Clinical Toxicology
ISSN: 0009-9309 (Print) (Online) Journal homepage: http://www.tandfonline.com/loi/ictx18
The Behavioral Pharmacology of Phencyclidine Robert L. Balster & L. D. Chait To cite this article: Robert L. Balster & L. D. Chait (1976) The Behavioral Pharmacology of Phencyclidine, Clinical Toxicology, 9:4, 513-528, DOI: 10.3109/15563657608988153 To link to this article: http://dx.doi.org/10.3109/15563657608988153
Published online: 25 Sep 2008.
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CLINICAL TOXICOLOGY 9( 4), pp. 513- 528 ( 1976)
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The Behavioral Pharmacology of Phencyclidine*
ROBERT L. BALSTER and L. D. CHAIT Pharmacology Department Medical College of Virginia Virginia Commonwealth University Richmond, Virginia
It has now been about 20 years since a number of l-arylcyclohexylamine compounds were developed as possible anesthetic agents. One of these compounds, ketamine, has been marketed as a general anesthetic and another, phencyclidine ( P C P ) , has found i t s way into the illicit market place. Due particularly to this latter development, there is now a renewed interest in the biologic effects of these compounds, and P C P in particular. In this paper we assess the current status of o u r knowledge concerning the behavioral effects of P C P in various animal species by reviewing the literature and by presenting some original data from our own laboratory. We also consider, to some extent, relevant studies on the behavioral effects of ketamine since it is a structurally related compound and probably s h a r e s many common properties with PCP. Our intention is to discuss the species specificity of the behavioral effects of PCP, compare these effects to other psychoactive drugs, and point out what little is known about clinically important interactions between P C P and other drugs. We also consider research on the intravenous self-administration of P C P by monkeys and discuss evidence on the development of tolerance to this drug. *Preparation of this manuscript and original research supported by USPHS Grants DA-00490, DA-01442, and T 32 GM-07111. 513 Copyright 0 1976 by Marcel Dekker, Inc. All Rights Reserved. Neither this work nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher.
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E F F E C T S ON G R O S S B E H A V I O R PCP can cause CNS stimulation and depression, which vary markedly depending upon the dose and species used. In mice and rats, the predominant effect is excitant hyperactivity. In experiments employing jiggle boxes and actophotometers, Chen et al. [l] found that at comparable doses, P C P is about one-half a s effective a s methamphetamine in increasing motor activity in these species. As the dose was increased, the animals showed a dose-related decrement in ability to stay on a rotating rod, even though symptomatically they were still highly excited. At still higher doses, ataxia increased, until finally catalepsy and t r e m o r s resulted. The spectrum of activity of P C P in most other species is somewhat different. At low doses, cats, dogs, pigeons, hamsters, guinea pigs, and monkeys usually become quiet and calm. Increasing doses of PCP lead successively to ataxia, catalepsy, and surgical anesthesia. Above the surgical anesthetic dose, clonic convulsions were found to occur in some, but not all, of the species tested. Chen and Weston [2] found that in rhesus monkeys, doses of P C P of less than 1 mg/kg produced mild sedation o r tameness. At 2.5 mg/kg semicoma and stupor occurred. Surgical anesthesia was present at 5 mg/kg and convulsions at 15 mg/kg. PCP is used routinely in our laboratory for purposes of handling rhesus monkeys. A dose of 1.0 mg/kg i.m. will produce sufficient sedation to allow easy handling and manipulation of the animal within 15 min. Acute effects commonly produced by this dose include marked ataxia (inability to support weight o r stand), nystagmus, inability to track moving objects (although eyes often remain open), and rhythmical movements of the limbs and/or tongue-the intensity of which varies markedly from one administration to the next. Occasionally, excessive salivation is seen. Doses of P C P from 0.025-1.0 mg/kg i.m. have been administered to a number of squirrel monkeys in this laboratory. At the higher doses, the effects seen a r e similar to those observed in the rhesus monkeydocility and ataxia are always produced and excessive salivation is seen occasionally in certain animals. At lower doses an excitatory effect is sometimes seen, consisting of fast stereotypic swaying movements and wild flailing of the a r m s . Unusual scratching o r rapid brushing of the skin and rubbing of the eyes and nose can also be observed on occasion. About two hours after administration, the animals' behavior is essentially normal, except perhaps for mild ataxia. The gross behavioral effects of moderate doses of P C P in subhuman primates resemble those reported in man including the ataxia, rhythmical movements, nystagmus, and at high doses, coma [3, 41. The response of mice and r a t s to P C P appears markedly more sympathomimetic than that of primates. This raises the question that different
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mechanisms of action may be responsible for some of the effects of P C P in these species and suggests that the results of experiments in rodents be evaluated carefully for their applicability to man.
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E F F E C T S ON C O N D I T I O N E D B E H A V I O R Study of the subtle behavioral effects of psychoactive drugs in laboratory animals is best accomplished using learned behaviors. In contrast to the rather extensive study of the effects of other drugs of abuse on conditioned behavior, there have been only a few studies of PCP. Adey and Dunlop [5] studied the effects of P C P in the cat on conditioned approach performance in a T-maze. Within 10 to 15 min after an i.p. dose of 1-3 mg/kg, the animals' performance was greatly disrupted. During recovery, 16-24 h r after injection, the cats vacillated between periods of correct performance and failure to respond. With lower doses, in the range of 0.3- 1.0 mg/kg, only brief periods of impaired performance occurred, lasting from a few seconds to one minute. Domino [6] tested the effects of P C P in r a t s trained for a conditioned avoidance response. Animals were trained to a criterion of 95- 100% successful avoidance responses, and were given doses of 1, 2, 4, and 8 mg/kg P C P S.C. Increasing doses of P C P progressively blocked conditioned avoidance. These s a m e doses also blocked escape responding and resulted in gross disorganization of behavior. Therefore, it was concluded that the disrupting effect of P C P on this learned behavior was nonspecific in nature. This is in contrast to the effects of major tranquilizing drugs such a s chlorpromazine which generally have a more specific action on avoidance responding. Domino, Caldwell, and Henke [7] found that doses of P C P which did not significantly disturb escape responding in the s a m e task, did retard acquisition in a manner similar to that of LSD and amobarbital. The effects of P C P on learned behavior of monkeys were studied by Brown and Bass [El. They examined accuracy and response latency in a three-choice avoidance paradigm where the subjects were required to p r e s s a key with the smallest form (the letter E ) to avoid an electric shock. The animals were trained until they made no e r r o r s . At doses of 0.5 mg/kg the animals were unable to respond. However, at lower doses (0.05-0.25 mg/kg) there was a dose-dependent increase in response latency for the more difficult discriminations. In this respect, the results with P C P were comparable to their results with pentobarbital and dissimilar to the results with LSD where difficulty had no effect on the magnitude of the change in response latency. There has been one report of the effects of P C P and ketamine on food-reinforced operant behavior. Wenger and Dews [9] used mice
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trained on a multiple FI FR schedule of food reinforcement. They concluded that both PCP and ketamine produce amphetamine-like effects on schedule controlled behavior in the mouse in that at low doses they all tended to increase responding during the FI component while decreasing response rate during the FR component. Our laboratory has examined the acute effects of PCP on food reinforced operant behavior in the rhesus monkey preparatory to studies on tolerance development. These results a r e presented in some detail in a later section of this paper. Suffice it to say now that on a chain FI FR schedule only response rate decreases were observed and these occurred at doses as low a s 0.05 mg/kg. Learned behaviors have been shown to be highly useful to characterize and quantitate the effects of psychoactive drugs. The few studies completed with PCP have demonstrated some similarities and differences between PCP and other drugs and have shown that these behaviors a r e sensitive to PCP. There is a need for a more substantial research interest in the learned behavioral effects of this important compound. P H E N C Y C L I D I N E AS A D I S C R I M I N A T I V E S T I M U L U S One of the interesting properties of a number of psychoactive drugs is their ability to serve a s discriminative stimuli for choice behavior in experimental animals. In these experiments, drugs serve the same function which traditionally has been served using exteroceptive stimuli such a s lights and tones; that is, animals a r e required to perform one of two alternative responses dependent upon the presence o r absence of drugs. For example, rats can be trained to enter the left arm of a T-maze when they have been given a drug, and the right arm when they have been given vehicle injection. If the animal is able to learn to discriminate the drug from the vehicle state, the particular drug is said to have established stimulus control. Subsequently, these animals can be tested with other drugs. The percentage of left turns can be taken as an indication of the degree to which the discriminative stimulus properties of the test drug a r e similar to those of the drug under which the animal was trained (transfer experiment). When experiments of this kind a r e carried out, compounds which share similar discriminative stimulus properties frequently a r e found to share a large number of other pharmacologic properties and produce similar subjective effects in man [lo, 111. Overton [12] reported an experiment using PCP at doses of 5-20 mg/kg as a discriminative stimulus for T-maze escape learning in rats. Although details of the results were not presented, discriminative control over response choice was obtained within a few trials. Overton and Lebman [13] have also reported that ketamine rapidly
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develops discriminative control over T- maze behavior. They also found that the discriminative properties of ketamine were not s i m i l a r to those of pentobarbital. A more detailed study was undertaken by Overton [ 141 to determine the discriminability of ketamine, PCP, and pentobarbital. Rats were trained in a shock-escape T-maze task t o turn right under the drug condition and left after vehicle injections. During training, ketamine and P C P produced unexpectedly severe behavioral toxicity; that is, these drugs impaired the accuracy of maze performance at doses low enough for basic motor ability to remain intact. Pentobarbital did not produce this response disorganization. Transfer tests indicated that the stimulus effects of pentobarbital differed markedly from those of ketamine and PCP. P C P and ketamine did not produce identical stimulus effects, but their actions were sufficiently s i m i l a r s o that they tended to mimic each other during transfer tests. J a r b e and Henriksson [15] attempted to use 2.0 mg/kg P C P and saline a s the discriminative stimuli in a T-shaped water maze with rats. They were unable to obtain evidence for stimulus control. They did find, however, that in animals trained using A-9-tetrahydrocannabinol (A-9-THC) and vehicle a s discriminative stimuli, P C P failed t o produce THC-like stimulus effects, suggesting that in the rat THC and P C P are not acting in the s a m e manner. Jarbe, Johansson, and Henriksson [ 161, this time utilizing an electrified T-maze rather than a water maze, were able to show a dose-related formation of drug discrimination with P C P (1.0-4.0 mg/ kg) versus saline. The r a t s also readily learned to discriminate ditran ( a potent anticholinergic) from PCP. Transfer tests were carried out with a number of other drugs. Morphine, chlorpromazine, ditran, pentobarbital, A- g-THC, and A- 8-THC all failed to evidence transfer to PCP, suggesting that these drugs do not mimic P C P in rats. However, a dose-related transfer was found for ketamine and cyclohexamine, compounds which a r e structurally related to PCP. The order of potency for the cyclohexamine derivatives with respect to stimulus control is: cyclohexamine > P C P > ketamine. In short, the studies to date employing P C P a s a discriminative stimulus indicate that P C P and structurally related cyclohexamines produce subjective effects in r a t s different from any other c l a s s of psychoactive compounds tested, but s i m i l a r to each other. As we stated earlier, there is reason to suspect that the behavioral pharmacology of P C P differs in r a t s and primates. All of the discriminative stimulus studies have been carried out in rats; nevertheless, the conclusion that P C P and related cyclohexamines constitute a distinct c l a s s of psychoactive drugs is consistent with the conclusion from a previous review based primarily on other behavioral and neurophysiologic data [6].
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INTERACTIONS BETWEEN PHENCYCLIDINE AND O T H E R DRUGS With the exceptions of alcohol, heroin, and marijuana, u s e r s seldom confine their drug intake to a single compound. Not only a r e amphetamines, barbiturates, and hallucinogens often used by the s a m e individuals, but they a r e often combined with alcohol and marijuana use. F o r this reason, it is important to determine the possibility of drug interactions resulting in increased toxicity. F o r example, the dangers of combining the use of alcohol and o t h e r d e p r e s s a n t s such a s barbitur a t e s and minor tranquilizers a r e well known. Since P C P is considered a hallucinogen by the drug-using subculture, it is likely to be abused in conjunction with other drugs of abuse. F o r example, t h e r e a r e many anecdotal r e p o r t s of P C P dust being sprinkled on marijuana before smoking. There have been few r e p o r t s dealing specifically with the effects of combinations of P C P with other drugs. In t h e i r original a r t i c l e on the pharmacology of PCP, Chen et al. [l] found that P C P was v e r y effective in suppressing tonic-extensor s e i z u r e s in mice induced by pentylenetetrazol, slightly effective in suppressing caffeine-induced s e i z u r e s , but ineffective in suppressing strychnine-induced seizures. P C P did, however, significantly reduce the lethal effect of strychnine and caffeine. In jiggle box experiments with r a t s , they found that the excitatory effect produced by 4.0 mg/kg P C P could be suppressed by various CNS depressants, including chlorpromazine, phenobarbital, and phenytoin. As described above, P C P blocks avoidance and escape behavior in rats. Chlorpromazine previously had been shown to block the depressant effect of LSD on the s a m e conditioned avoidance procedure, and s o m e r e s e a r c h e r s [17, 181 feel that chlorpromazine alleviates s o m e of the effects of LSD in man. However, Domino [6] reported that when doses of either LSD o r chlorpromazine, which by themselves only minimally affected avoidance responding, were combined with P C P , marked potentiation of the depressant action of P C P was observed. Further evidence that chlorpromazine does not antagonize the behavioral effects of P C P is provided by a study done in o u r laboratory. Rhesus monkeys, trained on a chain FI FR operant schedule f o r food reinforcement, who had previously been employed in a chronic P C P tolerance experiment ( t o be discussed in m o r e detail below), w e r e given various doses of chlorpromazine alone and in combination with 0.4 mg/kg PCP. The effects on FR response r a t e are shown in Fig. 1. This dose of P C P given alone caused approximately a 55% d e c r e a s e in responding. When combined with chlorpromazine o v e r a wide dose range, no evidence for antagonism of this effect was observed, even at a dose of chlorpromazine (0.06 mg/kg) which produced little effect on behavior when given alone,
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FIG. 1. Effect of chlorpromazine alone (e-) and in combination with 0.4 mg/kg P C P (M ) on FR responding in two r h e s u s monkeys. The point at z e r o chlorpromazine dose r e p r e s e n t s the effect of P C P alone. Sofia and Knobloch [19] reported an investigation of the effect of A-9-THC pretreatment on ketamine anesthesia in mice. P r e t r e a t ment with 20 mg/kg THC produced a significant i n c r e a s e in the duration of action and number of mice exhibiting a l o s s of the righting reflex when given 30 min p r i o r to i.v. administration of ketamine. The LD5,, of ketamine, however, was not affected by the THC pretreatment. When mice were pretreated with various d o s e s of THC ( 10-40 mg/kg) p r i o r to a fixed dose of ketamine (32 mg/kg), dosedependent elevations in sleeping time were observed. P r y o r and Braude [20] used a battery of t e s t s to evaluate the interactions between THC and P C P in rats. Conditioned avoidance was impaired in a dose-dependent manner by both d r u g s alone, and t h e i r interaction was synergistic. PCP, ineffective alone, a l s o potentiated the d e c r e a s e in h e a r t r a t e and body t e m p e r a t u r e caused by THC. Some leads as to possible drug interactions with P C P can be taken from the veterinary u s e of this compound. We have been using P C P in combination with sodium pentobarbital f o r anesthesia in r h e s u s monkeys for a number of years. The animals a r e initially given an immobilizing dose of P C P ( 1 mg/kg i.m.1 and p r e p a r e d f o r surgery. Since this effect l a s t s only for about 45 min, just p r i o r
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to surgery the animals a r e completely anesthetized with pentobarbital. The dose of pentobarbital required to reach a plane of surgical anesthesia i s reduced to about 10 mg/kg i.v. as a consequence of PCP pretreatment. This represents a potentiation of the effects of pentobarbital from two- to threefold. All the effects of pentobarbital appear to be potentiated by PCP including respiratory depression, even though PCP alone normally does not produce respiratory depression. It is probable, therefore, that abuse of combinations of PCP with barbiturates and other depressants, including alcohol, would be potentially dangerous. Normally sublethal doses of barbiturates o r alcohol may be potentiated by concurrent PCP administration to produce serious respiratory depression. In summary, it seems clear from these scattered preliminary studies that there i s reason to expect clinically significant interactions between PCP and other drugs of abuse including marijuana and CNS depressants. Also, the two studies relating to the interaction of PCP and chlorpromazine provide little basis for the use of chlorpromazine during acute PCP emergencies. More research relating to interactions between PCP and other drugs is clearly needed. SELF-ADMINISTRATION O F PHENCYCLIDINE One of the properties of many drugs of abuse is that when given intravenously they can reinforce lever pressing i n a number of animal species. This has been demonstrated for opiates, psychomotor stimulants, barbiturates, and alcohol [21, 221. There a r e two reports that PCP is self-administered by rhesus monkeys. This represents the only hallucinogen that monkeys will reliably self-administer [23], and is another example of the uniqueness of PCP. Pickens, Thompson, and Muchow [24] established self-administration in two rhesus monkeys with cocaine. PCP was then substituted at a dose of 0.05 mg/kg/injection. Initially, drug was available 24 h r / day, but access was later reduced to 2 hr/day. The monkeys initially overdosed to the point of hypnosis over the first two daily sessions. Drug intake eventually stabilized, then gradually increased, suggesting tolerance. When availability was reduced to 2 hr/day, no further increase in hourly drug intake was obtained. Balster et al. [25] trained three rhesus monkeys to lever p r e s s ( F R 10) for cocaine injections during daily 3-hr sessions. PCP was then substituted for cocaine for six consecutive days. Between tests the animals were returned to cocaine administration for a minimum of three days to reestablish baseline. Doses p e r injection of PCP of 3.1, 6.2, 12.5, and 25.0 pg/kg and saline were tested in each animal. Each monkey self-administered at least three unit doses of P C P above his saline control range. Total PCP intake per session was
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found to be positively related to dose p e r injection. Intake levels reached 0.5 to 1.2 mg/kg/session, and observation of the animals showed then to be highly intoxicated. In this s a m e study, two drug naive monkeys were used to determine i f they would self-administer P C P when given unlimited 24 hr/day access. Their control rate of saline self-administration was first determined for 10 days. The next day P C P was substituted for saline for eight consecutive days. Each response produced an injection of 50 pg/kg PCP. On the first day of P C P access, both monkeys increased their response rates over their saline levels. Although there was dayto-day variability, the response rate for P C P continued above saline control levels. Especially during the first few days of P C P access, the animals were highly intoxicated. Frequently the animals could be found lying on the floor of the cage in awkward positions, briefly raising themselves up to p r e s s the lever only to fall back down to the floor after the subsequent injection. Periods of almost complete anesthetization were followed by periods in which the animals were only mildly uncoordinated. In this respect, the self-administration of P C P resembles pentobarbital and ethanol when studied under comparable conditions [23, 261. These drugs, too, a r e self-administered to intoxicating doses often resulting in anesthetization. When a c c e s s to P C P was limited to 4 hr/day, the animals increased their hourly intake to about 12 infusions. At these rates, the animals self-administered about 2.5 mg/ kg/4-hr session. These high levels of intake a r e evidence for tolerance development, since they a r e well above the i.m. dose necessary for anesthesia in naive animals. When P C P access was terminated and saline made available 4 hr/day, response rate decreased to well below the levels seen for drug reinforcement. It is interesting that P C P can serve as a reinforcer for drug selfadministration behavior in laboratory animals. Since it is the only "hallucinogen" which has been reliably demonstrated to do so, it suggests that a qualitatively different mechanism may account for the abuse potential of P C P than for more conventional indole and substituted phenethylamine hallucinogens. The active constituent of marijuana is also not readily self-administered [27, 281 by laboratory monkeys. The fact that P C P is self-administered by rhesus monkeys can be put to use in laboratory studies of P C P abuse. Intravenous selfadministration has been shown to be a useful model of opiate, psychomotor stimulant, barbiturate, and alcohol abuse [22] , allowing the careful study of behavioral and pharmacologic variables affecting drug self-administration behavior. Similar studies can and should be carried out with PCP. Drug self-administration studies have also been used to predict the abuse potential of new compounds [27, 291. Since P C P is self-administered, this allows the preclinical evaluation of PCP-like abuse potential of structurally o r pharmacologically related drugs.
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TOLERANCE DEVELOPMENT There have been no published reports on the development of tolerance to the learned behavioral effects of either P C P o r ketamine. A number of investigators, however, have looked at tolerance to the anesthetic effects of these compounds in animals, and the results have been conflicting. Kuhn and Ark0 [30] gave 975 anesthetic episodes of ketamine to 25 chimpanzees over a two-year period. Induction time, anesthetic time, and recovery time were measured for each episode. No evidence of tolerance development was seen. However, this report was based on a series of clinical experiences and was not designed a s an experimental study. In all the animals there was a wide range of days between anesthetic injections, a regimen not very conducive to the development of tolerance. On the other hand, Martin et al. [31] report that in their veterinary experience with PCP, repeated use ( 3 times/week) in macaques and juvenile chimpanzees resulted in a shortened period of effectiveness after several weeks of use. The s a m e decrease in effectiveness at a given dose occurs after several months when it is administered to adult baboons at irregular intervals every few weeks. They also report that tolerance develops to ketamine. After three doses in a oneweek period, juvenile chimpanzees required about 50% more drug to produce the same anesthetic effect initially obtained. Bree et al. [32] gave rhesus monkeys, s t r e s s e d with injections of pseudomonas organisms and dermabrasion, anesthetic doses of ketamine (25 mg/ kg i.m.) 3-5 times p e r week for 24 anesthetizations. Duration of anesthesia decreased over the chronic administration to roughly 60% of that seen initially. A similar observation has been made in repeated ketamine anesthesia during the treatment for burns in humans
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We have completed a preliminary study on the development of tolerance to the effects of P C P on operant behavior in rhesus monkeys. Three male monkeys, well trained on a complex schedule (chain FI F R ) of food reinforcement, were used. On this schedule the first response t o occur after 9 min ( F I 9) resulted in a change in the stimulus lights for one minute during which every 10 responses ( F R 10) resulted in the delivery of a 1 g banana-flavored food pellet. This chain was repeated eight times each session. Responses during the FI and the FR components were recorded separately. Initially an acute dose-response curve (pre-chronic) was obtained for i.m. P C P administration. At least three daily control sessions intervened between each dose of PCP. The monkeys were then given daily injections of P C P prior to their experimental sessions, beginning at 0.2 mg/kg and gradually increasing to 1.0 mg/kg over a four-month period. One week after the injections were discontinued, another (post-chronic) dose-response curve was obtained. Figure 2 shows
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FIG. 2. Acute effects of P C P on responding in both components of a chain FI FR schedule of food reinforcement in three rhesus monkeys. Closed circles (0-0 ) represent effects obtained prior to chronic P C P administration and open circles ( O--Q ) represent effects obtained after chronic P C P administration.
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the pre- and post-chronic dose-response curves for FT and FR responding for the three animals. A significant shift of the postchronic dose-response curve to the right can be seen in the graphs for two of the three animals. This is indicative of tolerance development. The third animal (D-4103) showed no evidence of tolerance development. Further evidence of tolerance development was obtained in these s a m e animals by comparing their gross behavior after an acute dose of PCP to that of three naive animals. On the last day of the chronic period of PCP administration, the three monkeys, a s well a s three naive monkeys, were given 1.0 mg/kg PCP. Several observational ratings were taken by two independent observers at various time intervals up to 150 min after the injection. These ratings included inability to stand up on hindlimbs to reach for a food pellet, inability to track a food pellet moved laterally across the field of vision, inability to reach out and take an offered pellet, and nystagmus. As Fig. 3 suggests, tolerance appears to develop to some, but not all, of the d r u g ' s effects, a s indicated by a faster recovery time of the monkeys which had received P C P on a chronic basis. There is some evidence in laboratory animals that under appropriate conditions, mild tolerance can develop to the behavioral effects of PCP. Much of this evidence points to a shortened duration of action with repeated administration although a decrease in the peak response rate disrupting effects was also seen in the rhesus monkey. In this study, P C P was given daily, seven days p e r week, for four months and only a two- to threefold shift in the dose-effect curve was obtained, and that in only two out of the three monkeys. This chronic regimen would probably constitute the upper limit of a human use pattern, and perhaps only with such heavy use would tolerance be a factor. Clearly the temporal pattern of injections necessary and sufficient to evidence tolerance development is an important research question. CONCLUSIONS Studies of the behavioral effects of P C P have been limited. There a r e some important species differences in the response to this drug with subhuman primates showing a constellation of effects most similar to those in man. Rodents may have a species-specific excitatory response to PCP; however, the relevance of rodent studies to the human behavioral pharmacology of P C P remains to be determined. Behavioral studies suggest that P C P represents an entirely new class of psychoactive drugs, sharing some effects with related arylcyclohexylamines such a s ketamine and cyclohexamine. In contrast to
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TIME AFTER INJECTION (min) FIG. 3. Observational ratings of the acute effects of 1.0 mg/kg PCP on r h e s u s monkeys
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that had received chronic PCP ( w ) and naive monkeys (G--? ). Each of the t h r e e monkeys in each group was rated by two o b s e r v e r s who s c o r e d the presence (1) o r absence (0) of the indicated d r u g effects a t various t i m e s post-injection. S c o r e s represent the s u m of the ratings of both o b s e r v e r s f o r each group of animals. Mean interobserver agreement o v e r all t i m e intervals was 92.5% (range 79.2- 100).
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other hallucinogens, it can s e r v e a s a reinforcer when given i.v. to rhesus monkeys. There is some evidence for tolerance development to the duration and intensity of the behavioral effects of P C P with frequent administration. An important conclusion to draw from this review of the behavioral pharmacology of P C P is that very little research with this drug has been conducted. Specific a r e a s in which we recommend further study include the further characterization of the effects of P C P on learned behavior and studies of the interactions between P C P and other drugs of abuse as well a s the search f o r potentially useful antagonists of PCP. Self-administration studies can explore important behavioral and pharmacologic determinants of P C P reinforcement as well a s provide a useful screening procedure for abuse liability of other pharmacologically related compounds. The relationship between frequency of administration and behavioral tolerance to P C P is still unknown and the role of tolerance in the frequency and quantity of P C P self-administration is still to be determined. There have been no published studies of a concerted effort to examine the physical dependence potential of PCP. Our study of once daily P C P administration for four months showed no evidence for physical dependence. REFERENCES G. Chen, C. R. Ensor, D. Russell, and B. Bohner, The pharmacology of 1- ( 1-phenylcyclohexyl) piperidine HC1, J. Pharmacol. Exptl. Therap., 241 (1959). G. Chen and J. Weston, The analgesic and anesthetic effect of 1- ( 1-phenylcyclohexyl) piperidine HC1 on the monkey, Anesth. Analg., 39, 132 (1960). F. E. Greifenstein, M. DeVault, J. Yoskitake, and J. E. Gajewski, A study of a 1-aryl cyclo hexyl amine for anesthesia, Anesth. Analg., - 37, 283 (1958). R. S. Burns, S. E. Lerner, and R Corrado, Phencyclidinestates of acute intoxication and fatalities, West. J. Med., 123, 345 (1975). W. R. Adey and C. W. Dunlop, The action of certain cyclohexamines on hippocampal system during approach performance in the cat, J. Pharmacol. Exptl. Therap., 130,418 (1960). E. F. Domino, Neurobiology of phencyclidine (Sernyl), a drug with an unusual spectrum of pharmacological activity, Int. Rev. Neurobiol., 6, 303 (1964). E. F. Domin;, D. F. Caldwell, and R Henke, Effects of psychoactive agents on acquisition of conditioned pole jumping in rats, Psychopharmacologia, 8, 285 ( 1965).
127,
52 7
Downloaded by [Australian National University] at 18:13 07 November 2015
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H. Brown and W. C. Bass, Effect of drugs on visually controlled avoidance behavior in rhesus monkeys: a psychophysical analysis, Psychopharmacologia, 11, 143 ( 1967). G. R. Wenger and P. B. Dews, ThTeffects of some CNS-active drugs on schedule-controlled behavior maintained by food presentation in the mouse, Federation Proc., 34,766 (1975). H. Barry, n1, Classification of drugs according to their discriminable effects in rats, Federation Proc., 33, 1814 (1974). C. R. Schuster and R L. Balster, "The DiscriGinative Stimulus Properties of Drugs'' in Advances in Behavioral Pharmacology, Vol. I (T. Thompson and P. B. Dews, eds.), Academic, New York, in press, D. A. Overton, Experimental methods for the study of statedependent learning, Federation Proc., 33, 1800 (1974). D. A. Overton and R. I. Lebman, "Rapirdrug discrimination produced by ketamine, a dissociative anesthetic," paper presented a t the annual meeting of the American Psychological Association, 1973. D. A. Overton, A comparison of the discriminable CNS effects of ketamine, phencyclidine and pentobarbital, Arch. Int. Pharmacodyn., 215, 180 (1975). T. U. C. J a r b e and B. G. Henriksson, Discriminative response control produced with hashish, tetrahydrocannabinols (delta8-THC and delta- 9- THC) and other drugs, Psychopharmacologia, 40, l(1974). T. U. Jarbe, J. 0. Johansson, and B. G. Henriksson, Drug discrimination in rats: the effects of phencyclidine and ditran, Psychopharmacologia, 42, 33 ( 1975). R. L. Taylor, J. I. M a u E r , and J. R. Tinklenberg, Management of "bad trips" in an evolving drug scene, ~JAVMA, 213, 422 (1970). N. S. Kline, S. F. Alexander, and A. Chamberlain, Psychotropic Drugs: A Manual for Emergency Management of Overdosage, Medical Economics, Oradell, N.J., 1974, p. 51. R D. Sofia and L. C. Knobloch, The effects of delta-9-tetrahydrocannabinol pretreatment on ketamine, thiopental o r CT1341 induced loss of righting reflex in mice, Arch. Int. Pharmacodyn., 207,270 (1974). G. T. P r y o r and M. C. Braude, Interactions between delta-9tetrahydrocannabinol ( THC) and phencyclidine (PC), The Pharmacologist, 17, 182 (1975). C. R. S c h u s t z and T. Thompson, Self-administration of and behavioral dependence on drugs, Ann. Rev. Pharmacol., 9, 483 (1969). C. R. Schuster and C. E. Johanson, "The Use of Animal Models for the Study of Drug Abuse" in Research Advances in Alcohol ~
Downloaded by [Australian National University] at 18:13 07 November 2015
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BALSTER AND CHAIT and Drug Problems (R. J. Gibbins, Y. Israel, and H. Kalant, eds.), Wiley, New York, 1974, pp. 1-31. G. Deneau, T. Yanagita, and M. H. Seevers, Self-administration of psychoactive substances by the monkey, Psychopharmacologia, 16, 30, (1969). R. Pickens, T. Thompson, and D. C. Muchow, "Cannabis and Phencyclidine Self-administration by Animals" in Psychic Dependence. Bayer-Symposium IV (L. Goldberg and F. Hoffmeister, eds. ), Springer-Verlag, New York, 1973, pp. 78-86. R. L. Balster, C. E. Johanson, R T, Harris, and C. R Schuster, Phencyclidine self-administration in the rhesus monkey, Pharmacol. Biochem. Behavior, 1, 167 (1973). G. D. Winger and J. H. Woods, The reinforcing property of ethanol in the rhesus monkey, Ann. N.Y. Acad. Sci., __ 215, 162 (1973). T. Yanagita, "An Experimental Framework for Evaluation of Dependence Liability of Various Types of Drug in MonkeysTti n Pharmacology and the Future of Man. Proceedings of the 5th International Congress of Pharmacology, Karger, Basel, 1973, pp. 7-17. R. T. Harris, W. Waters, and D. McLendon, Evaluation of reinforcing capability of delta- 9-tetrahydrocannabinol in rhesus monkeys, P s y c h o p h a r x o l o g i a , 37, 23 (1974). C. R Schuster and R L. Balster7Self-administration of Agonists" in Agonist and Antagonist Actions of Narcotic Analgesic Drugs (H. W. Kosterlitz, H. 0. J. Collier and J. Villarreal, eds.), University P a r k Press, Baltimore, 1973, pp. 243254. U. S. G. Kuhn, III, and R J. Arko, Repeated ketamine anesthesia in the chimpanzee, JAVMA, 165, 838 (1974). D. P. Martin. C. C. Darrow. 11. T A . Valerio. and S. A. Leiseca, Methods of anesthesia in nonhuman primates, Lab. Animal Sci., 22, 837 (1972). M. M. Bree. TFeller. and G. Corssen. Safetv and tolerance of repeated anesthesia with CI- 581 (ketamine) monkeys, Anesth. Analg 9 46, 596 (1967). W. B j a r n s e n and G. Corssen, CI- 581: A new non-barbiturate short-acting anesthetic f o r surgery in burns, Michigan Med., 66, 177 (1967). -0
ISSN: 0009-9309 (Print) (Online) Journal homepage: http://www.tandfonline.com/loi/ictx18
The Behavioral Pharmacology of Phencyclidine Robert L. Balster & L. D. Chait To cite this article: Robert L. Balster & L. D. Chait (1976) The Behavioral Pharmacology of Phencyclidine, Clinical Toxicology, 9:4, 513-528, DOI: 10.3109/15563657608988153 To link to this article: http://dx.doi.org/10.3109/15563657608988153
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CLINICAL TOXICOLOGY 9( 4), pp. 513- 528 ( 1976)
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The Behavioral Pharmacology of Phencyclidine*
ROBERT L. BALSTER and L. D. CHAIT Pharmacology Department Medical College of Virginia Virginia Commonwealth University Richmond, Virginia
It has now been about 20 years since a number of l-arylcyclohexylamine compounds were developed as possible anesthetic agents. One of these compounds, ketamine, has been marketed as a general anesthetic and another, phencyclidine ( P C P ) , has found i t s way into the illicit market place. Due particularly to this latter development, there is now a renewed interest in the biologic effects of these compounds, and P C P in particular. In this paper we assess the current status of o u r knowledge concerning the behavioral effects of P C P in various animal species by reviewing the literature and by presenting some original data from our own laboratory. We also consider, to some extent, relevant studies on the behavioral effects of ketamine since it is a structurally related compound and probably s h a r e s many common properties with PCP. Our intention is to discuss the species specificity of the behavioral effects of PCP, compare these effects to other psychoactive drugs, and point out what little is known about clinically important interactions between P C P and other drugs. We also consider research on the intravenous self-administration of P C P by monkeys and discuss evidence on the development of tolerance to this drug. *Preparation of this manuscript and original research supported by USPHS Grants DA-00490, DA-01442, and T 32 GM-07111. 513 Copyright 0 1976 by Marcel Dekker, Inc. All Rights Reserved. Neither this work nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher.
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E F F E C T S ON G R O S S B E H A V I O R PCP can cause CNS stimulation and depression, which vary markedly depending upon the dose and species used. In mice and rats, the predominant effect is excitant hyperactivity. In experiments employing jiggle boxes and actophotometers, Chen et al. [l] found that at comparable doses, P C P is about one-half a s effective a s methamphetamine in increasing motor activity in these species. As the dose was increased, the animals showed a dose-related decrement in ability to stay on a rotating rod, even though symptomatically they were still highly excited. At still higher doses, ataxia increased, until finally catalepsy and t r e m o r s resulted. The spectrum of activity of P C P in most other species is somewhat different. At low doses, cats, dogs, pigeons, hamsters, guinea pigs, and monkeys usually become quiet and calm. Increasing doses of PCP lead successively to ataxia, catalepsy, and surgical anesthesia. Above the surgical anesthetic dose, clonic convulsions were found to occur in some, but not all, of the species tested. Chen and Weston [2] found that in rhesus monkeys, doses of P C P of less than 1 mg/kg produced mild sedation o r tameness. At 2.5 mg/kg semicoma and stupor occurred. Surgical anesthesia was present at 5 mg/kg and convulsions at 15 mg/kg. PCP is used routinely in our laboratory for purposes of handling rhesus monkeys. A dose of 1.0 mg/kg i.m. will produce sufficient sedation to allow easy handling and manipulation of the animal within 15 min. Acute effects commonly produced by this dose include marked ataxia (inability to support weight o r stand), nystagmus, inability to track moving objects (although eyes often remain open), and rhythmical movements of the limbs and/or tongue-the intensity of which varies markedly from one administration to the next. Occasionally, excessive salivation is seen. Doses of P C P from 0.025-1.0 mg/kg i.m. have been administered to a number of squirrel monkeys in this laboratory. At the higher doses, the effects seen a r e similar to those observed in the rhesus monkeydocility and ataxia are always produced and excessive salivation is seen occasionally in certain animals. At lower doses an excitatory effect is sometimes seen, consisting of fast stereotypic swaying movements and wild flailing of the a r m s . Unusual scratching o r rapid brushing of the skin and rubbing of the eyes and nose can also be observed on occasion. About two hours after administration, the animals' behavior is essentially normal, except perhaps for mild ataxia. The gross behavioral effects of moderate doses of P C P in subhuman primates resemble those reported in man including the ataxia, rhythmical movements, nystagmus, and at high doses, coma [3, 41. The response of mice and r a t s to P C P appears markedly more sympathomimetic than that of primates. This raises the question that different
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mechanisms of action may be responsible for some of the effects of P C P in these species and suggests that the results of experiments in rodents be evaluated carefully for their applicability to man.
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E F F E C T S ON C O N D I T I O N E D B E H A V I O R Study of the subtle behavioral effects of psychoactive drugs in laboratory animals is best accomplished using learned behaviors. In contrast to the rather extensive study of the effects of other drugs of abuse on conditioned behavior, there have been only a few studies of PCP. Adey and Dunlop [5] studied the effects of P C P in the cat on conditioned approach performance in a T-maze. Within 10 to 15 min after an i.p. dose of 1-3 mg/kg, the animals' performance was greatly disrupted. During recovery, 16-24 h r after injection, the cats vacillated between periods of correct performance and failure to respond. With lower doses, in the range of 0.3- 1.0 mg/kg, only brief periods of impaired performance occurred, lasting from a few seconds to one minute. Domino [6] tested the effects of P C P in r a t s trained for a conditioned avoidance response. Animals were trained to a criterion of 95- 100% successful avoidance responses, and were given doses of 1, 2, 4, and 8 mg/kg P C P S.C. Increasing doses of P C P progressively blocked conditioned avoidance. These s a m e doses also blocked escape responding and resulted in gross disorganization of behavior. Therefore, it was concluded that the disrupting effect of P C P on this learned behavior was nonspecific in nature. This is in contrast to the effects of major tranquilizing drugs such a s chlorpromazine which generally have a more specific action on avoidance responding. Domino, Caldwell, and Henke [7] found that doses of P C P which did not significantly disturb escape responding in the s a m e task, did retard acquisition in a manner similar to that of LSD and amobarbital. The effects of P C P on learned behavior of monkeys were studied by Brown and Bass [El. They examined accuracy and response latency in a three-choice avoidance paradigm where the subjects were required to p r e s s a key with the smallest form (the letter E ) to avoid an electric shock. The animals were trained until they made no e r r o r s . At doses of 0.5 mg/kg the animals were unable to respond. However, at lower doses (0.05-0.25 mg/kg) there was a dose-dependent increase in response latency for the more difficult discriminations. In this respect, the results with P C P were comparable to their results with pentobarbital and dissimilar to the results with LSD where difficulty had no effect on the magnitude of the change in response latency. There has been one report of the effects of P C P and ketamine on food-reinforced operant behavior. Wenger and Dews [9] used mice
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trained on a multiple FI FR schedule of food reinforcement. They concluded that both PCP and ketamine produce amphetamine-like effects on schedule controlled behavior in the mouse in that at low doses they all tended to increase responding during the FI component while decreasing response rate during the FR component. Our laboratory has examined the acute effects of PCP on food reinforced operant behavior in the rhesus monkey preparatory to studies on tolerance development. These results a r e presented in some detail in a later section of this paper. Suffice it to say now that on a chain FI FR schedule only response rate decreases were observed and these occurred at doses as low a s 0.05 mg/kg. Learned behaviors have been shown to be highly useful to characterize and quantitate the effects of psychoactive drugs. The few studies completed with PCP have demonstrated some similarities and differences between PCP and other drugs and have shown that these behaviors a r e sensitive to PCP. There is a need for a more substantial research interest in the learned behavioral effects of this important compound. P H E N C Y C L I D I N E AS A D I S C R I M I N A T I V E S T I M U L U S One of the interesting properties of a number of psychoactive drugs is their ability to serve a s discriminative stimuli for choice behavior in experimental animals. In these experiments, drugs serve the same function which traditionally has been served using exteroceptive stimuli such a s lights and tones; that is, animals a r e required to perform one of two alternative responses dependent upon the presence o r absence of drugs. For example, rats can be trained to enter the left arm of a T-maze when they have been given a drug, and the right arm when they have been given vehicle injection. If the animal is able to learn to discriminate the drug from the vehicle state, the particular drug is said to have established stimulus control. Subsequently, these animals can be tested with other drugs. The percentage of left turns can be taken as an indication of the degree to which the discriminative stimulus properties of the test drug a r e similar to those of the drug under which the animal was trained (transfer experiment). When experiments of this kind a r e carried out, compounds which share similar discriminative stimulus properties frequently a r e found to share a large number of other pharmacologic properties and produce similar subjective effects in man [lo, 111. Overton [12] reported an experiment using PCP at doses of 5-20 mg/kg as a discriminative stimulus for T-maze escape learning in rats. Although details of the results were not presented, discriminative control over response choice was obtained within a few trials. Overton and Lebman [13] have also reported that ketamine rapidly
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develops discriminative control over T- maze behavior. They also found that the discriminative properties of ketamine were not s i m i l a r to those of pentobarbital. A more detailed study was undertaken by Overton [ 141 to determine the discriminability of ketamine, PCP, and pentobarbital. Rats were trained in a shock-escape T-maze task t o turn right under the drug condition and left after vehicle injections. During training, ketamine and P C P produced unexpectedly severe behavioral toxicity; that is, these drugs impaired the accuracy of maze performance at doses low enough for basic motor ability to remain intact. Pentobarbital did not produce this response disorganization. Transfer tests indicated that the stimulus effects of pentobarbital differed markedly from those of ketamine and PCP. P C P and ketamine did not produce identical stimulus effects, but their actions were sufficiently s i m i l a r s o that they tended to mimic each other during transfer tests. J a r b e and Henriksson [15] attempted to use 2.0 mg/kg P C P and saline a s the discriminative stimuli in a T-shaped water maze with rats. They were unable to obtain evidence for stimulus control. They did find, however, that in animals trained using A-9-tetrahydrocannabinol (A-9-THC) and vehicle a s discriminative stimuli, P C P failed t o produce THC-like stimulus effects, suggesting that in the rat THC and P C P are not acting in the s a m e manner. Jarbe, Johansson, and Henriksson [ 161, this time utilizing an electrified T-maze rather than a water maze, were able to show a dose-related formation of drug discrimination with P C P (1.0-4.0 mg/ kg) versus saline. The r a t s also readily learned to discriminate ditran ( a potent anticholinergic) from PCP. Transfer tests were carried out with a number of other drugs. Morphine, chlorpromazine, ditran, pentobarbital, A- g-THC, and A- 8-THC all failed to evidence transfer to PCP, suggesting that these drugs do not mimic P C P in rats. However, a dose-related transfer was found for ketamine and cyclohexamine, compounds which a r e structurally related to PCP. The order of potency for the cyclohexamine derivatives with respect to stimulus control is: cyclohexamine > P C P > ketamine. In short, the studies to date employing P C P a s a discriminative stimulus indicate that P C P and structurally related cyclohexamines produce subjective effects in r a t s different from any other c l a s s of psychoactive compounds tested, but s i m i l a r to each other. As we stated earlier, there is reason to suspect that the behavioral pharmacology of P C P differs in r a t s and primates. All of the discriminative stimulus studies have been carried out in rats; nevertheless, the conclusion that P C P and related cyclohexamines constitute a distinct c l a s s of psychoactive drugs is consistent with the conclusion from a previous review based primarily on other behavioral and neurophysiologic data [6].
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INTERACTIONS BETWEEN PHENCYCLIDINE AND O T H E R DRUGS With the exceptions of alcohol, heroin, and marijuana, u s e r s seldom confine their drug intake to a single compound. Not only a r e amphetamines, barbiturates, and hallucinogens often used by the s a m e individuals, but they a r e often combined with alcohol and marijuana use. F o r this reason, it is important to determine the possibility of drug interactions resulting in increased toxicity. F o r example, the dangers of combining the use of alcohol and o t h e r d e p r e s s a n t s such a s barbitur a t e s and minor tranquilizers a r e well known. Since P C P is considered a hallucinogen by the drug-using subculture, it is likely to be abused in conjunction with other drugs of abuse. F o r example, t h e r e a r e many anecdotal r e p o r t s of P C P dust being sprinkled on marijuana before smoking. There have been few r e p o r t s dealing specifically with the effects of combinations of P C P with other drugs. In t h e i r original a r t i c l e on the pharmacology of PCP, Chen et al. [l] found that P C P was v e r y effective in suppressing tonic-extensor s e i z u r e s in mice induced by pentylenetetrazol, slightly effective in suppressing caffeine-induced s e i z u r e s , but ineffective in suppressing strychnine-induced seizures. P C P did, however, significantly reduce the lethal effect of strychnine and caffeine. In jiggle box experiments with r a t s , they found that the excitatory effect produced by 4.0 mg/kg P C P could be suppressed by various CNS depressants, including chlorpromazine, phenobarbital, and phenytoin. As described above, P C P blocks avoidance and escape behavior in rats. Chlorpromazine previously had been shown to block the depressant effect of LSD on the s a m e conditioned avoidance procedure, and s o m e r e s e a r c h e r s [17, 181 feel that chlorpromazine alleviates s o m e of the effects of LSD in man. However, Domino [6] reported that when doses of either LSD o r chlorpromazine, which by themselves only minimally affected avoidance responding, were combined with P C P , marked potentiation of the depressant action of P C P was observed. Further evidence that chlorpromazine does not antagonize the behavioral effects of P C P is provided by a study done in o u r laboratory. Rhesus monkeys, trained on a chain FI FR operant schedule f o r food reinforcement, who had previously been employed in a chronic P C P tolerance experiment ( t o be discussed in m o r e detail below), w e r e given various doses of chlorpromazine alone and in combination with 0.4 mg/kg PCP. The effects on FR response r a t e are shown in Fig. 1. This dose of P C P given alone caused approximately a 55% d e c r e a s e in responding. When combined with chlorpromazine o v e r a wide dose range, no evidence for antagonism of this effect was observed, even at a dose of chlorpromazine (0.06 mg/kg) which produced little effect on behavior when given alone,
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FIG. 1. Effect of chlorpromazine alone (e-) and in combination with 0.4 mg/kg P C P (M ) on FR responding in two r h e s u s monkeys. The point at z e r o chlorpromazine dose r e p r e s e n t s the effect of P C P alone. Sofia and Knobloch [19] reported an investigation of the effect of A-9-THC pretreatment on ketamine anesthesia in mice. P r e t r e a t ment with 20 mg/kg THC produced a significant i n c r e a s e in the duration of action and number of mice exhibiting a l o s s of the righting reflex when given 30 min p r i o r to i.v. administration of ketamine. The LD5,, of ketamine, however, was not affected by the THC pretreatment. When mice were pretreated with various d o s e s of THC ( 10-40 mg/kg) p r i o r to a fixed dose of ketamine (32 mg/kg), dosedependent elevations in sleeping time were observed. P r y o r and Braude [20] used a battery of t e s t s to evaluate the interactions between THC and P C P in rats. Conditioned avoidance was impaired in a dose-dependent manner by both d r u g s alone, and t h e i r interaction was synergistic. PCP, ineffective alone, a l s o potentiated the d e c r e a s e in h e a r t r a t e and body t e m p e r a t u r e caused by THC. Some leads as to possible drug interactions with P C P can be taken from the veterinary u s e of this compound. We have been using P C P in combination with sodium pentobarbital f o r anesthesia in r h e s u s monkeys for a number of years. The animals a r e initially given an immobilizing dose of P C P ( 1 mg/kg i.m.1 and p r e p a r e d f o r surgery. Since this effect l a s t s only for about 45 min, just p r i o r
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to surgery the animals a r e completely anesthetized with pentobarbital. The dose of pentobarbital required to reach a plane of surgical anesthesia i s reduced to about 10 mg/kg i.v. as a consequence of PCP pretreatment. This represents a potentiation of the effects of pentobarbital from two- to threefold. All the effects of pentobarbital appear to be potentiated by PCP including respiratory depression, even though PCP alone normally does not produce respiratory depression. It is probable, therefore, that abuse of combinations of PCP with barbiturates and other depressants, including alcohol, would be potentially dangerous. Normally sublethal doses of barbiturates o r alcohol may be potentiated by concurrent PCP administration to produce serious respiratory depression. In summary, it seems clear from these scattered preliminary studies that there i s reason to expect clinically significant interactions between PCP and other drugs of abuse including marijuana and CNS depressants. Also, the two studies relating to the interaction of PCP and chlorpromazine provide little basis for the use of chlorpromazine during acute PCP emergencies. More research relating to interactions between PCP and other drugs is clearly needed. SELF-ADMINISTRATION O F PHENCYCLIDINE One of the properties of many drugs of abuse is that when given intravenously they can reinforce lever pressing i n a number of animal species. This has been demonstrated for opiates, psychomotor stimulants, barbiturates, and alcohol [21, 221. There a r e two reports that PCP is self-administered by rhesus monkeys. This represents the only hallucinogen that monkeys will reliably self-administer [23], and is another example of the uniqueness of PCP. Pickens, Thompson, and Muchow [24] established self-administration in two rhesus monkeys with cocaine. PCP was then substituted at a dose of 0.05 mg/kg/injection. Initially, drug was available 24 h r / day, but access was later reduced to 2 hr/day. The monkeys initially overdosed to the point of hypnosis over the first two daily sessions. Drug intake eventually stabilized, then gradually increased, suggesting tolerance. When availability was reduced to 2 hr/day, no further increase in hourly drug intake was obtained. Balster et al. [25] trained three rhesus monkeys to lever p r e s s ( F R 10) for cocaine injections during daily 3-hr sessions. PCP was then substituted for cocaine for six consecutive days. Between tests the animals were returned to cocaine administration for a minimum of three days to reestablish baseline. Doses p e r injection of PCP of 3.1, 6.2, 12.5, and 25.0 pg/kg and saline were tested in each animal. Each monkey self-administered at least three unit doses of P C P above his saline control range. Total PCP intake per session was
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found to be positively related to dose p e r injection. Intake levels reached 0.5 to 1.2 mg/kg/session, and observation of the animals showed then to be highly intoxicated. In this s a m e study, two drug naive monkeys were used to determine i f they would self-administer P C P when given unlimited 24 hr/day access. Their control rate of saline self-administration was first determined for 10 days. The next day P C P was substituted for saline for eight consecutive days. Each response produced an injection of 50 pg/kg PCP. On the first day of P C P access, both monkeys increased their response rates over their saline levels. Although there was dayto-day variability, the response rate for P C P continued above saline control levels. Especially during the first few days of P C P access, the animals were highly intoxicated. Frequently the animals could be found lying on the floor of the cage in awkward positions, briefly raising themselves up to p r e s s the lever only to fall back down to the floor after the subsequent injection. Periods of almost complete anesthetization were followed by periods in which the animals were only mildly uncoordinated. In this respect, the self-administration of P C P resembles pentobarbital and ethanol when studied under comparable conditions [23, 261. These drugs, too, a r e self-administered to intoxicating doses often resulting in anesthetization. When a c c e s s to P C P was limited to 4 hr/day, the animals increased their hourly intake to about 12 infusions. At these rates, the animals self-administered about 2.5 mg/ kg/4-hr session. These high levels of intake a r e evidence for tolerance development, since they a r e well above the i.m. dose necessary for anesthesia in naive animals. When P C P access was terminated and saline made available 4 hr/day, response rate decreased to well below the levels seen for drug reinforcement. It is interesting that P C P can serve as a reinforcer for drug selfadministration behavior in laboratory animals. Since it is the only "hallucinogen" which has been reliably demonstrated to do so, it suggests that a qualitatively different mechanism may account for the abuse potential of P C P than for more conventional indole and substituted phenethylamine hallucinogens. The active constituent of marijuana is also not readily self-administered [27, 281 by laboratory monkeys. The fact that P C P is self-administered by rhesus monkeys can be put to use in laboratory studies of P C P abuse. Intravenous selfadministration has been shown to be a useful model of opiate, psychomotor stimulant, barbiturate, and alcohol abuse [22] , allowing the careful study of behavioral and pharmacologic variables affecting drug self-administration behavior. Similar studies can and should be carried out with PCP. Drug self-administration studies have also been used to predict the abuse potential of new compounds [27, 291. Since P C P is self-administered, this allows the preclinical evaluation of PCP-like abuse potential of structurally o r pharmacologically related drugs.
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TOLERANCE DEVELOPMENT There have been no published reports on the development of tolerance to the learned behavioral effects of either P C P o r ketamine. A number of investigators, however, have looked at tolerance to the anesthetic effects of these compounds in animals, and the results have been conflicting. Kuhn and Ark0 [30] gave 975 anesthetic episodes of ketamine to 25 chimpanzees over a two-year period. Induction time, anesthetic time, and recovery time were measured for each episode. No evidence of tolerance development was seen. However, this report was based on a series of clinical experiences and was not designed a s an experimental study. In all the animals there was a wide range of days between anesthetic injections, a regimen not very conducive to the development of tolerance. On the other hand, Martin et al. [31] report that in their veterinary experience with PCP, repeated use ( 3 times/week) in macaques and juvenile chimpanzees resulted in a shortened period of effectiveness after several weeks of use. The s a m e decrease in effectiveness at a given dose occurs after several months when it is administered to adult baboons at irregular intervals every few weeks. They also report that tolerance develops to ketamine. After three doses in a oneweek period, juvenile chimpanzees required about 50% more drug to produce the same anesthetic effect initially obtained. Bree et al. [32] gave rhesus monkeys, s t r e s s e d with injections of pseudomonas organisms and dermabrasion, anesthetic doses of ketamine (25 mg/ kg i.m.) 3-5 times p e r week for 24 anesthetizations. Duration of anesthesia decreased over the chronic administration to roughly 60% of that seen initially. A similar observation has been made in repeated ketamine anesthesia during the treatment for burns in humans
WI
*
We have completed a preliminary study on the development of tolerance to the effects of P C P on operant behavior in rhesus monkeys. Three male monkeys, well trained on a complex schedule (chain FI F R ) of food reinforcement, were used. On this schedule the first response t o occur after 9 min ( F I 9) resulted in a change in the stimulus lights for one minute during which every 10 responses ( F R 10) resulted in the delivery of a 1 g banana-flavored food pellet. This chain was repeated eight times each session. Responses during the FI and the FR components were recorded separately. Initially an acute dose-response curve (pre-chronic) was obtained for i.m. P C P administration. At least three daily control sessions intervened between each dose of PCP. The monkeys were then given daily injections of P C P prior to their experimental sessions, beginning at 0.2 mg/kg and gradually increasing to 1.0 mg/kg over a four-month period. One week after the injections were discontinued, another (post-chronic) dose-response curve was obtained. Figure 2 shows
BEHAVIORAL PHARMACOLOGY
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FR
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1
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,
0.0 0.025 0.05 0.10 0.20 0.40 0.80
0.0 0.025 0.05 0.10 0.20 0.40 0.80
DOSE (mg/kq)
FIG. 2. Acute effects of P C P on responding in both components of a chain FI FR schedule of food reinforcement in three rhesus monkeys. Closed circles (0-0 ) represent effects obtained prior to chronic P C P administration and open circles ( O--Q ) represent effects obtained after chronic P C P administration.
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the pre- and post-chronic dose-response curves for FT and FR responding for the three animals. A significant shift of the postchronic dose-response curve to the right can be seen in the graphs for two of the three animals. This is indicative of tolerance development. The third animal (D-4103) showed no evidence of tolerance development. Further evidence of tolerance development was obtained in these s a m e animals by comparing their gross behavior after an acute dose of PCP to that of three naive animals. On the last day of the chronic period of PCP administration, the three monkeys, a s well a s three naive monkeys, were given 1.0 mg/kg PCP. Several observational ratings were taken by two independent observers at various time intervals up to 150 min after the injection. These ratings included inability to stand up on hindlimbs to reach for a food pellet, inability to track a food pellet moved laterally across the field of vision, inability to reach out and take an offered pellet, and nystagmus. As Fig. 3 suggests, tolerance appears to develop to some, but not all, of the d r u g ' s effects, a s indicated by a faster recovery time of the monkeys which had received P C P on a chronic basis. There is some evidence in laboratory animals that under appropriate conditions, mild tolerance can develop to the behavioral effects of PCP. Much of this evidence points to a shortened duration of action with repeated administration although a decrease in the peak response rate disrupting effects was also seen in the rhesus monkey. In this study, P C P was given daily, seven days p e r week, for four months and only a two- to threefold shift in the dose-effect curve was obtained, and that in only two out of the three monkeys. This chronic regimen would probably constitute the upper limit of a human use pattern, and perhaps only with such heavy use would tolerance be a factor. Clearly the temporal pattern of injections necessary and sufficient to evidence tolerance development is an important research question. CONCLUSIONS Studies of the behavioral effects of P C P have been limited. There a r e some important species differences in the response to this drug with subhuman primates showing a constellation of effects most similar to those in man. Rodents may have a species-specific excitatory response to PCP; however, the relevance of rodent studies to the human behavioral pharmacology of P C P remains to be determined. Behavioral studies suggest that P C P represents an entirely new class of psychoactive drugs, sharing some effects with related arylcyclohexylamines such a s ketamine and cyclohexamine. In contrast to
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TIME AFTER INJECTION (min) FIG. 3. Observational ratings of the acute effects of 1.0 mg/kg PCP on r h e s u s monkeys
0
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INABILITY TO STAND
that had received chronic PCP ( w ) and naive monkeys (G--? ). Each of the t h r e e monkeys in each group was rated by two o b s e r v e r s who s c o r e d the presence (1) o r absence (0) of the indicated d r u g effects a t various t i m e s post-injection. S c o r e s represent the s u m of the ratings of both o b s e r v e r s f o r each group of animals. Mean interobserver agreement o v e r all t i m e intervals was 92.5% (range 79.2- 100).
m
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6
INABILITY TO TAKE FOOD PELLET
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other hallucinogens, it can s e r v e a s a reinforcer when given i.v. to rhesus monkeys. There is some evidence for tolerance development to the duration and intensity of the behavioral effects of P C P with frequent administration. An important conclusion to draw from this review of the behavioral pharmacology of P C P is that very little research with this drug has been conducted. Specific a r e a s in which we recommend further study include the further characterization of the effects of P C P on learned behavior and studies of the interactions between P C P and other drugs of abuse as well a s the search f o r potentially useful antagonists of PCP. Self-administration studies can explore important behavioral and pharmacologic determinants of P C P reinforcement as well a s provide a useful screening procedure for abuse liability of other pharmacologically related compounds. The relationship between frequency of administration and behavioral tolerance to P C P is still unknown and the role of tolerance in the frequency and quantity of P C P self-administration is still to be determined. There have been no published studies of a concerted effort to examine the physical dependence potential of PCP. Our study of once daily P C P administration for four months showed no evidence for physical dependence. REFERENCES G. Chen, C. R. Ensor, D. Russell, and B. Bohner, The pharmacology of 1- ( 1-phenylcyclohexyl) piperidine HC1, J. Pharmacol. Exptl. Therap., 241 (1959). G. Chen and J. Weston, The analgesic and anesthetic effect of 1- ( 1-phenylcyclohexyl) piperidine HC1 on the monkey, Anesth. Analg., 39, 132 (1960). F. E. Greifenstein, M. DeVault, J. Yoskitake, and J. E. Gajewski, A study of a 1-aryl cyclo hexyl amine for anesthesia, Anesth. Analg., - 37, 283 (1958). R. S. Burns, S. E. Lerner, and R Corrado, Phencyclidinestates of acute intoxication and fatalities, West. J. Med., 123, 345 (1975). W. R. Adey and C. W. Dunlop, The action of certain cyclohexamines on hippocampal system during approach performance in the cat, J. Pharmacol. Exptl. Therap., 130,418 (1960). E. F. Domino, Neurobiology of phencyclidine (Sernyl), a drug with an unusual spectrum of pharmacological activity, Int. Rev. Neurobiol., 6, 303 (1964). E. F. Domin;, D. F. Caldwell, and R Henke, Effects of psychoactive agents on acquisition of conditioned pole jumping in rats, Psychopharmacologia, 8, 285 ( 1965).
127,
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H. Brown and W. C. Bass, Effect of drugs on visually controlled avoidance behavior in rhesus monkeys: a psychophysical analysis, Psychopharmacologia, 11, 143 ( 1967). G. R. Wenger and P. B. Dews, ThTeffects of some CNS-active drugs on schedule-controlled behavior maintained by food presentation in the mouse, Federation Proc., 34,766 (1975). H. Barry, n1, Classification of drugs according to their discriminable effects in rats, Federation Proc., 33, 1814 (1974). C. R. Schuster and R L. Balster, "The DiscriGinative Stimulus Properties of Drugs'' in Advances in Behavioral Pharmacology, Vol. I (T. Thompson and P. B. Dews, eds.), Academic, New York, in press, D. A. Overton, Experimental methods for the study of statedependent learning, Federation Proc., 33, 1800 (1974). D. A. Overton and R. I. Lebman, "Rapirdrug discrimination produced by ketamine, a dissociative anesthetic," paper presented a t the annual meeting of the American Psychological Association, 1973. D. A. Overton, A comparison of the discriminable CNS effects of ketamine, phencyclidine and pentobarbital, Arch. Int. Pharmacodyn., 215, 180 (1975). T. U. C. J a r b e and B. G. Henriksson, Discriminative response control produced with hashish, tetrahydrocannabinols (delta8-THC and delta- 9- THC) and other drugs, Psychopharmacologia, 40, l(1974). T. U. Jarbe, J. 0. Johansson, and B. G. Henriksson, Drug discrimination in rats: the effects of phencyclidine and ditran, Psychopharmacologia, 42, 33 ( 1975). R. L. Taylor, J. I. M a u E r , and J. R. Tinklenberg, Management of "bad trips" in an evolving drug scene, ~JAVMA, 213, 422 (1970). N. S. Kline, S. F. Alexander, and A. Chamberlain, Psychotropic Drugs: A Manual for Emergency Management of Overdosage, Medical Economics, Oradell, N.J., 1974, p. 51. R D. Sofia and L. C. Knobloch, The effects of delta-9-tetrahydrocannabinol pretreatment on ketamine, thiopental o r CT1341 induced loss of righting reflex in mice, Arch. Int. Pharmacodyn., 207,270 (1974). G. T. P r y o r and M. C. Braude, Interactions between delta-9tetrahydrocannabinol ( THC) and phencyclidine (PC), The Pharmacologist, 17, 182 (1975). C. R. S c h u s t z and T. Thompson, Self-administration of and behavioral dependence on drugs, Ann. Rev. Pharmacol., 9, 483 (1969). C. R. Schuster and C. E. Johanson, "The Use of Animal Models for the Study of Drug Abuse" in Research Advances in Alcohol ~
Downloaded by [Australian National University] at 18:13 07 November 2015
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BALSTER AND CHAIT and Drug Problems (R. J. Gibbins, Y. Israel, and H. Kalant, eds.), Wiley, New York, 1974, pp. 1-31. G. Deneau, T. Yanagita, and M. H. Seevers, Self-administration of psychoactive substances by the monkey, Psychopharmacologia, 16, 30, (1969). R. Pickens, T. Thompson, and D. C. Muchow, "Cannabis and Phencyclidine Self-administration by Animals" in Psychic Dependence. Bayer-Symposium IV (L. Goldberg and F. Hoffmeister, eds. ), Springer-Verlag, New York, 1973, pp. 78-86. R. L. Balster, C. E. Johanson, R T, Harris, and C. R Schuster, Phencyclidine self-administration in the rhesus monkey, Pharmacol. Biochem. Behavior, 1, 167 (1973). G. D. Winger and J. H. Woods, The reinforcing property of ethanol in the rhesus monkey, Ann. N.Y. Acad. Sci., __ 215, 162 (1973). T. Yanagita, "An Experimental Framework for Evaluation of Dependence Liability of Various Types of Drug in MonkeysTti n Pharmacology and the Future of Man. Proceedings of the 5th International Congress of Pharmacology, Karger, Basel, 1973, pp. 7-17. R. T. Harris, W. Waters, and D. McLendon, Evaluation of reinforcing capability of delta- 9-tetrahydrocannabinol in rhesus monkeys, P s y c h o p h a r x o l o g i a , 37, 23 (1974). C. R Schuster and R L. Balster7Self-administration of Agonists" in Agonist and Antagonist Actions of Narcotic Analgesic Drugs (H. W. Kosterlitz, H. 0. J. Collier and J. Villarreal, eds.), University P a r k Press, Baltimore, 1973, pp. 243254. U. S. G. Kuhn, III, and R J. Arko, Repeated ketamine anesthesia in the chimpanzee, JAVMA, 165, 838 (1974). D. P. Martin. C. C. Darrow. 11. T A . Valerio. and S. A. Leiseca, Methods of anesthesia in nonhuman primates, Lab. Animal Sci., 22, 837 (1972). M. M. Bree. TFeller. and G. Corssen. Safetv and tolerance of repeated anesthesia with CI- 581 (ketamine) monkeys, Anesth. Analg 9 46, 596 (1967). W. B j a r n s e n and G. Corssen, CI- 581: A new non-barbiturate short-acting anesthetic f o r surgery in burns, Michigan Med., 66, 177 (1967). -0
