Gender and alcohol dosing: a procedure for producing comparable breath alcohol curves for men and women.

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 x 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.

A randomised, double-blind study of cicaprost, an oral prostacyclin analogue, in the treatment of Raynaud's phenomenon secondary to systemic sclerosis.

Cicaprost is a new synthetic prostacylin analogue which is metabolically stable and bioavailable after oral administration; in previous studies it has been shown to have vasodilator antiplatelet effects. In this pilot study, we investigated the clinical efficacy of and patient tolerance to two dosage levels of cicaprost (2.5 micrograms tds and 5 micrograms tds) in the treatment of Raynaud's phenomenon secondary to systemic sclerosis (SSc). This was a three centre, double-blind, placebo controlled study of 49 patients carried out over four winter months. For a period of 10 days, 16 patients were given a placebo, 16 received cicaprost 2.5 micrograms tds and 17 received cicaprost 5 micrograms tds. Response was assessed based on the total number and duration of Raynaud's attacks, the average severity of the attacks, the number of painful attacks as a proportion of all attacks, a digital ulcer count, and the patients' opinion of the treatment. Although the clinical and laboratory parameters of digital vasospasm did not show statistically significant improvement in those who received cicaprost compared with those on the placebo, the severity of attacks lessened in the patients who received cicaprost 5 micrograms tds, and a statistically significant difference was seen in the average severity at week 2 post-treatment (p = 0.02). The apparent lack of overall significance was probably related to the short treatment period and relatively low doses of cicaprost used in this exploratory study. Longer studies with dose titration are probably needed to demonstrate the beneficial effects, if any, of cicaprost in patients with Raynaud's secondary to SSc, and these are being planned.

Homeostatic theory of drug tolerance: a general model of physiological adaptation.

At the heart of homeostatic theory is the idea that explicit or implicit behavioral demands placed on physiological systems are required for the biological detection of homeostatic disturbances. The detection of drug-induced disturbances is required to drive the development of all systemic tolerance, both associative and nonassociative (i.e., both forms of tolerance are behaviorally contingent). A wide range of findings ranging from morphine-induced analgesia to ethanol-induced hyposexuality shows that contingent tolerance is pervasive and may be universal. The theory also stipulates that behavioral demands placed on the target system will govern the loss of both associative and nonassociative tolerance (physiological). The present formulation integrates contingent, associative, and nonassociative tolerance and drug-opposite withdrawal reactions within a unified theory.

Chronic selective blockade of mu opioid receptors produces analgesia and augmentation of the effects of a kappa agonist.

We have previously demonstrated that, when administered chronically, naloxone and naltrexone have the paradoxical effect of producing analgesia in rats. In this study, rats treated chronically with intracerebroventricular (i.c.v.) microinjections, and mice treated chronically with subcutaneous (s.c.) injections of naloxone or beta-funaltrexamine (beta-FNA) developed analgesia on daily hot plate tests. There was not drug effect on the first day of hot plate testing, but significant increases in paw lick latency developed over subsequent acquisition sessions for animals treated with beta-FNA or naloxone. An augmented analgesic response to a 5 mg/kg s.c. injection of the kappa opioid agonist, U50-488H, was observed in mice previously treated with naloxone or beta-FNA. The primary findings of the present study were: (1) chronic blockade of mu opioid receptors is sufficient to produce analgesia on repeated hot plate tests in both rats and mice; (2) chronic blockade of mu receptors in the presence of stressful stimuli results in augmentation of kappa agonist-induced analgesia; and (3) the phenomenon of opioid blockade-induced analgesia (OBA) occurs in mice as well as rats.

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 degrees 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.

A contingent, conditioned suppression of eating following chronic benzodiazepine-induced hyperphagia.

While the hyperphagic effect of chloradizepoxide (CDP) has been reported by some to be enhanced with chronic drug treatment, the processes underlying this phenomenon are not well understood. In the present study, it was predicted that following chronic exposure to CDP-induced hyperphagia, animals given a placebo in place of their usual drug injection might be expected to exhibit evidence of a conditioned, drug-like response. Such a finding would then be consistent with an underlying process of behavioral sensitization. In Experiment 1a, Male Sprague-Dawley rats were randomly assigned to one of two groups receiving intraperitoneal (IP) injections of either 5 mg/kg CDP (Group CDP) or physiological saline (1 ml/kg; Group SAL) administered over 15 drug treatment days. Thirty minutes after each injection, all animals were given 30 min access to sweetened condensed milk. A significant enhancement of CDP-induced hyperphagia was observed over treatment sessions, confirming an earlier report. Unexpectedly, in the Placebo Test, the CDP animals exhibited a supression of milk consumption relative to that of the SAL group. Using the same animals, this finding was successfully replicated in Experiment 1b. In Experiment 2, it was hypothesized that if this conditioned, drug-opposite response were to reflect the involvement of some underlying compensatory, homeostatic mechanism, then it should only be observable under food-contingent conditions of chronic drug treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Naloxone-induced analgesia and morphine supersensitivity effects are contingent upon prior exposure to analgesic testing.

Repeated administrations 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 (hot-plate 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.

Enhancement of naloxone-induced analgesia by pretreatment with morphine.

Recently there have been demonstrations of a form of analgesia in rats that depends on the repeated administration of an opiate antagonist for its occurrence. The mechanism of this naloxone-induced analgesia (NIA) is not clear. This experiment tested the hypothesis that the relationship between behavioral effects of previous experience with opiate agonists and antagonists would be reciprocal with respect to analgesia. Consistent with such an hypothesis, prior exposure to morphine increased sensitivity to the effect of naloxone as measured by the rate of acquisition of NIA. Although receptor functions were not measured, reciprocal changes in the regulation of opiate receptors by opiate receptors by opiate agonists and antagonists may underlie the behavioral effects observed in this experiment.

Naloxone-induced analgesia: effects of the benzodiazepine antagonist Ro 15-1788.

Repeated exposure to pain under the influence of the opiate antagonists naloxone and naltrexone leads to the recruitment of substantial analgesia as measured by paw-lick latency on the hot-plate test (4,11). One hypothesis to explain this naloxone-induced analgesia (NIA) is that nociceptive stimulation in the face of opiate blockade becomes stressful enough to activate an analgesic adaptation that otherwise would not occur. This hypothesis was examined in two experiments by the administration of a benzodiazepine antagonist with anxiogenic properties (Ro 15-1788, in a dose of 10 mg/kg) in conjunction with repeated administrations of naloxone (5 mg/kg). One experiment incorporated defecation as a relatively direct measure of stress. Ro 15-1788 reliably augmented NIA. Defecation was increased by naloxone alone and in combination with Ro 15-1788. Overall, the results were most consistent with the hypothesis that NIA is a form of stress-induced analgesia that is at least partly nonopiate in nature.

Benzodiazepine-induced hyperphagia: a test of the hunger-mimetic model.

The 'hunger-mimetic' model is a prominent explanatory account of benzodiazepine-induced hyperphagia. A salient feature of food deprivation (hunger) in laboratory animals is 'finicky' eating, or an enhanced reactivity to the palatability of food. If the hunger-mimetic model is correct, a similar finicky pattern of increased eating should be observed both in hungry (food-deprived) rats and in benzodiazepine-treated, hyperphagic rats. Two groups of rats were matched on measures of ad lib baseline intake of both a highly palatable food (sweetened condensed milk) and a food low in palatability (milk adulterated with 37.5 mg% quinine). Subsequently one group was placed on a moderate food deprivation schedule while the second group was maintained on ad lib food but was injected (IP) with 5 mg/kg chlordiazepoxide (CDP) 30 min prior to food presentation tests. Single-bottle tests indicated that while the food deprived animals exhibited a greater augmentation of eating when given the high-palatability food, the animals pretreated with CDP exhibited an indiscriminate elevation of eating across both foods. Similarly, on two-bottle choice tests the food-deprived rats exhibited an enhanced preference for the high-palatability food, whereas the CDP-treated animals did not change from baseline food preference. These results fail to support the hunger-mimetic model of benzodiazepine-induced hyperphagia. Alternative models based on a perseverative, disinhibitory action of benzodiazepines are discussed.

"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.

Tolerance to morphine analgesia is reduced by the novel addition or omission of an alcohol cue.

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.

Drug deprivation and reinforcement by diazepam in a dependent population.

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 "tapered" 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 "supplementation", 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 comparisons 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.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

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.