Howard Cappell

Withdrawal reaction after long-term therapeutic use of benzodiazepines.

We conducted a double-blind, placebo-controlled trail in which 40 patients who had undergone long-term therapy with benzodiazepines were switched to placebo or to diazepam in a dose approximately equivalent to their usual dose of the benzodiazepine; the dose of diazepam was then tapered during an eight-week period. Patients were assessed clinically and psychologically and had weekly sessions of behavioral therapy. The subjects who received placebo had more symptoms, assessed their symptoms as more severe, and stopped taking the study drug at a higher rate than those receiving the tapering doses of diazepam. The subjects in the placebo group also had symptoms shortly after being switched to placebo, whereas those in the diazepam group had symptoms much later. Some withdrawal symptoms were distinct from those of anxiety (e.g., tinnitus, involuntary movement, and perceptual changes). Withdrawal symptoms occurred earlier in patients who had received short-acting benzodiazepines than in those who had received long-acting benzodiazepines. Symptoms gradually disappeared over a four-week period in both the placebo and the diazepam groups. Serial determination of plasma benzodiazepine concentrations was a useful way to assess compliance, treatment outcome, and relapse during withdrawal. We conclude that a clinically important, mild, but distinct withdrawal syndrome occurs after discontinuation of long-term therapeutic use of benzodiazepines.

Alcohol is an effective cue in the conditional control of tolerance to alcohol

To assess the effectiveness of a pharmacological cue as a conditional stimulus in the Pavlovian model of drug tolerance, two groups of Wistar rats received equal numbers of IP injections of a low and a high dose of alcohol. One group (Paired) received a low dose (0.8 g/kg) of alcohol followed 60 min later by the high dose (2.5 g/kg). Another group (Unpaired) received the low and high doses on an unpaired basis. When tested for tolerance to the hypothermic effect of the high dose of alcohol, only the Paired group showed tolerance, and only if the low dose preceded the high. When a saline injection preceded the high dose injection, the Paired group showed a loss of tolerance. The Paired group also showed a compensatory hyperthermia following the low dose injection. Animals from the Paired group that received repeated administrations of the low dose followed by saline, showed a significant extinction effect as compared with animals that received repeated saline injections only. These findings support the Pavlovian model of conditional tolerance, extending the realm of effective conditional stimuli to include a low dose of a drug.

Antagonism of morphine-induced aversive conditioning by naloxone

In Experiment 1, 4 doses of morphine and 4 doses of naloxone were tested for their ability to induce a conditioned aversion to saccharin in rats. Morphine was much more potent than naloxone which had only weak effects at the highest dose (12.96 mg/kg). Based on the determinations of Experiment 1, doses of 0.096, 0.96 and 0.6 mg/kg of morphine in a second experiment. The highest dose of naloxone was an effective antagonist of morphine-induced aversion. The antagonism was incomplete, but this may have reflected the particular dose combinations that were employed. Although 12.96 mg/kg of naloxone induced only a weak conditioned aversion to saccharin in Experiment 1, 9.6 mg/kg had a substantial effect in Experiment 2. Thus naloxone was itself an agent of aversive conditioning at a dose which significantly antagonized the aversive effects of morphine. Because of the successful demonstraion of antagonism, it was suggested that there may be common pharmacological mechanisms involved in both positive reinforcement and aversive conditioning by drugs of the opiate class.

Effects of pentobarbital and cocaine in rats expecting pentobarbital

Rats received extensive exposure to pentobarbital in a distinctive environment, and were subsequently tested for tolerance to the sedative effects of pentobarbital either in the distinctive environment or in an environment previously associated only with saline. Rats tested when expecting pentobarbital (i.e., in the usual drug environment) were tolerant, but rats tested when not expecting the drug (i.e., in the saline environment) were not tolerant. These results extend demonstrations of conditional tolerance to the general behavioral arousal effects of a sedative hypnotic. Subsequently, the same rats were administered cocaine either when expecting pentobarbital or when not expecting pentobarbital. Rats administered cocaine when expecting pentobarbital exhibited more intense forms of cocaine-induced behavior than rats administered cocaine but not expecting pentobarbital. These results establish the phenomenon of conditional cross-potentiation between conditional drug states and unconditional drug-effects.

Paradoxical analgesia induced by naloxone and naltrexone

Analgesic effects of pellet implantation of the opiate antagonists naloxone and naltrexone and of chronic administration of naloxone by subcutaneous injection were examined. Rats were implanted with a slow-release pellet containing 10 mg naloxone or 10 mg naltrexone and tested for paw-lick latency on a hotplate apparatus. Controls were implanted with placebo pellets or given saline injections as appropriate. There were five test trials at intervals up to 72 h after implantation of naloxone and up to 120 h after the implantation of naltrexone. In a separate experiment, 5 mg/kg naloxone was injected; there were single trials on 5 consecutive days. All drug-treated animals displayed clear and substantial analgesia by their second test trial. This “paradoxical” analgesia was gradually reversed in the pellet-implant groups as tissue levels of the antagonists declined, but increased progressively with each trial involving injections. It was hypothesized that blockade of endogenous opiates by antagonists resulted in a form of “super-pain” on the hotplate, which in turn activated a normally redundant “backup” analgesic system. The results with naloxone injections show that unlike opiate-mediated analgesia, this hypothetical system is resistant to tolerance.

Pavlovian control of cross-tolerance between pentobarbital and ethanol

Tolerance to several effects of a number of drugs has been shown to depend on Pavlovian conditioning processes. Experiment I extended the compensatory conditioning model (Siegel 1975) to tolerance to the hypothermic effect of pentobarbital (30 mg/kg). In Experiment I, rats that acquired hypothermic tolerance in one environment did not display tolerance when tested in an environment not previously associated with drug administration. In Experiment II, rats were made tolerant to the hypothermic effect of pentobarbital (30 mg/kg) and tested for cross-tolerance to ethanol (2.5 g/kg). Cross-tolerance was observed, but it was significantly reduced if the test was in an environment different from the one in which tolerance to pentobarbital was originally acquired. Thus, the compensatory conditioning model accounts for at least part of the tolerance and crosstolerance to the thermic effects of alcohol and pentobarbital. The physiological processes in the CNS underlying tolerance and cross-tolerance for these drugs, therefore, are controlled by associative processes.

Pavlovian conditioning and addictive behavior: relapse to oral self-administration of morphine

The effect of conditional environmental stimuli on morphine consumption in rats was examined. Rats were first trained to consume a morphine solution (increased from 0.5 mg/ml to 1.2 mg/ml) by a forced drinking procedure spanning 235 days. Then, a period of abstinence of 81 days was given. They next received injections of morphine in one environment and injections of saline in a different environment (30 injections of morphine, dose increased from 5 mg/kg to 40 mg/kg). At the end of this phase, the effects of conditional environmental stimuli on tolerance to the analgesic effect of 40 mg/kg morphine were examined. Consistent with previous results, analgesic tolerance was most pronounced in the context of the cues previously associated with subcutaneous morphine injections. Finally, the effects of the different environments on consumption of morphine were determined in one-bottle and two-bottle tests. In a two-bottle test, there was almost no consumption of the morphine solution regardless of environment. In a one-bottle test, significantly more morphine was consumed in the drug environment than in the saline environment. The results are discussed in relation to theoretical views of the role of environmental stimuli in tolerance and drug dependence.

Role of central versus peripheral opioid receptors in analgesia induced by repeated administration of opioid antagonists

Although analgesia induced by blockade of opioid receptors has been well established, it is still unknown whether its development is mediated by the blockade of centrally located opioid receptors. Therefore, rats were treated with either systemically or ICV applied naloxone or quaternary naltrexone (QN), an opioid antagonist that does not easily penetrate the blood-brain barrier. Following antagonist administration, each animal was tested for paw lick latency on a 51° C hot plate. Hot plate testing and drug injections were carried out for 4 consecutive days. Rats treated with ICV microinjections of QN or naloxone displayed paw lick latencies that were significantly longer than those observed in control animals. In contrast, rats treated with SC injections of QN did not show any increase in paw lick latency, whereas rats treated with SC injections of naloxone displayed paw lick latencies that were significantly longer than those of control rats. These results are consistent with the hypothesis that the blockade of central opioid receptors underlies the development of an analgesic response.

Effects of amygdala lesions on taste aversions produced by amphetamine and LiCl.

Rats which sustained bilateral damage to the amygdala were treated with one of two diversely acting agents (either d-amphetamine sulphate 4 mg/kg, or lithium chloride 0.24 M) in a taste aversion paradigm. Both groups of animals showed an attenuation of the aversion on the first test day after the initial pairing with the drug thus demonstrating that this effect of the lesion was not UCS specific. The implication of these findings for the hypothesis concerning the role of the amygdala in taste aversion conditioning is discussed.

Associative control of tolerance to the sedative and hypothermic effects of chlordiazepoxide.

Pavlovian control of tolerance to the sedative and hypothermic effects of chlordiazepoxide (CDP) was demonstrated in two experiments. In Experiment I, drug-experienced rats were repeatedly treated with CDP (30 mg/kg) in one environment (CS+); on alternate days, they were given saline injections in a different environment (CS-). Duration of sleeping and inactivity were used as measures of sedation. A comparable conditioning procedure was used in Experiment II, but tolerance to the hypothermic effect of CDP was the dependent measure. During tolerance testing, rats from both Experiments I and II were given CDP in one of three environments, CS+, CS-, or a novel environment (CSnov). In Experiment I, rats were equally tolerant in all three test environments when duration of sleep was assessed. However, when inactivity was used as the measure of tolerance, rats showed tolerance in CS+ and CS-, and significantly less tolerance in CSnov. Drug-naive controls showed similar nontolerant responses to CDP in all environments, thus ruling out the possibility that the effect of sedation was mediated nonassociatively. In Experiment II, drug-experienced rats showed tolerance to CDP-induced hypothermia in CS+ and CS- but less tolerance in CSnov. A compensatory hyperthermia was observed when these rats were given saline in CS+. There was some evidence for a generalization gradient in the conditional control of tolerance in both experiments.