 1 in a theoretical paper suggested that activation of the "reward or depression of the punishment system would have comparable results-a lessening of drives, accompanied by a sense of gratification and the reinforcement of the behavior leading to these effects." Kumar et af.'? also


evoked the hypothalamic reward system in attempting to explain drug-seeking behavior. However, these investigators did not look directly at opiate effects on intracranial self-stimulation. Subsequently the hypothesis that the “high” or euphoriant effects of morphine are related to activation of the reward system has been made by a number of investigators.i3--’5

The lack of tolerance to the threshold lowering effect of morphine suggests that the narcotic user may be continuing to use the drug not simply to avoid withdrawal signs. If there was tolerance to the euphoric effect, avoidance of withdrawal would be the major pharmacological reinforcer unless one sub- scribed to the previously mentioned theory that the aversiveness of the drug effect becomes positively reinforcing. Studies of street users of heroin by McAuliffe and Gordon i6 report that physically dependent subjects (and most likely tolerant to many of the actions of the drug) still report a sustained euphoria or high that can be differentiable from the “rush” associated with the intravenous injection of heroin. This study was designed to test the hypothesis of Lindesmith ii that the primary reinforcer for continued use of heroin is the avoidance of withdrawal signs. Meyer and Mirin i0 in an experimental study of heroin use in man shed further light on the reinforcers involved in continued drug use. They reported that despite an increase in a more dysphoric mood state and an increase in psychopathology as chronic use continues, each drug injection caused a brief period (30-60 min) of positive mood. They stated that “these acute effects are significantly reinforcing so that drug self- administration is perpetrated in the face of measurable degree of psychological and social deterioration.”

A number of theories have been proposed to explain continued and com- pulsive opiate use, and it is clear that social and psychological influences are most important. Certainly there may be conditioned abstinence, as experi- mentally demonstrated by Wikler and Pescor,fios fil that accounts for some of the continued use; however, there seems to be a primary unconditioned effect of opioids that is reinforcing.

CONCLUSIONS

These experiments clearly indicate that morphine increases the sensitivity of animals to rewarding brain stimulation and suggest that brain-stimulation reward may be a useful model for understanding the rewarding effects of the opiate drugs. Naloxone’s ability to attentuate the threshold-lowering effect of ampetamine, cocaine, and PCP and to potentiate the threshold-raising effect of chlorpromazine suggests that there is an important interaction between the catecholiminergic and endorphinergic systems. Finally, this interaction may have relevance for the clinical use of naloxone with neuroleptics in the treatment of schizophrenic patients.

REFERENCES

1. LETTIERI, D. J., M. SAYERS & H. W. PEARSON, Eds. 1980. Theories on Drug Abuse: Selected Contemporary Perspectives. NlDA Research Monograph 30. US. Government Printing Office, Washington, D.C.


2. BECKEIT, H. D. 1974. Hypotheses concerning the etiology of heroin addiction. In Addiction. P. G. Bourne, Ed. pp. 38-54. Academic Press. New York.

3. CHEIN, I., D. L. GERARD, R. E. LEE & E. ROSENFELD, Eds. 1964. The Road to H. Basic Books. New York.

4. WIKLER, A. 1952. A psychodynamic study of patients during experimental self-regulated readdiction to morphine. Psychiat. Quart. 2 6 270-293.

5. KHANTZIAN, E. J. 1974. Opiate Addiction: A critique of theory and some implications for treatment. Am. J . Psychother. 28: 59-70.

6. DOLE, V. P. & M. E. NYSWANDER. 1967. Addiction-A metabolic disease. Arch. Int. Med. 120: 19-24.

7. MELLO, N. K. 1978. Control of drug self-administration: The role of aversive consequences. In Phencyclidine (PCP) Abuse: An Appraisal. R. C. Peterson & R. C. Stillman, Eds. pp. 289-308. NIDA Research Monograph 21. U.S. Government Printing Office, Washington, D.C.

8. KELLEHER, R. T., W. C. RIDDLE & L. COOK. 1963. Persistent behavior maintained by unavoidable shocks. J. Exp. Anal. Behav. 6(4): 507-517.

9. KELLEHER, R. T. & W. H. MORSE. 1968. Schedules using noxious stimuli 111. Responding maintained with response-produced electrical shocks. J. Exp. Anal. Behav. ll(6): 819-838.

10. KORNETSKY, C., R. U. ESPOSITO, S. MCLEAN & J. 0. JACOBSON. 1979. Intra- cranial self-stimulation thresholds: A model for the hedonic effects of drugs of abuse. Arch. Gen. Psychiat. 3 6 289-292.

11 . KORNETSKY, C. & R. U. ESPOSITO. 1979. Euphorigenic drugs: Effects on the reward pathways of the brain. Fed. Proc. 3 8 2473-2476.

12. OLDS, J. & P. MILNER. 1954. Positive reinforcement produced by electrical stimulation of septa1 area and other regions of rat brain. J. Comp. Physiol. Psychol. 47: 419427.

13. OLDS, J. & R. P. TRAVIS. 1960. Effects of chlorpromazine, meprobamate, pentobarbital and morphine on self-stimulation. J. Pharmacol. Exp. Ther. 128: 397-404.

14. ADAMS, W. J., S. A. LORENS & C. L. MITCHELL. 1972. Morphine enhances lateral hypothalamic self-stimulation in the rat. Proc. SOC. Exp. Biol. 140: 770-771.

15. WEEKS, J. 1962. Experimental morphine addiction: method for automatic intravenous injections in unrestrained rats. Science 1 3 8 143-144.

16. NELSEN, J. M. & C. KORNETSKY. 1972. Morphine induced EEG changes in central motivational systems: evidence for single dose tolerance. Fifth Int. Cong. Pharmacol. 166.

17. NELSEN, J. M. 1970. Single dose tolerance to morphine sulfate: Electroen- cephalographic correlates in central motivational systems. Doctoral Disserta- tion, Boston University. No. 70-22425. University Microfilms, Ann Arbor, MI.

18. COCHIN, J. & C. KORNETSKY. 1964. Development and loss of tolerance to morphine in the rat after single and multiple injections. J. Pharmacol. Exp. Ther. 145: 1-10.

19. KORNETSKY, C. & G. BAIN. 1968. Morphine: Single-dose tolerance. Science

20. HODOS, W. & E. VALENSTEIN. 1962. A evaluation of response rate as a measure of rewarding intracranial stimulation. J. Comp. Physiol. Psychol.

21. VALENSTEIN, E. S. 1964. Problems of measurement and interpretation with

22. PAYTON, M. The relationship between absolute threshold and rate of response

162: 1011-1012.

5% 80-84.

reinforcing brain stimulation. Psychol. Rev. 71: 415437.

for brain-stimulation reward. Manuscript in preparation.


23. MARCUS, R. A. 1973. Morphine: Effects on positive and negative intracranial reinforcement thresholds. Doctoral dissertation, Boston University. University Microfilms. Ann Arbor, MI.

24. MARCUS, R. & C. KORNETSKY. 1974. Negative and positive intracranial reinforcement thresholds: Effects of morphine. Psychopharmacologia 38: 1-13.

25. CORNSWEET, T. N. 1962. The staircase method in psychophysics. Am. J. Psychol. 75: 485-491.

26. STEVENS, S. S. 1951. Mathematics, measurement, and psychophysics. In Hand- book of Experimental Psychology. S. S. Stevens, Ed. pp. 1-49. John Wiley and Sons. New York.

27. KORNETSKY, C. & G. T. BAIN. 1982. Effects of opiates on rewarding electrical brain stimulation. In Neurobiology of Opiate Reward Mechanisms. J. E. Smith & J. D. Lane, Eds. Elsevier/North Holland Biomedical Press. In press.

28. ESPOSITO, R. & C. KORNETSKY. 1977. Morphine lowering of self-stimulation thresholds: Lack of tolerance with long term administration. Science 195:

29. ESPOSITO, R. U., S. MCLEAN & C. KORNETSKY. 1979. Effects of morphine on intracranial self-stimulation to various brain stem loci. Brain Res. 168: 425- 429.

30. LORENS, S. A. & C. L. MITCHELL. 1973. Influence of morphine on lateral hypothalamic self-stimulation in the rat. Psychopharmacologia 32: 271-277.

31. BUSH, H. D., M. F. BUSH, M. A. MILLER & L. D. REID. 1976. Addictive agents and intracranial stimulation: Daily morphine and lateral hypothalamic self-stimulation. Physiol. Psychiat. 4: 79-85.

32. GLICK, S. D. & G. RAPAPORT. 1974. Tolerance to the facilitatory effect of morphine on self-stimulation of the medial forebrain bundle of rats. Res. Commun. Chem. Pathol. Pharmacol. 9: 647-652.

33. ESPOSITO, R. U. & C. KORNETSKY. 1978. Opioids and rewarding brain stimulation. Neurosci Biobehav. Rev. 2: 115-122.

34. BELLUZZI, J. D. & L. STEIN. 1977. Enkephalin may mediate euphoria and drive reduction reward. Nature 266: 556-558.

35. STEIN, L. & J. D. BELLUZZI. 1979. Brain endorphins: possible role in reward and memory formation. Fed. Proc. 38 2468-2472.

36. STAPELTON, J. M., V. J. MERRIMAN, C. L. COOOLE, S . D. GELBARD AND L. D. REID. 1979. Naloxone reduces pressing for intracranial stimulation of sites in the periaqueductal gray area, accumbens nucleus, substantia nigra, and lateral hypothalamus. Physiol. Psychol. 7(4): 427-436.

37. WAUQUIER, A., C. J. E. NIEMEGEERS & H. LAL. 1974. Differential antagonism by naloxone of inhibitory effects of haloperidol and morphine on brain self- stimulation. Psychopharmacologia 37: 303-3 10.

38. HOLTZMAN, S. G. 1976. Comparison of the effects of morphine, pentazocine, cyclazocine, and amphetamine on intracranial self-stimulation in the rat. Psychopharmacologia 4 6 223-227.

39. VAN DER KOOY, D., F. G. LEPUNE & A. G. PHILLIPS. 1977. Apparent in- dependence of opiate reinforcement and electrical self-stimulation systems in rat brain. Life Sci. 20: 981-986.

40. LORENS, S. A. & S. M. SAINATI. 1978. Naloxone blocks the excitatory effect of ethanol and chlordiazepoxide on lateral hypothalamic self-stimulation behavior. Life Sci. 23: 1359-1364.

41. STILWELL, D. J., R. A. LEVIIT, C. A. HORN, M. D. IRVIN, K. GROSS, D. s. PARSONS, R. H. Scan & E. L. BRADLEY. 1980. Naloxone and shuttlebox self-stimulation in the rat. Pharmacol. Biochem. Behav. 13: 739-742.

42. ESPOSITO, R. U., W. PERRY & C. KORNETSKY. 1980. Effects of d-amphetamine and naloxone on brain stimulation reward. Psychopharmacology 69: 187-191.

189-191.

’


43. PERRY, W., R. U. ESPOSITO & C. KORNETSKY. 1981. Effects of chronic naloxone treatment on brain-stimulation reward, Pharmacol. Biochem. Behav. 14:

44. ESPOSITO, R. U., A. H. D. MOTOLA & C. KORNETSKY. 1978. Cocaine: Acute effects on reinforcement thresholds for self-stimulation behavior to the medial forebrain bundle. Pharmacol. Biochem. Behav. 8: 437-439.

45. KORNETSKY, C., G. BAIN & M. RIEDL. 1981. Effects of cocaine and naloxone on brain-stimulation reward. Pharmacologist 23: 192.

46. KORNETSKY, C., R. A. MARKOWITZ & R. U. ESPOSITO. 1981. Phencyclidine and naloxone: Effects on sensitivity to aversive and rewarding stimulation in the rat. In PCP (Phencyclidine) : Historical and Current Perspectives. F. Domino, Ed. pp. 321-330. NPP Books. Ann Arbor, MI.

47. GERMAN, D. C. & D. M. BOWDEN. 1974. Catecholamine systems as the neural substrate for intracranial self-stimulation: A hypothesis. Brain Res. 73: 381- 419.

48. CROW, T. J. 1976. Specific monoamine systems as reward pathways: Evidence for the hypothesis that activation of the ventral mesencephalic dopaminergic neurones and noradrenergic neurones of the locus coeruleus complex will support self-stimulation responding. In Brain-Stimulation Reward. A. Wau- quier and E. T. Rolls, Eds. pp. 211-238. American Elsevier Publishing Co. New York.

49. WISE, R. A. 1978. Catecholamine theories of reward: A critical review. Brain Res. 152: 215-247.

50. FIBIGER, H. C. 1978. Drugs and reinforcement mechanisms: A critical review of the catecholamine theory. In Annual Review of Pharmacology and Toxicology. R. George, R. Okun & A. K. Cho, Eds. pp. 37-56. Annual Re- views, Inc. Palo Alto, CA.

51. ESPOSITO, R. U., W. PERRY & C. KORNETSKY. 1980. Chlorpromazine and brain-stimulation reward: Potentiation of effects by naloxone. Society for Neuroscience Abstracts 6: 700.

52. ESPOSITO, R. U., W. PERRY & C. KORNETSKY. 1981. Chlorpromazine and brain-stimulation reward: Potentiation of effects by naloxone. Pharmacol. Bio- chem. Behav. 15: 903-905.

1978. Differential effects upon liminal-escape pain thresholds of neuroleptic, anti- depressant, and anxiolytic agents. Fed. Proc. 37: 470.

54. KELLY, D. D., M. BRUTUS & R. J . BODNAR. 1978. Differential effects of naloxone upon elevation of liminal escape pain thresholds induced by psycho- tropic drugs: Reversal of chlordiazepoxide but enhancement of neuroleptic “analgesia.” 7th Int. Con. Pharmacol. (Abstract) 119 (No. 270).

55. WISE, R. A. 1982. Neuroleptics and operant behavior: The anhedonia hypothesis. Behav. Brain Sci. In press.

56. MIRSKY, A. F. & C. KORNETSKY. 1964. On the dissimilar effects of drugs on the Digit Symbol Substitution and Continuous Performance Tests. Psycho- pharmacologia 5: 161-177.

57. DAVIS, G. C., W. E. BUNNEY, E. G. DEFRAITES, I . E. KLEINMAN, D. P. VAN KAMMEN, R. M. POST & R. J. WYATT. 1977. Intravenous naloxone administration in schizophrenia and affective illness. Science 197: 74-77.

58. EMRICH, H. M., C. CORDING, S. PIRCE, A. KNOLLING, D. VZERSSEN & A. HERZ. 1977. Indication of an antipsychotic action of the opiate antagonist naloxone. Pharmakopsychiat. Neuropharmakol. 1 0 265-270.

59. GUNNE, L.-M., L. LINDSTROM & L. TERENIUS. Naloxone-induced reversal of schizophrenic hallucinations. J. Neural Trans. 4 0 13-19.

60. WATSON, S., P. A. BERGER, H. AKIL, M. J. MILLS & J. D. BARCHAS. 1978. Effects of naloxone in schizophrenia: Reduction in hallucinations in a sub- population of subjects. Science 201: 73-76.

247-249.

53. KELLY, D. D., R. J. BODNAR, M. BRUTUS, C. F. WOODS & M. GLUSMAN.

25 8 Annals New York Academy of Sciences

61. LORENS, S. A. 1976. Comparison of the effects of morphine on hypothalamic and medial frontal cortex self-stimulation in the rat. Psychopharmacology

62. JACKLER, F., S. S. STEINER, R. J. BODNAR, R. F. ARKERMANN, W. T. NELSON & S. J. ELLMAN. 1979. Morphine and intracranial self-stimulation in the hypothalamus and dorsal brainstem: Differential effects of dose, time, and site. Int. J. Neurosci. 9: 21-35.

63. BROEKKAMP, C. L., J. H. VAN DEN BOGGARD, H. J. HEIJNEN, R. H. ROPS, A. R. COOLS & J. M. VAN ROSSUM. 1976. Separation of inhibiting and stimulating effects of morphine on self-stimulation behavior by intracerebral microinjec- tions. Eur. J. Pharmacol. 4: 443-446.

64. LIEBMAN, J. & S. D. SEGAL. 1977. Differential effects of morphine and d-amphetamine on self-stimulation from closely adjacent regions in rat mid- brain. Brain Res. 136: 103-117.

65. SCHENK, S. T. WILLIAMS, A. COUPAL & P. SHIZGAL. 1980. A comparison between the effects, of morphine on the rewarding and aversive properties of lateral hypothalamic and central gray stimulation. Physiolog. Psychol. 8

66. KORNETSKY, C. & R. U. ESPOSITO. 1981. Reward and detection thresholds for brain stimulation: Dissociative effects of cocaine. Brain Res. 209 496-500.

67. PHILLIPS, A. G. & F. G. LEPAINE. 1978. Electrical stimulation of the amyg- dala as a conditioned stimulus in a bait-shyness paradigm. Science 201: 536-538.

68. SWETT, J. E. & C. M. BOURASSA. 1980. Detection thresholds to stimulation of ventrobasal complex in cats. Brain Res. 183: 313-328.

69. SEM-JACOBSEN, C. W. & A. TORKILDSEN. 1960. Depth recording and electrical stimulation in the human brain. In Electrical Studies on the Unanesthesized Brain. E. R. Ramey & D. S. O’Doherty, Eds. pp. 275-290. Paul S. Hoeber. New York.

70. HEATH, R. G. & W. A. MICKLE. 1960. Evaluation of seven years experience with depth electrode studies in human patients. In Electrical Studies on the Unanesthesized Brain. E. R. Ramey & D. S. ODoherty, Eds. pp. 214-242. Paul S. Hoeber. New York.

71. COLLIER, H. 0. J. 1968. Supersensitivity and dependence. Nature 20 228- 231.

72. KUMAR, R., E. MITCHELL & I. P. STOLERMAN. 1971. Disturbed patterns of behavior in morphine tolerant and abstinent rats. Brit. J. Pharmacol. 42: 473-484.

73. LEVITT, R. A., I. H. BALTZER, T. M. EVERS, D. J. STILWELL & J. E. FURBY. 1977. Morphine and shuttle-box self-stimulation in the rat: A model for euphoria. Psychopharmacology 54: 307-3 11.

74. FARBER, P. D. & L. D. REID. 1976. Addictive agents and intracranial stimulation (ICS): Daily morphine and pressing for combinations of positive and negative ICS. Physiol. Psychol. 4: 262-268.

75. WISE, R. 1980. Actions of drugs of abuse on brain reward systems. Phar- macol. Biochem. Behav. 13 (Suppl. 1): 213-224.

76. MCAULIFFE, W. E. & R. A. GORDON. 1974. A test of Lindesmith’s theory of addiction: The frequency of euphoria among long term addicts. Am. J. SOC.

77. LINDESMITH, A. R. 1965. Problems in the social psychology of addiction. In Narcotics. D. M. Wilner & G. G. Kassebaum, Eds. pp. 118-139. McGraw- Hill. New York.

78. MEYER, R. E. & S. M. MIRIN. 1979. The Heroin Stimulus. Plenum Press. New York.

79. MIRIN, S. M., R. E. MEYER & H. B. MCNAMEE. 1976. Psychopathology and mood during heroin use. Arch. Gen. Psychiat. 33: 1503-1508.

48: 217-224.

372-378.

79: 795-840.


80. WIKLER, A. & F. T. PESCOR. 1967. Classical conditioning of a morphine abstinence phenomenon, reinforcement of opioid-drinking behavior and “relapse” in morphine addicted rats. Psychopharmacologia 10: 255-284.

81. WIKLER, A. & F. T. PESCOR. 1970. Persistence of “relapse-tendencies” of rats previously made physically dependent on morphine. Psychopharmacologia 16: 375-384.

DISCUSSION OF THE PAPER

UNIDENTIFIED SPEAKER: Would naloxone change the threshold for the adversive, punishing stimuli?

C. KORNETSKY (Boston University School of Medicine, Boston, M A ) : Yes, we have actually done that, and if electrodes are put into areas of the brain that are aversive, that is, not rewarding at any intensity, you find a very systematic dose-effect increase in sensitivity in those areas. In other words, the threshold is lowered.

UNIDENTIFIED SPEAKER: At what dose of naloxone? KORNETSKY: Doses of 2 and 4 mg/ kg. A. L. STEIN (University of California at Zrvine) : Your last experiment is a

particularly interesting one and gave me the following idea-an idea that may resolve both our findings and explain some of the effects you have shown.

In the last experiment naloxone demonstrated a profound effect in the presence of chlorpromazine. It made me wonder whether most self-stimulation sites involve the action of opioids and catecholamines jointly. In certain sites, such as the substantia nigra and the medial forebrain bundle, where we show naloxone insensitivity, the opiate effect may be largely masked by massive release of catecholamines. If you block those catecholamine effects with chlorpromazine, then you may see a residual opiate effect which can be nicely blocked by naloxone.

So this method of using the two kinds of antagonists may, in fact, reflect that at many self-stimulation sites there are simultaneously both endorphin- and catecholamine-reversed actions. This idea may be particularly inviting because Hokfelt has shown that many catecholamine-containing neurons also may contain endorphins. Conceivably, both transmitters may be simultaneously re!eased from the same neuron and may interact to produce behavioral reinforcement.

KORNETSKY: If you are correct, Dr. Stein, it would explain the discrepancy between our results, or at least one aspect of the discrepancy.

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