Biomedical subjects

R R Griffiths

Publications and source records attributed to R R Griffiths.

At least 109 records · Page 6Linked to original sources

PubMed1990

Dose-response evaluation of the amnestic effects of triazolam and pentobarbital in normal subjects.

The effects of placebo, triazolam (0.25, 0.5, and 0.75 mg), and pentobarbital (100, 200, and 300 mg) were examined in seven normal male volunteers using a double-blind, Latin Square, balanced crossover design. Before and at hourly intervals after oral drug administration at approximately 10 a.m., subjects completed subject ratings of drug effects, psychomotor performance tasks, and two versions of a number recall task in which eight-digit number stimuli were recalled by reproduction on a numeric keypad. In one version, number stimuli were displayed on a video screen for varying lengths of time (3, 6, or 9 seconds) before immediate recall. In another version, subjects initially reproduced a continuously displayed number and then recalled the number following an immediate or a 16-second delay interval. Both triazolam and pentobarbital produced dose-related effects on all measures. Relative potency comparisons showed that triazolam was 270-384 times more potent than pentobarbital on subject ratings and psychomotor measures but was 406-647 times more potent than pentobarbital on measures of recall impairment. Recall performance deficits produced by both triazolam and pentobarbital at short (3-second) stimulus presentation times were attenuated at longer presentation times. With the variable delay task, triazolam but not pentobarbital interacted with the delay interval and produced impairments only at the 16-second delay condition. These data indicate that both triazolam and pentobarbital quantitatively impair acquisitional processes involved in short-term recall performance. Furthermore, triazolam may have a greater potential than pentobarbital to produce memory impairment, as reflected by its greater relative potency on these measures and its tendency to interfere with retention over short delay intervals.

Adult↗

PubMed1990

Low-dose caffeine physical dependence in humans.

This study investigated the effects of terminating low dose levels of caffeine (100 mg/day) in 7 normal humans. Substitution of placebo capsules for caffeine capsules occurred under double-blind conditions while subjects rated various dimensions of their mood and behavior. In the first phase of the study, substitution of placebo for 12 consecutive days resulted in an orderly withdrawal syndrome in 4 subjects which peaked on days 1 or 2 and progressively decreased toward prewithdrawal levels over about 1 week. Data from the remaining three subjects provided no evidence of withdrawal. In the second phase of the study, the generality of the withdrawal effect was examined by repeatedly substituting placebo for 100 mg/day of caffeine for 1-day periods separated by an average of 9 days. Despite differences within and across subjects with respect to the presence, nature and magnitude of symptoms, each of the seven subjects demonstrated a statistically significant withdrawal effect. Although the phenomenon of caffeine withdrawal has been described previously, the present report documents that the incidence of caffeine withdrawal is higher (100% of subjects), the daily dose level at which withdrawal occurs is lower (roughly equivalent to the amount of caffeine in a single cup of strong brewed coffee or 3 cans of caffeinated soft drink) and the range of symptoms experienced is broader (including headache, fatigue and other dysphoric mood changes, muscle pain/stiffness, flu-like feelings, nausea/vomiting and craving for caffeine) than heretofore recognized.

Adult↗

PubMed1990

Zolpidem and triazolam in humans: behavioral and subjective effects and abuse liability.

Zolpidem, which is currently marketed in Europe as a hypnotic, is a short-duration imidazopyridine whose actions are mediated at the gamma-aminobutyric acid benzodiazepine receptor complex. However, zolpidem produces a variety of biochemical differences from classic benzodiazepine agonists including showing selectivity for the central BZ1 (omega 1) receptor subtype as well as showing a different pattern of distribution of binding sites. This study compared zolpidem to the benzodiazepine hypnotic triazolam in 15 healthy male volunteers with histories of sedative drug abuse. Placebo, zolpidem (15, 30 and 45 mg) and triazolam (0.25, 0.5 and 0.75 mg) were administered p.o. in a mixed sequence in a double-blind, cross-over design. The onset time with zolpidem was faster than with triazolam, with peak effects of both drugs occurring at 1 to 2 hr after administration. Both zolpidem and triazolam produced dose-related decrements in performance on various performance tasks including circular lights, reaction time, balance, number recall and the digit symbol substitution test. Both drugs also produced similar dose-related changes on various observer ratings including overall strength of drug effect. Triazolam, but not zolpidem, increased subject- and observer-rated sleepiness and produced greater impairment on a picture memory task. Zolpidem, but not triazolam, produced increases in subject ratings of various somatic symptoms (e.g., dizzy, anxious and queasy) and there were 9 days on which subjects vomited after zolpidem, but none after triazolam. Although the highest dose of both drugs was identified by subjects as being active, the highest dose of triazolam was identified as being barbiturate, benzodiazepine or alcohol, almost twice as often as the highest dose of zolpidem. Overall, this study shows that although zolpidem produces many effects in common with triazolam, it also has a unique profile of effects distinguishable from classic benzodiazepine agonists. The mechanism(s) underlying these differences is unclear, but may be related to the atypical biochemical profile of zolpidem.

Adult↗

PubMed1990

Low-dose caffeine discrimination in humans.

A novel drug discrimination procedure was used to study the discriminability and subjective effects of caffeine in seven human volunteers who abstained from dietary sources of caffeine. Daily sessions involved p.o. ingestion of two capsules sequentially, one of which contained caffeine and the other placebo, under double-blind conditions. Each day subjects attempted to identify and were later informed which capsule contained caffeine and which contained placebo. All subjects acquired rapidly the initial discrimination (100 or 178 mg vs. placebo). Examination of progressively lower caffeine doses showed that accuracy and ratings of confidence in accuracy were increasing functions of dose. There were individual differences in the lowest discriminable dose: three subjects discriminated 56 mg, three discriminated 18 mg and one discriminated 10 mg. Discrimination accuracy was usually higher after the second capsule than after the first capsule. All subjects indicated that they believed that they made the discrimination predominantly on the basis of central effects of caffeine vs. placebo, such as changes in mood and socializing. Compared to placebo, 100 mg of caffeine increased ratings of alertness, well-being, social disposition, motivation for work, concentration, energy and self-confidence and decreased ratings of headache and sleepiness. This dose of caffeine also produced a large increase in a measure of "euphoria." The present study documents biological activity of caffeine at lower doses than heretofore recognized. The general approach to investigating the effects of low drug doses may have broad application in human psychopharmacology research for characterizing other subtle psychotropic effects.

Adult↗

PubMed1989

Behavioral differentiation of benzodiazepine ligands after repeated administration in baboons.

Baboons received repeated daily administration of saline, 5.6 mg/kg midazolam, 5.0 mg/kg flumazenil (Ro15-1788), 3.2 mg/kg 3-carboethoxy-beta-carboline hydrochloride (beta CCE) or 10 mg/kg beta CCE for 5 days. Behavioral signs of sedation and excitation were scored for 1 h after i.m. injections. Daily administration of these benzodiazepine-receptor ligands differentiated their behavioral effects; repeated midazolam resulted in tolerance to the sedative and ataxic effects; repeated beta CCE resulted in sensitization to its convulsant properties; and repeated flumazenil or saline produced no changes in behavior. In a second study, baboons received repeated injections of midazolam (5.6, 11.2 or 20 mg/kg per day) for 6 days. All three groups became tolerant to the sedative and ataxic effects of midazolam. Acute injections of flumazenil (5.0 mg/kg) on day 5 produced a dose-dependent withdrawal syndrome. This flumazenil treatment produced a slight attenuation in the degree of tolerance to midazolam on day 6, suggesting that receptor sensitivity to the benzodiazepine agonist may have partially reset.

Animals↗

PubMed1989

Differential generalization to pentobarbital in rats trained to discriminate lorazepam, chlordiazepoxide, diazepam, or triazolam.

In drug discrimination studies benzodiazepine-trained animals have typically responded on the drug lever when tested with barbiturates. In a recent study, greater specificity appeared to be shown when lorazepam was used as a training drug. The generality and limits of this finding were explored in the present set of experiments. The asymmetrical cross-generalization found in lorazepam- and pentobarbital-trained baboons was replicated in rats and was shown not to be a function of either lorazepam (0.1., 0.32, or 1.0 mg/kg) or pentobarbital (10 or 25 mg/kg) training dose (i.e., pentobarbital-trained rats responded on the drug lever in tests with lorazepam, but lorazepam-trained rats did not show comparable pentobarbital generalization). In the next experiment, groups of rats were trained to discriminate chlordiazepoxide (10 mg/kg), triazolam (0.1 mg/kg), or diazepam (1.0 mg/kg). Generalization to both lorazepam and pentobarbital was shown by these rats. Finally after daily pentobarbital administration, lorazepam-trained rats made a sufficient number of responses after high pentobarbital doses to permit extension of the range of pentobarbital doses tested. Pentobarbital generalization increased, but still did not occur in all rats and was unreliable in successive tests in the same rats. These results suggest less homogeneity in the discriminative stimulus effects of "depressant drugs" than generally has been recognized.

Animals↗

PubMed1989

Diazepam and triazolam self-administration in sedative abusers: concordance of subject ratings, performance and drug self-administration.

The reinforcing effects of diazepam (DZ), triazolam (TZ) and placebo were examined in eight male subjects with histories of sedative abuse. DZ (40 or 80 mg), TZ (1.0 or 2.0 mg) and placebo were each individually available for oral self-administration using a double-blind within-subject design. After an initial sampling exposure, subjects could self-administer a single dose of drug on each of 6 days by completing a progressively increasing bicycle riding requirement. All subjects initially self-administered DZ and TZ but a decreasing number of subjects continued to self-administer drugs on the remaining days; there was no difference between DZ and TZ in the total number of self-administrations. Placebo was self-administered only by one subject on two occasions. Performance measures showed that TZ produced greater memory impairment than DZ and that DZ produced residual psychomotor impairment on the next day. With repeated dosing, evidence of tolerance was seen for both drugs on psychomotor and memory performance and subject ratings of drug liking. A few modest correlations of drug self-administration and subject-ratings were obtained, suggesting some correspondence of subject verbal and drug self-administration behaviors, but these measures did not covary in a completely consistent manner.

Adult↗

PubMed1989

Reinforcing effects of caffeine in coffee and capsules.

In a residential research ward the reinforcing and subjective effects of caffeine were studied under double-blind conditions in volunteer subjects with histories of heavy coffee drinking. In Experiment 1, 6 subjects had 13 opportunities each day to self-administer either a caffeine (100 mg) or a placebo capsule for periods of 14 to 61 days. All subjects developed a clear preference for caffeine, with intake of caffeine becoming relatively stable after preference had been attained. Preference for caffeine was demonstrated whether or not preference testing was preceded by a period of 10 to 37 days of caffeine abstinence, suggesting that a recent history of heavy caffeine intake (tolerance/dependence) was not a necessary condition for caffeine to function as a reinforcer. In Experiment 2, 6 subjects had 10 opportunities each day to self-administer a cup of coffee or (on different days) a capsule, dependent upon completing a work requirement that progressively increased and then decreased over days. Each day, one of four conditions was studied: caffeinated coffee (100 mg/cup), decaffeinated coffee, caffeine capsules (100 mg/capsule), or placebo capsules. Caffeinated coffee maintained the most self-administration, significantly higher than decaffeinated coffee and placebo capsules but not different from caffeine capsules. Both decaffeinated coffee and caffeine capsules were significantly higher than placebo capsules but not different from each other. In both experiments, subject ratings of "linking" of coffee or capsules covaried with the self-administration measures. These experiments provide the clearest demonstrations to date of the reinforcing effects of caffeine in capsules and in coffee.

Adult↗

PubMed1989

Repeated diazepam administration: effects on the acquisition and performance of response chains in humans.

The effects of repeated diazepam administration (80 mg) were assessed across a 12-hr time course with humans responding under a two-component multiple schedule of repeated acquisition and performance of response sequences. Subjects resided in an inpatient clinical research ward for the duration of the study. In each component of the multiple schedule, subjects completed sequences of 10 responses in a predetermined order using three keys of a numeric keypad. In the acquisition component, a new response sequence was to be acquired each session. In the performance component, the response sequence always remained the same. After stable responding was obtained and the effects of the placebo assessed, diazepam was administered for 3 consecutive days. The effects of repeated diazepam administration on overall percentage of errors across the two components of the multiple schedule were selective. In the acquisition component, the first dose of diazepam increased percentage errors with the magnitude of effects decreasing across the second and third days of diazepam administration. In the performance component, the percentage of errors was either minimally affected across all 3 days of diazepam administration or substantively increased on Day 1 with subsequent diazepam administrations having minimal effects. Effects on response rate were not selective. Diazepam decreased rates of responding in both schedule components, with the magnitude of effects decreasing across successive administrations. These results replicate previous findings in humans and nonhumans on the selective effects of diazepam on acquisition versus performance baselines. Also, the results suggest that the selective effects do not result from differences in reinforcement rate. Finally, the present results demonstrate that the selective recovery from repeated drug administration previously demonstrated in nonhumans using a repeated acquisition arrangement has generality to human behavior.

Adult↗

PubMed1989