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Biomedical subjects

R R Griffiths

Publications and source records attributed to R R Griffiths.

At least 55 records · Page 3Linked to original sources
PubMed1997

The role of dopamine in the behavioral effects of caffeine in animals and humans.

Dopamine has been proposed to mediate some of the behavioral effects of caffeine. This review discusses cellular mechanisms of action that could explain the role of dopamine in the behavioral effects of caffeine and summarizes the results of behavioral studies in both animals and humans that provide evidence for a role of dopamine in these effects. Caffeine is a competitive antagonist at adenosine receptors and produces a range of central and physiological effects that are opposite those of adenosine. Recently, caffeine has been shown to enhance dopaminergic activity, presumably by competitive antagonism at adenosine receptors that are colocalized and interact functionally with dopamine receptors. Thus, caffeine, as a competitive antagonist at adenosine receptors, may produce its behavioral effects by removing the negative modulatory effects of adenosine from dopamine receptors, thus stimulating dopaminergic activity. Consistent with this interpretation, preclinical behavioral studies show that caffeine produces behavioral effects similar to classic dopaminergically mediated stimulants such as cocaine and amphetamine, including increased locomotor activity, increased turning behavior in 6-hydroxydopamine-lesioned animals, stimulant-like discriminative stimulus effects, and self-administration. Furthermore, caffeine potentiates the effects of dopamine-mediated drugs on these same behaviors, and some of caffeine's effects on these behaviors can be blocked by dopamine receptor antagonists. Although more limited in scope, human studies also show that caffeine produces subjective, discriminative stimulus and reinforcing effects that have some similarities to those produced by cocaine and amphetamine.

Animals↗
PubMed1997

Acute participant-rated and behavioral effects of alprazolam and buspirone, alone and in combination with ethanol, in normal volunteers.

The acute behavioral effects of buspirone (15 and 30 mg/70 kg), alprazolam (0.75 and 1.5 mg/70 kg), and placebo, alone and in combination with ethanol (0-0.6 g/kg), were tested in 13 volunteers. Ethanol alone produced only a few significant behavioral effects. Alprazolam and buspirone produced comparable dose-related increases in participant ratings of sedation, but only alprazolam impaired performance. The buspirone-ethanol and alprazolam-ethanol combinations produced robust sedative-like participant-related drug effects that were similar in magnitude, but, in general, only the alprazolam-ethanol combinations impaired performance. These findings suggest that the participant-rated effects of therapeutic doses of buspirone in combination with moderate doses of ethanol are similar to those of therapeutic doses of alprazolam in combination with ethanol, but the performance-impairing effects of buspirone are distinguishable from those of alprazolam, alone and in combination with ethanol.

Adult↗
PubMed1997

Ethanol and pentobarbital: comparison of behavioral and subjective effects in sedative drug abusers.

The behavioral and subjective effects of acute oral doses of placebo, ethanol (0.5, 1.0, and 2.0 g/kg), and pentobarbital (150, 300, 600, and 750 mg/70 kg) were compared in 8 male volunteers with histories of sedative drug abuse using a double-blind, double-dummy, cross-over design. Ethanol and pentobarbital produced similar dose-related decrements in psychomotor and cognitive performance and exhibited a similar profile of effects on staff- and participant-rated measures. There was some evidence indicating that, at the highest dose, pentobarbital was perceived by participants as being more sedating than ethanol and that pentobarbital has a greater abuse liability than ethanol. In conjunction with the results of previous human laboratory studies comparing the effects of different types of sedative-hypnotic drugs, these results support a mostly barbiturate-like rather than benzodiazepine-like profile of effects for ethanol.

Adult↗
PubMed1997

Triazolam and zolpidem: a comparison of their psychomotor, cognitive, and subjective effects in healthy volunteers.

The psychomotor/cognitive performance, subject-rated, and observer-rated effects of single oral doses of the benzodiazepine hypnotic triazolam (0.125, 0.25, and 0.5 mg/70 kg) and the imidazopyridine hypnotic zolpidem (5, 10, and 20 mg/70 kg) were compared in 11 volunteers, in a double-blind, placebo-controlled, crossover design. Triazolam and zolpidem produced similar dose-related decrements on several performance measures, and similar dose-related increases on most observer-rated and several subject-rated measures. The drugs differed in the time course of their effects on these measures; the effects of zolpidem typically peaked 30 min earlier (1-1.5 h postdrug) than the effects of triazolam (1.5-2 h postdrug). Triazolam and zolpidem produced a different profile of effects on other performance measures which could not be attributed to time course differences. Triazolam produced significantly more impairment than zolpidem in time estimation. Triazolam, but not zolpidem, produced significant impairment on a short-term memory task. Zolpidem produced significantly more impairment than triazolam on several novel measures of performance on a computerized trail-making test. The observed differences between triazolam and zolpidem may be related to zolpidem's reported binding selectivity for the omega 1 receptor subtype.

Adult↗
PubMed1997

Human drug discrimination and multiple chemical sensitivity: caffeine exposure as an experimental model.

Multiple chemical sensitivity is a controversial diagnosis. Rigorous, controlled, laboratory-based research can reduce this controversy and lead to potential clinical confirmatory tests. The literature on human caffeine discrimination provides a rigorous methodology that can address reports that patients who suffer multiple chemical sensitivity (MCS) are sensitive to usually well-tolerated chemical doses; the studies require patients to discriminate caffeine from placebo under double-blind conditions. Several issues relevant to the conduct of caffeine discrimination studies using MCS patients as subjects are addressed; these issues include study design, determination of safe and tolerable training doses, and discrimination training. Such research will benefit patients and clinicians dealing with a diagnosis of MCS.

Caffeine↗
PubMed1997

Selectivity in the generalization profile in baboons trained to discriminate lorazepam: benzodiazepines, barbiturates and other sedative/anxiolytics.

The discriminative stimulus effects of benzodiazepines often have been indistinguishable from those of barbiturates or other sedative/anxiolytics. However, baboons and rats trained to discriminate lorazepam did not reliably generalize to pentobarbital in previous studies, although animals comparably trained to discriminate pentobarbital reliably generalized to lorazepam. The present study investigated the generalization profile for a variety of anxiolytic, sedative and other drugs in baboons trained to discriminate oral lorazepam (1.8 mg/kg). Triazolam, alprazolam, diazepam, midazolam, bromazepam, temazepam and nordiazepam occasioned >80% of total responses on the lorazepam-paired lever, in that order of potency, 60 min after oral dosing; chlordiazepoxide did so in three of five baboons. However, barbiturates (amobarbital, hexobarbital, methohexital, pentobarbital, phenobarbital, secobarbital) and methypryIon occasioned lorazepam-appropriate responding in only one or two baboons. Testing barbiturates at different pretreatment times (amobarbital, hexobarbital, pentobarbital or secobarbital) or by an i.m. route of administration (methohexital, pentobarbital) did not produce an increase in generalization. Neither other classic sedatives/anxiolytics (chloral hydrate, clomethiazole, ethanol, methaqualone, meprobamate, triclofos), nor anticonvulsants (phenytoin, valproic acid), nor drugs from other pharmacological classes shared discriminative-stimulus effects with lorazepam. These results, together with those from previous studies in which lorazepam or another benzodiazepine served as the training stimulus, indicate that lorazepam training results in a more selective generalization profile with respect to sedative/anxiolytic drugs than does training with other benzodiazepines.

Animals↗
PubMed1996

Preference for diazepam, but not buspirone, in moderate drinkers.

The purpose of the present study was to determine the preference for buspirone, an anxiolytic predicted to have minimal abuse potential, in comparison with diazepam in moderate drinkers. Preference for diazepam and buspirone was assessed in 55 moderate drinkers using a seven-session procedure consisting of four sampling sessions followed by three choice sessions. On each sampling session subjects ingested five capsules, one every 30 min. Color-coded capsules contained placebo on two sessions and drug on two sessions. Each drug capsule contained diazepam (4 mg) for 30 subjects and buspirone (5 mg) for 25 subjects. On choice sessions subjects chose whichever of the two color-coded capsules, i.e., drug or placebo, they wished to take. After ingesting one capsule, every 30 min they had the option of ingesting another capsule of the same color and content, for a maximum of seven capsules over the session (maximum of 28 mg diazepam or 35 mg buspirone). In the diazepam group 70% of subjects chose diazepam over placebo on at least two of the three choice sessions, whereas in the buspirone group only 24% of subjects chose buspirone over placebo on at least two sessions. Both diazepam and buspirone increased measures of sedation. Only diazepam increased ratings of liking and impaired performance, whereas only buspirone decreased ratings of feeling Friendly. These results replicate previous findings indicating that diazepam has reinforcing effects in moderate drinkers. Further, these results demonstrate the pharmacological specificity of this effect by showing that buspirone did not function as a reinforcer under these same conditions.

Adult↗
PubMed1996

Drug tasting may confound human drug discrimination studies.

Unpublished observations suggested that some subjects in human drug discrimination studies acquired a drug versus placebo discrimination by tasting the capsule contents. To evaluate the prevalence of this behavior and to develop approaches to circumvent this problem, 30 normal human subjects participated in a drug discrimination study in which the study capsules (i.e., lactose and lactose + quinine) could be discriminated by tasting the capsule contents but were otherwise pharmacologically indistinguishable. Twenty percent of the subjects significantly discriminated between the capsules; this discrimination was disrupted by employing thorough mouth checks following capsule administration. Based on these findings, we recommend that human drug discrimination studies incorporate procedures that minimize the possibility of drug tasting by requiring consumption of sufficient fluid in combination with rigorous mouth checks to ensure capsule swallowing.

Adult↗
PubMed1996

Mecamylamine does not precipitate withdrawal in cigarette smokers.

Mecamylamine is an antihypertensive that acts via nicotinic antagonism and has been suggested as an aid in smoking cessation. Nicotine dependent patients may not accept mecamylamine if it precipitates withdrawal, as it does in nicotine dependent rats. This study examined mecamylamine's effects using procedures designed to measure precipitated withdrawal symptoms in humans. Ten cigarette smokers (mean of 37.5 cigarettes/day) and ten non tobacco-using subjects participated in three 6-h sessions. After a 2-h baseline period in which smokers smoked one cigarette every 30 min, oral mecamylamine (0, 10, or 20 mg randomly ordered across sessions) was administered (double-blind). No smoking was allowed for the remainder of the session. Mecamylamine reduced blood pressure and increased heart rate relative to placebo in both the smokers and the non-tobacco users. No reliable direct subjective effects of mecamylamine were observed. Smokers' subjective reports of cigarette craving and tobacco withdrawal increased, and DSST performance was disrupted over the last 4 h of each session. Effects were independent of dose (placebo versus active). These results suggest that up to 20 mg mecamylamine will not precipitate nicotine withdrawal and that this medication would be acceptable for use in smoking cessation.

Adult↗
PubMed1996

Absorption rate of methylxanthines following capsules, cola and chocolate.

OBJECTIVE: To compare caffeine and theobromine absorption after oral administration of capsules, cola beverage and chocolate candy. METHODS: Three males and four females who abstained from methylxanthines received five methylxanthine-containing treatments: caffeine in capsules (72 mg), administered twice; theobromine in capsules (370 mg); cola beverage (72 mg caffeine) and chocolate candy (72 mg caffeine and 370 mg theobromine). Plasma methylxanthine levels were assayed from samples collected before and 0.25, 0.50, 0.75, 1.0, 1.5, 2.0, and 3.0 h after caffeine capsule and cola treatments and, additionally, at 4.0 and 6.0 h after theobromine capsule and chocolate treatments. RESULTS: Caffeine plasma concentrations increased rapidly and peaked at approximately 30 min following both capsule treatments 1 (Cmax: 1.93 micrograms.ml-1); and 2 (Cmax: 2.05 micrograms.ml-1). Relative to capsules, caffeine absorption from cola and chocolate was delayed and produced lower maximum caffeine plasma concentrations which peaked 1.5-2.0 h after treatment (For cola, Cmax: 1.57 micrograms.ml-1); and for chocolate, Cmax: 1.50 micrograms.ml-1. Theobromine plasma concentrations peaked approximately 3 h after capsule administration (Cmax: 6.72 micrograms.ml-1). Relative to capsules, theobromine absorption from chocolate was more rapid and produced higher maximum theobromine plasma concentrations which peaked approximately 2 h after treatment (Cmax: 8.05 micrograms.ml-1). CONCLUSIONS: The results suggest that a usual dietary portion of the cola or chocolate used in this study would produce behaviorally discriminable plasma levels of caffeine in most subjects and of theobromine in at least one subject.

Absorption↗
PubMed1996

Zolpidem, triazolam, and temazepam: behavioral and subject-rated effects in normal volunteers.

Zolpidem is an imidazopyridine hypnotic that is biochemically distinct from classic benzodiazepine agonists in that it may be selective for the BZ1 receptor subtype and shows a different pattern of distribution of binding sites. The present study compared the learning, recall, performance, subject-rated and observer-rated effects of zolpidem, triazolam, and temazepam in 11 healthy humans. Placebo, zolpidem (5, 10, and 20 mg/70 kg), triazolam (0.125, 0.25, and 0.50 mg/70 kg), and temazepam (15, 30, and 60 mg/70 kg) were administered orally in a randomized, double-blind, cross-over design. Zolpidem, triazolam, and temazepam produced orderly dose- and time-related impairment of learning, recall, and performance, and increased subject- and observer-rated estimates of strength of drug effect. The absolute magnitude of these effects at peak effect were comparable across the three compounds. The time to maximal drug effect was faster with zolpidem (0.5-1.0 hours) than with triazolam (1.5-2.0 hours) or temazepam (2-3 hours). These results suggest that despite the somewhat unique benzodiazepine receptor-binding profile of zolpidem, its behavioral and subject-rated effects are similar to those of benzodiazepine hypnotics (i.e., triazolam and temazepam).

Adult↗
PubMed1995

Alprazolam absorption kinetics affects abuse liability.

OBJECTIVE: To evaluate the behavioral, subjective, and reinforcing effects of immediate-release (IR) alprazolam and extended-release (XR) alprazolam to assess the effect of release rate on laboratory measures of abuse liability. METHODS: Fourteen healthy men with histories of sedative abuse participated as subjects in a double-blind crossover study. All subjects received placebo, 1 and 2 mg immediate-release alprazolam, and 2 and 3 mg extended-release alprazolam in random order. Behavioral performance, subjective effects, and alprazolam plasma concentrations were assessed repeatedly 1/2 hour before and 1/2, 1, 3, 5, 7, 9, 12, and 24 hours after drug administration. RESULTS: Mean peak alprazolam plasma concentrations occurred 1.7 and 9.2 hours after immediate-release alprazolam and extended-release alprazolam, respectively. Compared to placebo, 2 mg immediate-release alprazolam impaired all measures of psychomotor and cognitive performance (Digit Symbol Substitution Test), motor coordination (circular lights and balance), and memory (digit entry and recall); 2 mg extended-release alprazolam did not affect any of these measures and 3 mg extended-release alprazolam impaired circular lights only. Immediate-release alprazolam, 2 mg, increased all six measures of positive drug effects (e.g., ratings of liking or good effects); none of these measures were increased by 2 mg extended-release alprazolam and only three of the six measures were increased by 3 mg extended-release alprazolam. A drug versus money multiple-choice procedure designed to assess the relative reinforcing effects of each condition was administered 24 hour after the drug. The amount of money subjects were willing to "pay" to take the drug was significantly greater than placebo for both doses of immediate-release alprazolam but for neither dose of extended-release alprazolam. CONCLUSIONS: These data indicate that extended-release alprazolam has less potential for abuse than immediate-release alprazolam.

Adult↗
PubMed1995

Evaluating the reinforcement value of clinic-based privileges through a multiple choice procedure.

A novel multiple choice procedure was utilized to evaluate the potential reinforcement value of three clinic-based incentives available during routine methadone treatment: methadone take-homes, methadone dose increases, and extra counseling. Fourteen methadone maintenance patients who were not earning any of these incentives completed a multiple choice form in which they made choices between pairs of incentives and subsequently between each incentive and a series of monetary values. Choice behavior was intermittently reinforced by randomly awarding to patients one of their chosen preferences. Results demonstrated that take-homes were worth US$20.24 and were rated as more desirable than dose increases (US$13.89) and extra counseling (US$7.47). The study updates and extends past research in this area and provides a methodology for establishing both a monetary value for clinic-based incentives and an absolute magnitude between preferences. The procedure could be used to examine a larger number of potential reinforcers and to understand individual differences in responding to incentive-based treatment programs.

Adult↗
PubMed1995

Discriminative stimulus effects of diazepam and buspirone in normal volunteers.

A within-subject design was used to characterize the effects of dose manipulations on discriminative and self-reported effects of oral diazepam and buspirone. Subjects were trained to discriminate diazepam (10 mg) versus placebo (n = 10), or buspirone (10 or 15 mg) versus placebo (n = 9). The compounds were identified to subjects by letter code before discrimination training began. In later sessions, correct identifications at 2 hr after the oral administration of drug earned money. All subjects showed accurate discrimination performance during the test-of-acquisition phase. In a low-dose generalization phase, diazepam and buspirone produced dose-related increases in drug identifications across a four-fold range of doses. In a subsequent low-dose training phase, in which subjects were trained to discriminate progressively lower drug doses, the median lowest discriminable dose of diazepam and buspirone was 2.5 and 7.5 mg, respectively. Dose-response functions for drug identifications were shifted leftward in the low-dose training phase relative to the low-dose generalization phase, suggesting that reinforcement of progressively lower doses enhances drug discriminability. The self-reported effects of diazepam and buspirone were similar (e.g., both drugs increased ratings of drug strength and clumsy/uncoordinated) and different (e.g., diazepam but not buspirone increased ratings of drowsy/sleepy; buspirone but not diazepam increased ratings of tense/nervous). This study demonstrates discriminative and self-reported effects of diazepam and buspirone at doses lower than previously shown to be behaviorally active, and suggests that at commonly used clinical doses, diazepam is relatively more discriminable than buspirone.

Administration, Oral↗
PubMed1995

Intravenous caffeine in stimulant drug abusers: subjective reports and physiological effects.

The present study was conducted to examine the self-reported (i.e., subjective) and physiological effects of intravenous caffeine in 10 subjects with histories of stimulant drug abuse. Under double-blind conditions, subjects received each dose of caffeine (0, 37.5, 75, 150 or 300 mg/70 kg) twice according to a latin-square design; injections were 10 sec in duration and separated by at least 24 hr. Effects were measured before injection and repeatedly afterward for 60 min. Caffeine dose-dependently increased ratings of positive mood (e.g., increased ratings of drug liking and high), which peaked at 2 min after injection and progressively decreased. Caffeine also dose-dependently increased the frequency of stimulant identifications on the Pharmacological Class Identification Questionnaire (e.g., like cocaine, amphetamine). Caffeine also produced negative-mood effects (e.g., increased ratings of bad effects) and increases in self-reported desire for cocaine. In contrast to the positive-mood effects, the negative-mood effects were of smaller magnitude and only significant at the highest dose. Caffeine increased reports of unusual smells and tastes. Caffeine decreased heart rate (7 bpm) and skin temperature (4 degrees C), and increased systolic and diastolic blood pressures (8 and 6 mm Hg, respectively). The mood effects but not the physiological effects of intravenous caffeine were similar to those previously observed with cocaine in studies using similar methods and subjects. Intravenous caffeine administration may provide a useful model system for investigating factors relevant to the use and abuse of stimulant drugs.

Adult↗