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MECHANISM OF ACTION

Most investigators agree that the behavioral effects of PCP are mediated predominantly through RECEPTORS, which are proteins that are important for the normal functioning of cells within the body. Phencyclidine acts as an antagonist at the N-methyl-D-aspartate (NMDA) receptor-channel complex, which is one type of excitatory amino-acid receptor that is selectively activated by the agonists NMDA and GLUTAMATE. By definition, agonists produce stimulation while antagonists block the effects of agonists. When either glutamate or NMDA bind to the receptor, a channel within the cell membrane opens to allow sodium, calcium, and potassium ions to flow into and out of the cell. This movement of ions across the cell membrane causes a depolarization of the membrane which, if sufficiently large, causes the cell to fire. When the cell fires, an electrical charge passes along its membrane and NEUROTRANSMITTERS (chemicals that allow cells to communicate with each other) are released. Thus, glutamate and NMDA are important for normal cell-to-cell communication within the body.

PCP, as well as TCP, ketamine, dizocilpine (MK-801), and SKF 10,047 is representative of compounds that act as noncompetitive antagonists at the NMDA-receptor complex. The binding site for PCP resides within the channel and binding to this site physically prevents calcium and sodium ions from entering the cell while at the same time preventing potassium ions from leaving the cell. Blocking the movement of ions through the cell membrane in turn prevents the neuron from firing. In contrast to the noncompetitive antagonists, competitive antagonists such as CGS 19755, NPC 12626, CPP, and AP5 bind to the NMDA receptor itself without causing the ion channel to open. By simply occupying the receptor without activating it, competitive antagonists prevent NMDA from binding to and activating the receptor. Unlike noncompetitive antagonists, competitive NMDA-antagonist effects can be surmounted by higher doses of the agonist. However, the end result of both non-competitive and competitive antagonists is a reduction of neuronal firing.

PHARMACOKINETICS AND METABOLISM

PCP use in humans occurs through several routes of administration, including intranasal (snorted), intravenous, oral, and inhalation (smoked). When PCP is smoked in parsley cigarettes, approximately 70 percent of the total amount of PCP is inhaled. Of this amount, 38 percent is inhaled as PCP and 30 percent is inhaled as phenylcyclohexene, a by-product of PCP created when it is heated. Peak blood concentration of PCP occur after only five to ten minutes, which is occasionally followed by a second peak one to three hours later. PCP is predominantly excreted in urine after intranasal, intravenous, and oral administration. The rate of PCP elimination through the kidneys depends on both urine pH and urine-flow rate. More specifically, PCP elimination occurs more rapidly when urine is acidic and when urine is passed rapidly.

DISCRIMINATIVE STIMULUS EFFECTS

One useful method of evaluating the pharmacological characteristics of PCP, as well as a variety of other drugs, is the drug-discrimination procedure. Typically, animals that are slightly food restricted are trained to respond for food on one lever after drug administration and on another lever after saline. On days when the drug is administered before the session, responding on the drug-associated lever results in food delivery while responding on the saline-associated lever does not. Conversely, on days when saline is administered before the session, responding on the saline-associated lever results in food delivery while responding on the drug-associated lever does not. After a number of training days, animals learn to reliably respond on the drug lever after the drug injection and on the saline lever after saline injection. Once this discrimination has been established, a number of test drugs can be administered to determine whether or not they produce effects similar to the training drug. Test drugs that substitute for the training drug (i.e., cause responses on the drug-associated lever) are assumed to have discriminative stimulus effects that are similar to the training drug.

Using this procedure, several investigators have shown that PCP and other noncompetitive antagonists produce similar discriminative stimulus effects in a number of different species (see Willetts, Balster, & Leander, 1990 for a review). These results suggest that the mechanisms of action of PCP and other noncompetitive antagonists, such as ketamine and dizocilpine, are similar. Furthermore, the discriminative stimulus effects of competitive antagonists such as CGS 19755, NPC 12626 and CPP were also similar to each other, which is again consistent with the notion that the mechanisms of action of competitive antagonists are similar. Given that competitive and noncompetitive antagonists both reduce neuronal firing, it was of interest to compare the discriminative stimulus effects of these two types of antagonists. In most species, the discriminative stimulus effects of competitive and noncompetitive antagonists are very different from each other.

Another difference between the competitive and noncompetitive antagonists lies in their abilities to antagonize the discriminative stimulus effects of NMDA. While both types of antagonist are effective in blocking the convulsant and lethal effects of NMDA, competitive antagonists in general are much more effective than noncompetitive antagonists in blocking the discriminative stimulus effects of NMDA. The noncompetitive antagonists partially antagonize NMDA but only at doses that produced substantial behavioral suppression. While most effects of NMDA are antagonized by both competitive and noncompetitive antagonists, the behavioral-suppressing effects of noncompetitive antagonists often interfere with their ability to antagonize the discriminative stimulus effects of NMDA.

Finally, another important finding with competitive and noncompetitive antagonists involve their interaction with other receptor systems. Studies show that the discriminative stimulus effects of competitive antagonists such as CPP and NPA 12626 are similar to those produced by the BARBITURATE pentobarbital. Under certain conditions, the discriminative stimulus effects of PCP and pentobarbital were also similar. In addition to the interactions of NMDA antagonists with barbiturate receptors, some investigators have found similarities between PCP and ethanol (alcohol). These studies have proven to be important in describing both the similarities and differences between the noncompetitive and competitive NMDA-receptor antagonists.

TOLERANCE

Tolerance to a drug occurs when increasingly higher doses are needed to produce a specific effect or if drug effects diminish after repeated administration of the same dose of drug. It has not been possible to study tolerance to PCP in human subjects, but when interviewed, PCP users report that they increase the amount of PCP that they take over time (Carroll, 1990). Another indicator of tolerance development is that burn patients treated with ketamine for pain often require higher doses over time. It is easier to study tolerance to ketamine, PCP, and similar drugs in animals. Laboratory studies with rats have shown that tolerance developed to the effects of PCP on food-reinforced responding, to the effects of PCP and dizocilpine on steroid hormone (adrenocorticotropin and corticosterone) release, and to the cataleptic effects of ketamine. Supersensitivity, the opposite of tolerance, occurs when repeated drug exposure produces a greater effect at a given dose. Some investigators have found that tolerance develops to some effects of PCP, such as head weaving, turning, and back pedaling, while supersensitivity occurs with other behaviors, such as sniffing, rearing, and ambulation. Although some scientists have hypothesized that PCP tolerance and supersensitivity are mediated through non-NMDA-receptor systems, others have suggested that PCP tolerance may be mediated through the NMDA receptor system. Repeated administration of dizocilpine, a PCP-like compound, produced a reduction in the number of NMDA receptors in the rat brain, and that was correlated with tolerance to some of the behavioral effects produced by dizocilpine. Further studies will clarify the role of different receptor systems in the development of tolerance to the effects of PCP and related compounds.

Studies indicate that there are interactions between PCP and other drugs with respect to tolerance and supersensitivity of drug effects. For example, dizocilpine blocked the development of tolerance to morphine's analgesic (painkilling) effects, but it did not alter the analgesic effects when MORPHINE was administered acutely. Also, dizocilpine attenuated the development of tolerance to ethanol (ALCOHOL), and it inhibited sensitization to amphetamine and cocaine (DHHS Fourth Triennial Report to Congress on Drug Abuse and Drug Abuse Research, 1992).

DEPENDENCE

Physiological dependence on a drug is usually defined by a set of withdrawal symptoms that occur when steady use of the drug is discontinued. The withdrawal symptoms are typically the same for a given drug, and they follow a specific time course which ranges from about six to forty-eight hours, depending on the drug. The withdrawal symptoms may be rapidly reversed after one administration of the drug.

Most of what is known about PCP dependence is from experimental studies with animals. There are only limited reports of PCP withdrawal effects in humans. In 1981, Tennant et al. studied sixty-eight regular PCP users; they found that one-third of them had sought treatment or medication to relieve the effects of PCP withdrawal. Withdrawal symptoms that they commonly reported were depression, drug craving, increased appetite, and increased need for sleep. Another way PCP dependence has been documented in humans is in studies of babies born to PCP-using mothers. Withdrawal signs that have been noted are diarrhea, poor feeding, irritability, jerky movements, high-pitched cry, and inability to follow a stimulus visually.

In laboratory studies with monkeys, similar signs of PCP withdrawal have been noted. Balster and Woolverton (1980) gave rhesus monkeys continuous access to PCP directly into the blood stream for fifty days, using an intravenous cannula system. The monkeys were trained to respond on a lever for an infusion of PCP. When PCP was replaced with a salt and water solution used to dissolve the drug (vehicle), withdrawal signs were noted, such as poor feeding, weight loss, irritability, bruxism (coughing), vocalizations, piloerection (hair standing up), tremors, less exploratory behavior in the cage, and poor motor coordination. The withdrawal syndrome began within four to eight hours, peaked between twelve and sixteen hours, and had disappeared by twenty-four to forty-eight hours. These results have been repeated in studies with rats. Some studies have reported PCP withdrawal effects after as little as two weeks of exposure. Thus, long-term use of the drug may not be necessary to produce physical dependence.

Recent studies with animals have shown that not only a short period of exposure to PCP but low doses of PCP result in withdrawal effects when drug administration is discontinued. Operant conditioning experiments are used as sensitive tests of drug-withdrawal effects in animals. In these experiments, animals are trained to respond on a lever or push a button or other device to obtain a food reward. At the same time they are allowed to self-administer drugs orally or intravenously. When drug access is removed, a decrease in operant responding for food is often seen, even when the drug dose is sufficiently low to produce no observable signs of withdrawal. These measures have also been used to demonstrate withdrawal effects from drugs such as cocaine, caffeine, and nicotine. When regular use of these drugs is discontinued there are no observable signs of withdrawal during abstinence. The most severe reductions in the operant behavioral baselines occur during the first forty-eight hours of drug withdrawal, a time during which physical signs occur when higher maintenance doses are used; however, the behavioral disruptions often last for long periods of time. During withdrawal, when animals will not respond on a lever for food, they readily consume hand-fed food. Thus, the decrease in feeding may not be due to illness but to a decrease in the motivation to work for food.

In the first study that demonstrated disruption in operant behavior during PCP withdrawal, Slifer and coworkers (1984) treated monkeys with continuous intravenous infusions for ten days. They were required to make 100 responses on a lever for each food pellet. When access to PCP was terminated, responding for food decreased substantially for up to seven days and did not return to normal levels until the monkeys were again allowed access to PCP. Similar results were found by other investigators using monkeys trained to self-administer orally delivered PCP. There was little difference in the results, depending on whether the PCP was self-administered or experimenter administered. In the monkey studies, there was only a weak relationship between dose and the severity of the withdrawal effect, but in rats, PCP dose, blood levels, and magnitude of the withdrawal effect were closely related. Recent studies have shown that there is cross-dependence between drugs that are chemically similar to PCP—such as PCP and ketamine, dizocilpine, and the () isomer of SKF-10,047; however, cross-dependence was not demonstrated with either the racemate or (-) isomer of SKF-10,047 or with ethanol.

The PCP-withdrawal effect can be altered by changing schedules of reinforcement. In one study with monkeys, lever-press requirements or fixed ratios (FRs) for food were increased from 64 to 128 to 256 to 512 to 1024, and PCP-withdrawal effects were examined at each value. As the FR value increased, PCP withdrawal effects became more pronounced. At the two higher FRs, body weights declined and the severity of the withdrawal effect showed no further increases. To examine the effects of amount of food available, another experiment was conducted in which the FR was held constant at 1024 and the monkeys were either supplemented with 100 grams of hand-fed food or not. The amount of responding for earned food remained the same during supplemented and unsupplemented conditions, but when the effects of withdrawal were examined, a disruption in responding occurred only under the supplemented condition. When the monkeys had to earn their entire daily food ration, the withdrawal effect disappeared. These studies suggest that the severity of the PCP withdrawal effect is determined by the behavioral economics of food availability. The magnitude of PCP withdrawal increased as the price (FR of food) increased; but as the price became so high that body weight was lost, the PCP-withdrawal effect entirely disappeared. These data also suggest that PCP withdrawal is not necessarily an illness but a decreased level of motivation.

The use of drugs to treat the PCP-withdrawal syndrome has produced mixed results. When monkeys had access to orally delivered () SKF-10,047, the PCP-withdrawal-induced disruptions in food-maintained responding were reversed. This was not the case with (-) SKF-10,047 or the race-mate () SKF-10,047. Injections of dizocilpine before PCP withdrawal, or two days into PCP withdrawal, greatly reduced or reversed, respectively, the disruptions in food-reinforced responding. Dizocilpine also dose-dependently reduced PCP self-administration. In contrast, while BUPRENORPHINE, a partial AGONIST at the mu-opiate receptor, also dose-dependently reduced PCP self-administration, it had no effect on PCP-withdrawal-induced disruptions in food-maintained responding. When PCP was self-administered concurrently with ethyl alcohol (ethanol) and then PCP access was removed, PCP-withdrawal effects were as severe as when ethanol had not been available. Thus, ethanol did not alleviate the PCP withdrawal effect, although, as noted earlier, PCP and ethanol share discriminative stimulus effects (Grant et al., 1991). In other studies, PCP was self-administered concurrently with ethanol or caffeine. When PCP and the other drug were removed simultaneously, the withdrawal disruption was more severe than when PCP alone was withdrawn. (Further details of these withdrawal studies may be found in reviews by Carroll [1990] and by Carroll and Comer in the DHHS Fourth Triennial Report to Congress on Drug Abuse and Drug Abuse Research, 1992.)

REINFORCING EFFECTS

The reinforcing effects of a drug are determined by demonstrating that self-administration of the drug plus the solution it is dissolved in (vehicle) occurs in excess of self-administration of the vehicle alone. When drug-reinforced behavior is readily achieved in the animal laboratory, it is usually a good predictor that the drug has considerable abuse liability in the human population. The reinforcing effects of PCP have been studied using two animal models of self-administration, oral and intravenous. The intravenous route of self-administration requires the animal to make a specified number of responses on a lever or other manipulandum within a predefined time—then a fixed dose of the drug is delivered by an infusion pump via a catheter that is surgically implanted in a large vein that leads to the heart. Studies from various laboratories have demonstrated that intravenously delivered PCP functions as a reinforcer for rats, dogs, monkeys, and baboons.

Drugs that are chemically similar to PCP are also self-administered intravenously. These include drugs that have similar receptor-binding sites in the brain, such as ketamine, () SKF-10,047, dexoxadrol, and cyclazocine; and phencyclidine-like drugs that function as noncompetitive antagonists at the NMDA receptor, such as dizocilpine. Phencyclidine and dizocilpine self-administration is more reliably obtained when the animal has a history of self-administration of a drug with similar pharmacological or discriminative-stimulus effects. It has also been found that drugs that share discriminative-stimulus effect with PCP, such as () SKF-10,047, ketamine, PCE, TCP, and ethanol, are readily substituted for PCP in self-administration studies.

Oral PCP self-administration is established by presenting gradually increasing concentrations of PCP after the animal is given its daily food ration. After sufficient quantities of PCP are consumed, food is given after the drug self-administration session, and PCP consumption usually persists. This procedure provides a long-term stable baseline to examine variables that affect PCP-reinforced behavior. For example, alternative nondrug reinforcers, such as saccharin, reduce PCP-reinforced responding up to 90 percent of baseline if the FR for PCP is high or if the PCP concentration is very low. Free access to food decreases PCP self-administration, while even small reductions in the daily food allotment markedly increase PCP self-administration. Concurrent availability of ethanol also reduces PCP-reinforced responding.

A limited amount of information is available concerning drug pretreatment and PCP self-administration. Buprenorphine and dizocilpine pretreatment both resulted in dose-dependent decreases in PCP self-administration; however, potential treatment drugs such as fluoxetine and carbamazepine had no effect. Treatment with other drugs such as AMPHETAMINE or PENTOBARBITAL had a biphasic effect on PCP self-administration. Low doses of the pretreatment drugs increased PCP self-administration, and high doses decreased PCP self-administration.

TOXICITY

There is little evidence that long-term PCP use in adult humans (Luisada, 1981) and monkeys (see DHHS Fourth Triennial Report to Congress on Drug Abuse and Drug Abuse Research, 1992) results in any detectable organ or cellular damage. In monkeys that had been self-administrating PCP for eight years, tests of all organ systems, clinical chemistries, physical exams, and X rays revealed no differences between PCP-experienced and control animals that were the same age but had little drug experience. In humans, the form of toxicity most commonly associated with PCP use is a change in behavior. There have been a few accounts of bizarre and/or violent behavior associated with PCP use. Such reports have diminished since the preferred route of self-administration has shifted from oral (pill) to inhalation, which offers the users an ability to more carefully control the dose.

In monkeys, PCP produces a calming, tranquilizing effect. The immediate effects in humans are not seen in the hospital or clinic. Instead, the PCP user arrives in the emergency room several hours after PCP use, possibly while suffering acute withdrawal effects. Approximately twelve to fifteen hours after PCP was last taken, monkeys become agitated, violent, and aggressive. It is possible that many of the early reports of human violence and the PCP-related homicides were related to the withdrawal effects. It is necessary to determine the time course of unusual behavior and important to know the time of drug intake, although this is difficult to establish because the patient often loses memory of the drug-taking event.

Another unusual aspect of PCP toxicity is that users often complain of unpleasant effects long after chronic use has stopped. These reports could be caused by the fact that PCP is highly fat soluble and becomes stored for long periods of time in the body fat. During periods of weight loss, there is subsequent mobilization of fat-stored PCP into blood and brain tissues. Recent laboratory research with rats supports this hypothesis by demonstrating the ability of food deprivation to increase PCP levels in blood and brain (Coveney & Sparber, 1990).

Increasing data has become available on the effect of drugs of abuse on the offspring of dependent mothers, and it appears that the offspring of PCP users may be more vulnerable to the adverse effects of PCP than their adult counterparts. Golden and coworkers (1987) studied ninety-four PCP-ex-posed newborns and ninety-four nonexposed as controls; they found neurological abnormalities such as abnormal muscle tone and depressed reflexes in the exposed group. Another study followed twelve exposed infants for eighteen months and found a high percentage of medical problems (Howard et al., 1986). At six months the infants were irritable and hyperresponsive, and later they showed varying degrees of abnormalities in fine-motor, adaptive, language and social skills. A recent study of the offspring of forty-seven PCP abusers and thirty-eight nonusers found that neurological dysfunction was common in the infants of PCP-abusing mothers (Howard, Beckwith, & Rodning, 1990). There was greater apathy, irritability, jitters, and abnormal muscle tone and reflexes. Follow-up interviews at six and fifteen months, using the Gesell Developmental Exam, revealed poor language development and a lower developmental quotient in general; however, the long-term outcome for PCP-exposed newborns is unknown.

TREATMENT

There are currently no PCP ANTAGONISTS that are useful for treatment of PCP OVERDOSE. Symptomatic treatment may be given for suppressed breathing rates, fever, high blood pressure, and increased salivation. Convulsions are treated with DIAZEPAM. Elimination of the drug may be enhanced by making the urine more acidic and/or pumping stomach contents. Attempts to minimize environmental stimuli have helped to control violent and self-destructive behavior. Psychiatric care may be needed for an extensive psychotic phase that may follow overdose (Jaffe, 1989).

(SEE ALSO: ; Addiction: Concepts and Definitions; Adjunctive Drug Taking; Aggression and Drugs; Fetus: Effect of Drugs on the; Phencyclidine (PCP): Adverse Effects; ; Tolerance and Physical Dependence)

MARILYN E. CARROLL

SANDRA D. COMER