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Repeated administration of naloxone have been found to result in the development of analgesia. Pretreatment with naloxone can also produce supersensitivity to morphine. This study examined whether the development of these phenomena is affected by exposure to pain (hotplate testing) during opiate blockade. During acquisition, two experimental groups of rats received identical treatment with respect to repeated naloxone injections (5 mg/kg) and the environment in which the injections were administered. A “contingent” group (NAL-C) received hot-plate testing under the influence of naloxone, while a “noncontingent” group (NAL-NC) experienced hot-plate testing and naloxone separated by an interval of 24 h. At test, NAL-C rats manifested naloxone-induced analgesia (NIA) whereas the NAL-NC animals did not. The NAL-C rats also showed supersensitivity to the analgesic effects of morphine (3 mg/kg) and to the cataleptic effects of morphine (17.5 mg/kg) while the NAL-NC rats did not differ from saline controls. Thus, both NIA and morphine supersensitivity were completely dependent on testing in the drug state during acquisition; mere exposure to an identical regime of naloxone injections was insufficient to produce these phenomena.

Abstract: Individuals who were using therapeutic doses (approximately 15 mg diazepam or its equivalent daily) of a benzodiazepine persistently and wished to attempt to stop were recruited into a study offering a medically supported outpatient behavioral treatment with a goal of abstinence. All subjects received the same behavioral treatment that emphasized the development of strategies for coping with abstinence and alternatives to benzodiazepines as a coping mechanism. The goal of abstinence was to be achieved within approximately 8 weeks by means of gradual tapering of the daily dose. Some subjects (Group D, n=23) were randomly assigned to a condition in which their dose was to be tapered on a regime of active diazepam. Others (Group P, n=19) were switched to placebo at the first treatment session and ldquotaperedrdquo from this pharmacologically inert substitute for diazepam. Supplies of tablets of each preparation were provided by the experimenters, and subjects were specifically requested to use only those tablets. The principal dependent variable was ldquosupplementationrdquo, or use of a benzodiazepine other than that specifically authorized by the therapist. Supplementation was detected by measures of plasma benzodiazepine levels as compared to levels predicted if there had been strict compliance with the therapeutic regime. These comparsions were made by two expert judges who were blind to the subjects' experimental assignment. Self-report of supplementation was also obtained. Plasma level determinations indicated a significantly greater frequency of supplementation (84% versus 33% of subjects) for subjects in Group P. This was corroborated by self-report. These data support the assertion that dependence on low doses of benzodiazepines has a pharmacologic basis, and that there is a causal relationship between deprivation of a benzodiazepine and its self-administration in dependent persons.

Various attempts have been made to account for the fact that pertreatment with some pharmacological agents reduces the ability of such agents to induce conditioned aversion to a flavor. One explanation, based on the concept of tolerance, suggests that pretreatment is effective because it renders the animal less sensitive to direct effects of a given dose of the agent. A second explanation emphasizes the possibility that procedural consequences of pretreatment interfere with associability of flavor and drug effect during conditioning. The second explanation was tested in two experiments. In Experiment I nonreinforced presentations of drug administration cues completely reversed the attenuating effects of amphetamine pretreatment on gustatory conditioning by amphetamine. This finding was replicated and extended in the second experiment which was also designed to eliminate an alternative nonassociative explanation for the results. The principle of associative blocking may explain the effect of pretreatment on subsequent gustatory conditioning by drugs.

The pretreatment effect (PE) in gustatory avoidance conditioning refers to the fact that pretreatment with a variety of pharmacological agents subsequently reduces the ability of the same agents to induce gustatory aversion. Explanations of this phenomenon emphasize either tolerance or associative interference. Any explanation of the phenomenon must also account for the present findings which demonstrate the PE when agents of pretreatment and conditioning were pharmacologically dissimilar. Rats were pretreated with d-amphetamine and tested for acquisition of an aversion to saccharin conditioned by amphetamine or morphine. The PE was obtained regardless of the drug used in conditioning. An associative manipulation involving nonreinforced presentation of the drug administration cues (i.e., injections followed by saline instead of drug), that attenuated the PE when pretreatment and conditioning were with amphetamine, was also effective when the pretreatment agent was amphetamine and the conditioning agent was morphine. The findings were interpreted within a framework of compensatory conditioning of a general physiological mechanism common to all gustatory avoidance.

Pretreatment by a psychoactive drug can greatly attenuate the conditioning of gustatory avoidance by that drug. Although such findings have been interpreted in terms of tolerance, alternative explantions are possible. In a series of experiments, it was found that pretreatments with morphine or amphetamine massed at 24-h intervals were no more effective in attenuating conditioning than pretreatments spaced at 120-h intervals, but pretreatment with morphine provided more persistent protection against subsequent conditioning by itself than did amphetamine in a comparable previous experiment. The similarity of massed and spaced pretreatment effects can be interpreted without appealing to tolerance as a factor, but the greater persistence of morphine pretreatment implicates tolerance as a mechanism.

Although psychosocial variables affect the consequences of marihuana ingestion, little is known of the role of such variables as determinants of the self-administration of the drug. To pursue this question, three variables were manipulated in a factorial design. Marihuana use history was manipulated by selecting subjects at extremes of use frequency. To determine the possible contribution of learned smoking habits to consumption, subjects smoked either large or small cigarettes. Finally, cigarettes varying in concentration of delta-9 tetrahydrocannabinol (0.36%, 0.73% or 1.45%) were used. Subjects were simply asked to smoke until they had attained a “nice high”. Although there was some evidence of titration according to potency, subjects self-administrated more total tetrahydrocannabinol the more potent the material in attaining the same subjective endpoint of intoxication. More material was ingested in the form of large than small cigarettes. The latter variable accounted for nearly as much variance as did drug potency itself. This result illustrated the importance of an essentially cognitive variable as a determinant of drug intake. Finally, there was no difference in the amount required by frequent and infrequent users to attain the intoxication criterion. The latter result was in opposition to the assertion by Nahas (1973) that frequent exposure to cannabis will ultimately result in an increase in the amount required to produce the reinforcing effects of marihuana. It was emphasized that assertions about the contribution of various factors to drug-taking behavior should be withheld in the absence of data from experiments in which actual self-administration is the dependent variable.

Abstract: 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.

A recent study demonstrated that ethanol tolerance was reduced by the presentation of a novel extraneous stimulus at the time of test. In Pavlovian terms, this phenomenon is known as external inhibition. The present study sought to determine whether a drug cue could act as an external inhibitor of tolerance. Theoretically, either the occurrence of an unexpected stimulus or the nonoccurrence of an expected one can operate to disrupt already established conditioned responses. This prediction was assessed in the present study by the novel presentation or the novel omission of a drug cue at test. Two groups of rats were made completely tolerant to the analgesic effects of morphine. During tolerance acquisition the groups were treated identically except that one group always received a dose of alcohol 15 min following morphine. At test, animals experienced either the novel introduction or the novel omission of the alcohol cue. Both manipulations led to a reduction of morphine analgesia. Beyond their theoretical importance, these results have clinical implications in view of the frequency of multiple concurrent drug abuse.

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.

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.

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.

The evidence on tolerance to the effects of alcohol on memory functions is conflicting. Comparisons of populations differing in drinking history (alcoholics versus normal subjects) provide clear evidence of tolerance to alcohol's effect in many indices of psychomotor performance, but not to impairment of recall by alcohol. In contrast, acute or intrasessional tolerance to alcohol's effect on memory has been demonstrated. In the context of a larger experiment on the acquisition of tolerance in nonalcoholic subjects an assessment of the effects of repeated daily exposure to alcohol on verbal recall was possible. The experimental design incorporated 3 baseline days prior to the administration of alcohol, 10 consecutive days of exposure to alcohol (1.0 g/kg test dose, with supplementary 0.9 g/kg after testing) and 3 further days on which no alcohol was administered. Data on seven subjects were available for the memory task, which consisted of free recall of lists of 24 words grouped into six categories of four words each. On each day, recall was assessed both prior to and following the administration of a control beverage or alcohol. Alcohol reduced the number of words recalled (P<0.005) and, with repeated exposure, the impairment of recall by alcohol was reduced (P<0.005) providing evidence of tolerance. The effect of alcohol and the development of tolerance were reflected primarily in the number of categories represented in recall, whereas the number of words recalled per category was relatively unaffected by alcohol. It was conjectured that previous failures to find tolerance to alcohol's effect on memory may reflect deficits in neuropsychologic functioning resulting from years of heavy drinking.

Chronic prior treatment with amphetamine greatly attenuates the conditioned aversion to saccharin that may be produced by amphetamine. Two experiments were designed to determine some of the limiting conditions of this phenomenon. In Experiment 1, chronic treatment with 7.5 mg/kg of amphetamine was administered for 0, 1, 5, or 20 days prior to pairing saccharin with an injection of 1.0 mg/kg of d-amphetamine sulphate. The results indicated that between 5 and 20 days of treatment were necessary for the treatment to be effective in attenuating conditioned aversion. In Experiment 2, rats were withdrawn from treatment with 20 mg/kg of amphetamine for 1, 7, or 14 days prior to conditioning trials with 1.0 mg/kg of amphetamine. The prior treatment lost its effectiveness in attenuating conditioned aversion between 7 and 14 days after withdrawal. Although alternative explanations are possible, the time intervals required for acquisition and loss of the effectiveness of prior treatment are consistent with the hypothesis that tolerance is the mechanism underlying the observed effects.

A constraint upon intravenous drug self-administration techniques is that they are suitable only for assessing positively reinforcing consequences of drug action; they do not permit a distinction among several possible explanations for reduced or zero rates of self-administration by animals. The possibility that there is a significant punishing component to drug administration was investigated in an aversive taste conditioning paradigm. Mescaline, which is refused by monkeys, and d-amphetamine, which is self-administered by both rats and monkeys, were compared. Five min after drinking saccharin solution for the first time, groups of rats were injected intraperitoneally with saline or different doses of each drug. Conditioned taste aversion was clearly demonstrated with both drugs; on a second exposure to saccharin solution, fluid consumption was greatly depressed compared to control values. This was true even with a dose of d-amphetamine (2 mg/kg) known to be self-administered by rats. The results suggest that intravenous drug self-administration may involve a punishing component which is detectable only in an appropriate behavioral test. It was also noted that aversive taste conditioning was demonstrable at doses frequently used in behavioral pharmacological investigations.

Rats were given the opportunity to drink morphine solution following stabilization at three levels of “passive premedication”. Compared to saline treated controls, premedicated rats consumed more morphine solution, but medication level did not significantly affect morphine intake. Premedicated rats adjusted to a reduction in morphine solution concentration by increasing fluid intake substantially, but nonpremedicated rats did not. When morphine was offered in a vehicle of isotonic saline oral consumption rose sharply in premedicated rats but not in their nonpremedicated counterparts. “Drinker” and “nondrinker” rats were identified on the basis of initial response to oral morphine. Premedication eliminated resistance to morphine drinking, but even at the expense of severe fluid deprivation, nonpremedicated nondrinkers refused morphine throughout the entire experiment.

Previous research has suggested that psychosocial rather than strictly pharmacological factors may play a dominant role in the subjective response to “socially relevant” (i.e., low) doses of marihuana. The insensitivity of experienced marihuana users to pharmacological factors was studied in an ad lib self-administration situation. Subjects tested repeatedly with varying drug potencies were asked to smoke a sufficient amount to achieve a predefined subjective state of intoxication. Several indices of amount consumed suggested that effective titration of intake did not occur. Rather, subjects consumed more total THC the greater the potency of the material. Doses which produced a subjectively “optimal high” had significant behavioral and physiological effects. The results are consistent with the hypothesis that psychosocial variables may be more significant than pharmacological variables in determining the recreational intake of marihuana.

Some investigators have used evidence that a drug may induce conditioned taste aversion to dismiss other behavioral effects of the drug as due to general toxicity rather than specific pharmacological action. To test the validity of this position, behaviorally relevant doses of alcohol, chlordiazepoxide, and morphine were studied in an aversive taste conditioning paradigm. Drug injections were paired with exposure to saccharin solution on repeated trials. Each drug produced saccharin aversion at one or more doses. Since comparable doses are known to facilitate rather than impair behavior in some situations, the taste aversion test is insufficient to establish the general behavioral toxicity of particular drug doses.

Gender differences in peak breath alcohol concentrations (BrACs) reached in alcohol administration studies can make the interpretation of study findings difficult. This study evaluated the CBAC computer program as a way of minimizing gender differences in the BrAC curve. After consuming a predrink meal that was adjusted by body mass, 31 female and 27 male subjects consumed an alcoholic beverage targeted for either 0.04% or 0.08%. Mean peak BrACs for women and men were not significantly different. Similarly, the four BrAC readings obtained over the first 2 hr postdrink showed no gender differences. A dose × gender interaction was observed on time to peak BrAC, with women reaching peak BrAC faster than men only in the high dose groups. By decreasing gender differences in BrAC curves, this dosing procedure can aid in reducing the potential confound of dose and gender.

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.