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 symp toms 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 keta-mine, 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.)

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