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Reinstatement of Drug-Taking Behavior as a Method
of Assessing Incentive Motivational Properties of Drugs
Jane Stewart and Harriet de Wit
Center for Studies in Behavioral Neurobiology
Department of Psychology
Montreal, Quebec, Canada H3G 1M8
Department of Psychiatry
University of Chicago
Chicago, Illinois 60637
|Noncontingent "priming" presentations of positive reinforcers (or incentive events) can enhance and reinstate previously acquired instrumental responding for these reinforcers. We describe how this phenomenon may be used to study the motivational control of drug-taking behavior and the relapse to drug-taking in drug-free individuals.|
Positive reinforcers (or incentive events) produce motivational effects that outlast their presentation. These appetitive motivational consequences are reflected in post-incentive behaviors such as locomotion and exploration of the environment, repeated visits to a place associated with the presentation of the incentive, and activation of learned behaviors in the presence of stimuli previously associated with the incentive event (reinstatement). These post-incentive behaviors are thought to result from the activation, by the incentive event, of central appetitive motivational states involved in the initiation and maintenance of instrumental or voluntary behavior.
Both experimental evidence and casual observation suggest that the simple presentation of a reinforcing or incentive event is followed by a transient period of motivational change. Even the first presentation of an incentive event can alter the organism’s responsiveness to its environment. In the animal laboratory it is common practice to give noncontingent priming presentations of a reinforcer at the beginning of a session to "create interest" in the environment and to facilitate responding. The enhancement of responding after noncontingent delivery of a reinforcer has been reported for a wide range of events, including food, electrical brain stimulation (EBS) and self-administered drugs.
In animals that have been trained to self-administer drugs such as heroin or cocaine and that are then exposed to a period of extinction, the presentation of noncontingent priming injections of the self-administered drug leads to reinstatement of responding (de Wit and Stewart, 1981, 1983). In our studies of reinstatement, rats implanted with intravenous catheters are trained to self-administer a drug intravenously and are then given test sessions consisting of a period of self-administration followed by extinction conditions. Following cessation of responding, priming injections of the training drug or of test drugs are delivered intravenously by the experimenter. The temporal pattern and the frequency of responding following these priming drug injections are monitored. A similar methodology is used to specify the neural site of action of drugs responsible for the priming effects (Stewart, 1982, 1984). In rats trained to self-administer heroin or cocaine intravenously, the priming effects of drugs applied via intracerebral cannulae to specific sites within the central nervous system can be assessed. The results of studies using this technique suggest that priming and reinforcing properties of self-administered drugs are mediated by common mechanisms and that it is possible to separate these actions from other central and peripheral effects. We have argued that these priming effects of self-administered drugs reflect their incentive motivational properties.
Priming Effects of Reinforcers Other Than Drugs
The stimulating effects of appetizers were discussed by Pavlov (1919) who pointed to the familiar phenomenon that "a person who at first displays indifference to his customary meal, afterwards begins to eat with gusto if his taste has been stimulated by something piquant" (p. 108). Konorski (1967) demonstrated the priming effect by offering a small portion of food to hungry dogs in an environment where they had never previously received food. While the dogs were initially impassive and calm before the presentation of food, they afterwards displayed a strong "hunger reflex" characterized by motor restlessness and increased attention to gustatory and olfactory stimuli. Konorski demonstrated the specificity of this priming effect by training dogs to perform two different movements, one for food and one for water. When the dogs were subsequently tested while both hungry and thirsty, a small quantity of food led to the food movement whereas water delivery led to the water movement. He suggested that there was a similar priming effect in humans, that of the so-called "peanut phenomenon" in which "one nut will arouse a selective appetite for eating another one" (Konorski, 1967, p. 20). Despite the familiarity of this phenomenon as illustrated by such anecdotal examples, surprisingly few experimental studies have been undertaken to study it.
One laboratory example of such an effect is the local rate-enhancing effect of "free" food delivery in rats responding for food as the reinforcer (Deluty, 1976). Rats were trained to respond on a random interval schedule for food pellets, and then additional food pellets were delivered noncontingently at fixed or random times. Immediately after noncontingent delivery of food, there was an increase in response rate of 33% to 75% over baseline rates. One way to interpret these results is in terms of the priming or response-enhancing aftereffects of free food delivery.
Another example of the response-facilitatory effect of free food delivery is the reinitiation of responding that is seen when free food pellets are given during extinction (Eiserer, 1978; Reid, 1958; Skinner, 1938). In Eiserer’s (1978) experiment, rats were trained to bar press for food under food deprivation conditions and were then given a period of free-feeding before being tested in the extinction phase of the experiment. The animals were allowed to extinguish their bar pressing in the satiated condition, and when a period of two minutes occurred with no responses, a free food pellet was delivered. Animals reinitiated responding within one minute after the priming food delivery with a probability of 0.44 while the baseline probability of a response was only 0.19. Eiserer also scored the occurrence, following a free food delivery, of subthreshold components of the bar-press response (e.g., rearing and orienting to the bar) in addition to counting successfully executed bar presses. Ninety percent of the priming food deliveries were followed by either a completed bar press or by a subthreshold component of the response, whereas the baseline occurrence of these responses was only 42%. It is noteworthy that the delivery of a food pellet retained its effectiveness in restoring responding even though the animals were tested while in a sated condition.
In another demonstration of the priming effect of "free" reinforcers during extinction, Panksepp and Trowill (1967) used intraorally-delivered chocolate milk as the reinforcer in rats that were either food deprived or not food-deprived. Rats were prepared with fistulas to their mouths and were then trained to bar press for chocolate milk delivered intraorally. They were subsequently put under extinction conditions until their responding had ceased and then tested with noncontingent delivery of the chocolate milk. Both the deprived and the nondeprived rats reinitiated responding following delivery of chocolate milk (83% and 71% respectively of the animals in each group responded).
While in each of these studies free reinforcement delivery resulted in an enhancement of responding, the basis of this priming effect is not clear. In both Eiserer’s and Panksepp and Trowill’s experiments, the animals had been trained on a continuous reinforcement schedule, in which a delivery of the reinforcer usually immediately precedes the next reinforced response. It has been argued (e.g., Reid, 1958) that under these circumstances each reinforcement delivery constitutes a discriminative stimulus that "sets the occasion" for the next response. However, the phrase "setting the occasion" does not specify how the response is elicited. An implicit assumption in this conception is that presentation of a certain stimulus directly elicits the appropriate motoric response (the one that has been reinforced). Such an explanation is, however, ruled out by the flexibility and variability seen in the topography of responses. The data are more consistent with the idea that a motivational state is elicited by stimuli that signal reinforcers. It has been argued that presentation of any reinforcer or of a stimulus that predicts a reinforcer has motivationally arousing properties (e.g., Bindra, 1969; Bolles, 1972; Killeen, 1975, 1982). The increase in the vigor of responding that is seen after noncontingent food delivery may reflect, therefore, a general phenomenon of motivational arousal that occurs after delivery of a reinforcer or of a stimulus previously associated with a reinforcer (Bindra & Campbell, 1967; Bindra & Palfai, 1967, Sheffield & Campbell, 1954).
One of the most striking and the most thoroughly studied examples of the priming phenomenon occurs with electrical brain stimulation (EBS). Operant responding (e.g., bar pressing and runway running) for EBS is greatly facilitated by priming brain stimulation pulses delivered shortly before the opportunity to respond (Gallistel, 1973). Both magnitude of the response facilitation and the rate of decay of the effect are directly related to the intensity of the priming stimulation. The brain stimulation priming effect is so powerful that some theorists (e.g., Deutsch, 1960) have postulated that the initiation of self-stimulation behavior actually depends on the direct electrophysiological activation of a "drive" pathway by the priming (or immediately preceding) train of stimulation. A considerable amount of research has been undertaken concerning the question of whether the drive-inducing and reinforcing effects of brain stimulation are mediated by one or more neurophysiological systems. Recent data would suggest that these apparently separate phenomena are mediated, at least at some level, by the same set of neurons (see Hawkins, Roll, Puerto, & Yeomans, 1983). Furthermore, the findings that electrical stimulation of brain sites mediating reinforcing effects can enhance the positive incentive properties of species-typical objects of motivation (for a review, see Glickman & Schiff, 1967) suggests that motivational change is a primary property of reinforcer action. From a behavioral point of view, data on the response-enhancing effects of noncontingent trains of brain stimulation are consistent with the data from studies of conventional reinforcers and support the notion that noncontingent reinforcement delivery specifically enhances the tendency to respond to stimuli associated with that reinforcer at least for a short period of time.
In another set of studies, reinstatement by priming presentations of ethologically significant stimuli has been demonstrated. In ducklings (Eiserer & Hoffman, 1973) the brief presentation of an imprinted stimulus (a potent reinforcer) enhanced responding that had been reinforced previously by the presentation of the imprinted stimulus. Responding following the presentation increased as the duration of the presentation was increased. Distress vocalizations which occurred after withdrawal of the stimulus also increased with longer stimulus presentations. These results point to the specific motivational aftereffects that are aroused by both the presentation and the withdrawal of the positive incentive event, the priming stimulus.
Using cockroaches trained to cross an illuminated runway to darkness, Eiserer and Ramsay (1981) found that a brief priming presentation of the reinforcer (darkness) enhanced runway performance. The effect decayed rapidly if a delay was introduced between presentation of the priming stimulus and the opportunity to respond. As in the experiments with ducklings, stimulus presentations of longer duration led to greater responding.
In Betta spendens (Siamese fighting fish) trained to swim in a "runway" to view a conspecific stimulus, pre-exposure to a view of the conspecific (priming) decreased swimming time to the goal; longer exposures to the priming stimulus led to a stronger response (Hogan & Bols, 1980). The specificity of the priming effect was demonstrated in a choice experiment in which fish were given a choice between a food goalbox and an aggressive display goalbox. Priming with the display stimulus increased the animals’ choice of the display goalbox (at least when the display stimulus was visible at the choice-point). These results suggest that there is some specificity to the motivational state aroused by the priming stimulus but that the expression of the increased response tendency also depends on the contextual stimuli present in the animals’ environment.
Another example of priming was reported by Shettleworth (1978) in hamsters. When presentations of sunflower seed or nest paper were made intermittently to animals that were living in cages already supplied with seeds and paper, the animals began rearing at the dispenser panel, gnawing and digging around the dispenser panel, as if seeking further material. Eiserer and Ramsay (1981) have noted that such priming effects obtained with ethologically significant stimuli have characteristics similar to those obtained with rewarding EBS. They are strong, easy to obtain, and are related to the magnitude of the priming event. They have suggested that these similarities may be due to the fact that these incentive events appear to generate fewer satiety effects than do incentives such as food and water (see, for example, van der Kooy & Hogan, 1980). We suggest that priming effects such as those obtained with self-administered drugs also have some of the same characteristics.
Priming Effects with Self-Administered Drugs
Informal procedures used in the drug self-administration laboratory suggest that noncontingent infusions of the self-administered drug, presented at a time when the animal’s blood level of drug is relatively low, produce a strong facilitation of responding. Experimenters involved in the training of animals to self-administer drug routinely give "free" priming infusions at the beginning of sessions. Pickens and Harris (1968) reported that a single noncontingent priming infusion was sufficient to terminate a self-imposed period of abstinence in rats trained to self-administer amphetamine. A somewhat similar effect has been documented by Davis and Smith (1976) in rats and by Gerber and Stretch (1975) and Stretch and Gerber (1973) in monkeys. Davis and Smith found that presession injection of morphine restored morphine-reinforced bar pressing in rats after a period of extinction. In the Gerber and Stretch experiments, monkeys were trained to self-administer either cocaine or amphetamine. After self-administration training the monkeys were put on extinction conditions for several sessions until their rate of responding fell to low levels. Then test sessions were given in which the extinction conditions remained in effect, but prior to which the monkeys were given either intramuscular or intravenous injections of either the self-administered drug or another drug of the same or different class. Presession injections of the self-administered drug resulted in a powerful reinstatement of responding, producing patterns of responding within the session that were indistinguishable from the drug-reinforced sessions. There was also a strong facilitation of responding after pretreatment with another drug of the same class (i.e., cocaine pretreatment for monkeys trained to self-administer amphetamine, and amphetamine pretreatment for cocaine-trained animals) but only transient effects after pretreatment with drugs from another class (barbiturate or minor tranquilizer). One interpretation of these findings might be that the facilitatory effect of noncontingent drug injections on responding after extinction is an example of the discriminative stimulus control of responding by the drug. That is, the presession infusion of the self-administered drug re-established the stimulus conditions that were present when responding was reinforced in the self-administration sessions. The other drugs tested produced responding only to the extent that their stimulus properties are known to resemble the self-administered drug (Ando & Yanagita, l978; Colpaert, Niemegeers, & Janssen, 1979).
The similarity between the stimulus properties of different drugs has been examined in drug discrimination experiments (Overton, 1971; Stewart, 1962; Thompson & Pickens, 1971) in which drugs are used as the discriminative stimulus for responding for a positive reinforcer or avoidance of an aversive stimulus. In these experiments animals are trained to make one response (usually a lever press) after a presession injection of a drug, and another response (on a second lever) after a saline injection. Then on test sessions, other drugs are substituted for the training drug, and the animals’ tendency to respond on the drug- or saline-lever is taken to indicate the degree of similarity or dissimilarity of the test drug to the training drug. It is important to note here that while results from such drug discrimination experiments can provide useful information about the similarity and dissimilarity of the stimulus properties of a wide range of substances in experimental animals, these experiments do not tell us which actions of drugs form the basis of the discrimination. Do all or any discriminably similar stimulus properties lead to training-drug-related responding, or are some properties more important than others? It may be, for example, that the activation of common motivational states is the critical factor for the reinstatement of responding by drugs with apparently similar stimulus properties. Whether or not this is the case, what the Davis and Smith and the Gerber and Stretch experiments do show is that the presence of drug in the body enhances drug-related behavior in an animal returned to the environment where drug has in the past been available. It was the potential significance of this finding that led us to investigate the basis of the priming effect in the reinstatement of drug-taking in animals trained to self-administer stimulants and opiates intravenously (de Wit & Stewart, 1981, 1983; Stewart, 1982, 1984).
The idea that the ingestion of a formerly self-administered drug induces a strong motivational state or "craving" for the drug and that it retains the ability to do this over an indefinite period of abstinence from the drug is not new. Former cigarette smokers speak of the potential for relapse following the smoking of a single cigarette, and formerly uncontrolled drinkers of alcohol hold that one drink elicits an urge to have another. There is some experimental evidence from studies with human alcoholics that lends support to this idea (Hodgson, Rankin, & Stockwell, 1979). An interesting example of the priming effect in human opiate use comes from a study by Meyer and Mirin (1979) of patterns of heroin self-administration in hospitalized ex-heroin addicts. Ratings of craving for the drug were taken before and after heroin intake in subjects free to self-administer a fixed dose of heroin when they wanted it. Surprisingly, the subjects reported only a very modest decrease in craving from immediately before to after heroin infusion, and levels of craving during heroin self-administration never fell to levels as low as in drug-free periods. It seems likely that drug circulating in the blood acted as a priming stimulus maintaining interest in the drug and in drug-related stimuli.
Requirements of a Methodology for Reinstatement
of Drug Self-Administration by Priming Events
One requirement of a reinstatement methodology is that the effectiveness of the priming manipulation must be tested in animals experienced in drug-taking but which, at the time of test, are drug-free and are not engaging in drug-taking behavior. In order to be able to evaluate the effect of the priming event, however, the animal must be in a situation where it is free to engage in drug-taking or drug-seeking behavior. In short, the animal must be trained, drug-free and not currently responding but free to do so.
One situation in which these conditions might be obtained is in the test box at the beginning of periodic self-administration sessions. Animals returned to the test chamber from their home cages would be trained, drug-free and free to respond. The problem is that most of them do respond, some immediately, others with varying, unpredictable latencies. The effects of priming drug injections would be, therefore, difficult to estimate under these conditions.
Another circumstance in which the effects of priming injections have been observed is when animals are given 24-hour access to a drug. Under these conditions animals spontaneously cease responding for periods of time and priming injections have been reported to reinstate drug-taking (Pickens & Harris, 1968). While the method is attractive in that it seems to approximate quite realistically some human conditions for drug-taking, it is quite impractical from the standpoint of data collection; abstinence periods are unpredictable and maintaining animals in test chambers for long periods of time is difficult and expensive. Furthermore, though of considerable interest, little is known about the factors leading to these periods of spontaneous abstinence. If, for example, neurotransmitter pools were depleted, making a drug temporarily less effective, reinstatement might not occur.
Because of these considerations, the reinstatement paradigm that we have found most satisfactory for evaluating priming is one modified from those used in studies with food reinforcers (see Eiserer, 1978; Panksepp & Trowill, 1967). Animals are trained to self-administer drug intravenously and are then given periodic sessions in which drug self-administration is followed by extinction conditions. When responding has ceased for some standardized time period, the priming manipulations are tested. The added feature of this design is that extinction conditions are maintained throughout the test. The effectiveness of the priming manipulation is evaluated on a baseline of behavior maintained without additional drug intake. We have found with this method that it is possible to test animals repeatedly on both the reinitiation and maintenance of responding following the priming event. One comment made frequently in connection with this methodology is that perhaps the priming infusions act to reinstate behavior by "predicting the availability of drug." If this were the case, it would be expected that animals would learn quickly that priming infusions given during extinction do not lead to further drug availability and animals would cease to respond to them. The fact that we find persistence of responding after many sessions argues against such an interpretation.
Reinstatement of Intravenous Drug
Intravenous Priming Injections; Drug Self-Administration: Preparation and Training
Adult male rats weighing 250 to 350 g at the beginning of the experiments are used in our studies. Prior to surgical implantation of intravenous catheters, animals are routinely trained to bar press for food in test chambers used only for that purpose. Animals are introduced to a 23-hour food deprivation schedule for 3 to 5 days and are then placed in the training box for an hour a day until they press regularly for food pellets on a continuous reinforcement schedule. Following this, the deprivation schedule is terminated immediately. This period of training for food reduces the period of training necessary for intravenous drug self-administration. Animals adapt to handling and to being placed in test chambers and tend after such training to react readily to bar mechanism. Following recovery from the food deprivation schedule, animals are subjected to surgery.
Permanent, indwelling intravenous catheters are implanted into the left jugular vein under pentobarbital anesthesia (60 mg/kg). Animals are given, in addition, a 0.1 mg/kg injection of atropine sulphate to prevent saliva accumulation during surgery. Following surgery, animals are given a dose of 60,000 IU Penicillin G.
The catheters are constructed from a 110 mm piece of Silastic tubing (0.064 cm inner diameter, 0.119 cm outer diameter). At approximately 33 mm and 37 mm from the tapered end of the tubing, two rings of silastic glue are formed around the outer surface to cause slight swellings in the diameter of the tube. The jugular vein is exposed and the tapered end inserted in the vein just past the point of the first ring. The vein is tied with thread between the rings; the upper end of the vein is also secured to the catheter between the rings. The catheter is then passed subcutaneously to the top of the head where it exits into a connector made from 22-gauge stainless steel tubing that is then mounted on the skull with dental cement. A stainless-steel screw is also mounted in the dental cement, upside-down, with the threaded end exposed. A cap made from a piece of silastic tubing is placed over the open end of the connector when the animal is not in the test chamber. Catheters are flushed daily with heparinized (5 IU/ml) physiological saline for the first week after catheterization; this protects against the formation of embolisms in the vein. If catheter failure occurs (either leakage or blockage), animals are subjected to surgery and catheters are placed in the right jugular vein. During the week following surgery, animals are checked carefully for infections, for normal food and water intake and for urination.
Standard operant chambers are used for self-administration. The boxes are fitted with two bars only one of which is activated to deliver drug. The bars are mounted 9.0 cm from the floor to prevent accidental activation by the animal. A swivel (Brown, Amit, & Weeks, 1976) and the infusion tubing are suspended from the box. The infusion tubing leading from the rat’s head to the swivel is enclosed in a coil of stainless steel wire. One end of this wire is attached by a nut to the screw embedded in the cement on the animal’s head; the other end is attached to the swivel causing the swivel to move as the animal turns. Further tubing leads from the swivel to an infusion pump outside the chamber. Each depression of the bar starts a timer that activates the infusion pump for the number of seconds needed to deliver the appropriate amount of drug solution. Using a fixed concentration of drug solution, the duration of the infusion is determined by the animal’s weight and varies from approximately 9 to 13 seconds. Bar presses during infusions are counted but do not reset the pump delivery mechanism. All presses on both the activated and the "dummy" bar are recorded in time.
During self-administration training animals are connected to the infusion tubing in the test chamber for 2 to 3 hours daily during which the training drug, either cocaine HCl (1.0 mg/kg/infusion) or diacetylmorphine HCl (heroin, 100 mg/kg/infusion), is available for each press on the activated bar. Solutions are made up in physiological saline with 5 IU/ml heparin added. During training priming injections of the drug are deliberately avoided. Occasionally, on the first day of training, a food pellet is placed on the activated bar to elicit interest in the bar. Most importantly, the number of infusions taken by the animals in the early training sessions is closely monitored to avoid overdosing. Animals so learn to space their responses and develop regular patterns of intake.
In order to reduce infection and illness, the entire infusion system is flushed and cleaned regularly. Before being placed in the chambers, the animal’s catheter is checked for blockage or leakage by injecting a small amount of heparinized physiological saline directly into the head-mount opening.
Extinction and Test Sessions
Test sessions are begun when animals reliably initiate responding at the beginning of sessions and respond regularly throughout. Each test session consists of a varying period of 1 to 2 hours of self-administration followed by extinction conditions for the remainder of the session. Extinction conditions are introduced by substituting a syringe containing heparinized physiological saline for the one containing drug. After a standardized period of time has passed without responding, usually 30 minutes, priming injection trials are initiated. Frequently, on the first day that extinction conditions are introduced, response rates are high initially and responding continues for a long period of time; priming tests are started, then, on subsequent sessions.
Intravenous priming infusions are delivered by the experimenter from just above the swivel, with minimal disturbance to the animal. Because, however, the experimenter does enter the area, preliminary saline priming infusions are given prior to drug infusions. Thirty minutes later a test drug infusion is delivered. The drug infusions are followed by a saline solution that flushes the drug solution throughout the infusion system. Behavior is monitored for 3 hours following the infusion.
Reinstatement by Priming Infusions of the Training Drug
The effectiveness of priming by infusions of different doses of the training drug can be tested using the method described above. We have found the latency to respond, the peak period of responding and the duration of responding are all affected by the infusion doses. In general, higher doses lead to longer latencies to responding, longer durations of responding and sometimes to delayed peak rates. Figure 1 shows the results obtained using this method when different doses of the training drug are used as the priming event in cocaine- and heroin-trained animals.
Reinstatement by Priming Infusions of Drugs
Other Than the Training Drug
The effectiveness of priming infusions of drugs other than the
drug in reinstating drug-taking behavior can also be evaluated using
method. One can determine whether drugs with common pharmacological
or drugs which act on common neurochemical pathways or with common
properties (as determined in drug discrimination paradigms) can
responding for the training drug. This method may indicate the relation
between discriminable stimulus properties of drugs and their incentive
properties. If priming infusions act primarily by reactivating
motivational states, then other drugs that also arouse the motivational
state would be effective in reinstating drug-taking or drug-seeking
It is known, however, that stimuli that are repeatedly paired with the
positive incentive properties of drugs acquire the ability through
to activate a motivational state similar to that activated by the
event. Through such a mechanism, drugs without intrinsic incentive
but with discriminably similar stimulus properties to a
drug, could bring about reinstatement of drug-taking behavior. By the
token it is possible that drugs having incentive effects similar to
of the training drug, but having additional actions that result in very
different stimulus properties, might not bring about reinstatement of
original drug-taking behavior. Results of studies using this
can be found in papers by de Wit and Stewart (1981, 1983).
|Figure 1: Mean number of responses made under extinction conditions following intravenous priming injections of various doses of cocaine to animals trained to self-administer 1 mg/kg cocaine (left panel) and of heroin to animals trained to self-administer 100 mg heroin (right panel). Adapted with permission from de Wit and Stewart, 1981, 1983.|
Reinstatement of Drug Self-Administration Behavior
by Intracerebral Application of Drugs
Two questions arise from the intravenous priming experiments: (1) Can we specify which actions of the drugs are responsible for the priming effects, and (2) can we delineate the specific neural systems of the brain involved? The idea that priming injections reinstate behavior by activating appetitive motivational states suggests that drugs belonging to different pharmacological classes such as stimulants and opiates might have their priming effects via their actions on the same systems of the brain that mediate their positive reinforcing effects. It has been shown that the positive reinforcing properties of the stimulants, cocaine and amphetamine, depend on the integrity of the neurons of the mesolimbic dopamine system where they act to release dopamine from terminals or to block the mechanisms of transmitter inactivation (Creese & Iversen, 1975; de Wit & Wise, 1977; Lyness, Friedle, & Moore, 1979; Roberts, Koob, Klonoff, & Fibiger, 1980; Yokel & Wise, 1976). Further support for the idea that this system is critically involved comes from a study showing that animals will self-administer amphetamine to the terminal regions of these neurons in the nucleus accumbens (Monaco, Hernandez, & Hoebel, 1981). Recent evidence suggests that the reinforcing effects of opiates derive from their actions on these same dopamine neurons. Rats will self-administer morphine directly into the ventral tegmental area of the brain, the cell body region of these mesolimbic dopamine neurons (Bozarth & Wise, 1981a) and will display an increased preference for a place associated with central injections to the area (Bozarth & Wise, 1981b; Phillips & LePiane, 1980). Thus the appetitive motivational or positive incentive properties of opiates, like those of stimulants, appear to be mediated via the mesolimbic dopamine pathway. Opiates appear to excite one subpopulation of these neurons by acting on opiate receptors in the cell body region (Gysling & Wang, 1982, 1983; Matthews & German, 1982). Bilateral application of morphine to the region elicits forward locomotion and exploration of the environment (Joyce & Iversen, 1979; Vezina & Stewart, 1983), behavior normally elicited by positive incentive stimuli. In light of these observations, we have approached the problem of specifying the neural substrate involved in the priming effect by examining the effects of central application of drugs in animals previously trained to self-administer either heroin or cocaine intravenously.
In these experiments animals are trained to self-administer heroin or cocaine intravenously as described above. At the time of surgery, however, animals are prepared with intracerebral guide cannulae directed at different areas of the brain. Cannulae can be implanted either unilaterally or bilaterally, and animals can be prepared with cannulae placed in two or more sites.
Intracerebral Application of Drug
Guide cannulae, cut to appropriate lengths from 22-gauge stainless steel tubing, are lowered stereotaxically to positions 1.00 mm above the target area. The cannulae are held in place by embedding them in dental cement. Drug is delivered to the brain site in crystalline form via 28-gauge stainless steel inner injector tubes that extend 1.00 mm beyond the tip of the guide cannulae. "Dummy" inner tubes with caps are kept in place between drug applications. Drug is tapped into the 28-gauge applicator by making 10 taps on a thin layer of powdered drug placed on a hard surface. We have found by weighing bits of tubing before and after tapping that the amount of drug inserted remains relatively constant (in the case of morphine, for example, at approximately 18 mg). The applicators are checked under a microscope before and after tapping. Used applicators are cleaned in an ultrasonic cleaner containing 70% ethanol.
Using this method, we have found that drugs appear to be released very slowly from the end of the tubing. After being in the brain for up to 3 hours, some drug remains in the tubing. Furthermore, there appears to be little spread of drug into the surrounding areas. This, of course, will depend on cannula sites. We have found that placements as little as 1.00 mm away from an effective target site can prove to be ineffective. Efforts are made to avoid passing the cannulae through cerebral ventricles by lowering them at an angle when necessary.
One disadvantage of using crystalline application of drug is that drug delivery cannot be controlled remotely. In these experiments, therefore, animals are picked up and handled from time to time while in test chambers. This is done to ensure that any changes in responding that occur following the experimental manipulation are not due to merely disturbing the animal. Control injections of saline, intravenously or intraperitoneally, are given appropriately, and removal and reinsertion of the dummy applicators is also done.
Tests For Reinstatement
Test sessions are conducted as described for intravenous priming injections. Following a period of at least 1 hour without responding under extinction conditions, the animal is picked up and the inner dummy tube of one (or two in the case of bilaterally placed cannulae) of the cannulae is removed and replaced by an empty applicator. Thirty minutes later the empty applicator is removed and replaced by one containing drug. Each brain site is tested one or more times on different test days. Behavior is usually monitored for up to 3 hours following the application of the drug.
Specificity of the drug action can be tested in these experiments by pretreatment with specific antagonists of the test drug or with antagonists of the transmitter suspected of being involved in the drug action. Intracerebral application of inactive optical isomers of effective drugs can also be tested when they are available. Some examples of the effects on responding of intracerebral application of morphine to animals trained to self-administer either heroin or cocaine are shown in Figure 2.
What should be noted about these data is that priming effects of morphine applied centrally were specific to sites in the ventral tegmental area; application of morphine to other regions of the brain known to contain opiate receptors did not reinstate behavior. Also, the priming effect of morphine was blocked by pretreatment with the specific opiate antagonist, naltrexone HCl. And, finally, because morphine applied to the cell body region of the mesolimbic dopamine neurons was effective in reinstating behavior in both heroin- and cocaine-trained animals, it would appear that activation of this pathway involved in the appetitive motivational properties of these drugs is critical for the reinstatement by priming effect (see also Stewart, 1984).
Significance of Reinstatement by Priming Events
The fact that priming injections of self-administered drugs can
drug-taking and drug-seeking behavior has important implications for
understanding of the basis of relapse to and maintenance of drug-taking
behaviors. We have seen that the presence of the drug in the body has
capacity to activate learned behaviors in the presence of stimuli
associated with the drug. Furthermore, it appears from the
studies that the activation of appetitive motivational systems of the
is responsible for reinstatement by the priming drugs. The question
becomes: Could neutral stimuli, through their association with a
drug, i.e., through conditioning, come to elicit appetitive
states similar to those elicited by the drugs themselves and thereby
as priming events to reinitiate drug-taking.
|Figure 2: Mean number of responses made under extinction conditions following priming applications of morphine to sites in the ventral tegmental area (VTA), periventricular gray (PVG) and caudate nucleus (CAUD) in cocaine-trained animals (left panel) and heroin-trained animals (right panel). Cross-hatched portions of the bars in the upper part of the figure indicate responses made 30 minutes following pretreatment with naltrexone HCl, 2 mg/kg, intraperitoneally.|
Evidence that stimuli associated with self-administered drugs do acquire effects that mimic appetitive actions of drugs comes from studies on conditioned reinforcing effects of drug-paired stimuli in animals (Beach, 1957; Bozarth & Wise, 1981b; Davis & Smith, 1976; Katz & Gormezano, 1978; Phillips & LePiane, 1980; Reicher & Holman, 1977; Rossi & Reid, 1976; Schuster & Woods, 1968; Sherman, Roberts, Roskam, & Holman, 1980; van de Kooy, Mucha, O’Shaughnessy, & Bucenieks, 1982; White, Sklar, & Amit, 1977). Recently we have shown in our laboratory (Vezina & Stewart, 1983, 1984) that the distinctive environmental stimuli paired with morphine applications to the ventral tegmental area elicit increased locomotor activity mimicking the unconditioned action of the drug. Here we see that stimulus events that are associated with the appetitive motivational actions of the drug appear to acquire the ability to activate neural states similar to those activated by the drugs themselves. We would argue that the arousal of these states by conditioned stimuli (as well as by drugs themselves) acts to reinstate and to maintain drug-taking behavior by increasing the salience of other drug-related stimuli (Stewart, de Wit & Eikelboom, 1984).
This paper was prepared with the assistance of a grant to J. S. from the Medical Research Council of Canada (MA 6678).
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