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Biomedical subjects

R R Griffiths

Publications and source records attributed to R R Griffiths.

At least 91 records · Page 5Linked to original sources
PubMed1992

Caffeine tolerance and choice in humans.

Thirty-two healthy subjects with histories of moderate caffeine consumption abstained from dietary caffeine throughout the study. Subjects were stratified into two groups based on several factors including caffeine preference, which was assessed using a caffeine versus placebo choice procedure. Subsequently, subjects received either caffeine (300 mg t.i.d.) or placebo (placebo t.i.d.) for 18 consecutive days, and thereafter were exposed again to a caffeine versus placebo choice procedure. The study documented tolerance development to the subjective effects of caffeine: after chronic dosing, administration of caffeine produced significant subjective effects in the chronic placebo group but not in the chronic caffeine group. The study also provided indirect evidence for tolerance development: during chronic dosing, the chronic caffeine and placebo groups did not differ meaningfully on ratings of mood and subjective effect. When subjects were categorized into caffeine choosers or nonchoosers, caffeine choosers tended to report positive subjective effects of caffeine and negative subjective effects of placebo. Nonchoosers, in contrast, tended to report negative subjective effects of caffeine. Chronic caffeine did not alter the reinforcing effects of caffeine as assessed by caffeine versus placebo choice, possibly because the relatively short duration of caffeine abstinence in the placebo condition was not sufficient to result in maximal withdrawal effects after termination of the relatively high caffeine dose. This study provides the clearest evidence to date of complete tolerance development to a CNS effect of caffeine in humans.

Adult↗
PubMed1992

Low-dose caffeine discrimination and self-reported mood effects in normal volunteers.

A caffeine versus placebo discrimination procedure was used to determine the lowest caffeine dose that could produce discrimination and self-reported mood effects in normal volunteers. During daily sessions under double-blind conditions, caffeine-abstinent subjects orally ingested a capsule containing 178 mg caffeine or placebo. Before beginning discrimination training, the compounds were identified to subjects by letter codes. Fifteen, 30, and 45 min after capsule ingestion, subjects guessed the capsule's letter code. Correct guesses at 45 min earned money. After each session, subjects received a supplementary capsule containing caffeine or placebo to ensure that, within each phase of the study, subjects received the same daily dose of caffeine equal to the training dose. Five of the 15 subjects acquired the caffeine versus placebo discrimination within the first 20 sessions (greater than or equal to 75% correct); 6 other subjects acquired the discrimination with additional training. Nine subjects who acquired the discrimination were subsequently trained at progressively lower caffeine doses. In general, the lowest dose to produce discrimination (greater than or equal to 75% correct) was also the lowest dose to produce self-reported mood effects: 4 subjects showed discrimination and self-reported mood effects at 100 mg caffeine, 2 at 56 mg, 1 at 32 mg, and 1 at 18 mg. One of these subjects also showed self-reported mood effects at 10 mg. The present study documents discriminative stimulus and self-reported mood effects of caffeine at doses below those previously shown to affect any behavior in normal volunteers.

Adult↗
PubMed1992

Zolpidem behavioral pharmacology in baboons: self-injection, discrimination, tolerance and withdrawal.

This study examined in baboons various behavioral effects of zolpidem, a short-acting imidazopyridine hypnotic which has selectivity for subtypes of the benzodiazepine receptor. Intravenous drug self-injection was studied under a fixed-ratio 80- or 160-response schedule with a 3-hr timeout after each injection. Maximal rates of self-injection maintained by zolpidem (0.01-1 mg/kg) were consistently higher than those maintained by vehicle and the benzodiazepine hypnotic triazolam. Substitution of vehicle after about 2 weeks of zolpidem self-injection (7-8 mg/kg/day) resulted in a time-limited suppression of food pellet intake, indicating a drug withdrawal effect. In a drug discrimination study, baboons were trained to discriminate either lorazepam (1.8 mg/kg p.o.) or pentobarbital (10 mg/kg p.o.) from the no-drug condition. Zolpidem (0.1-18 mg/kg p.o.) occasioned both lorazepam- and pentobarbital-appropriate responding (greater than 80%) in a dose-dependent manner. In a final experiment, zolpidem (3.2 or 5.6 mg/kg i.m.) produced ataxia and sedation that progressively decreased over 7 consecutive days of administration. The withdrawal, discriminative stimulus effects and tolerance shown with zolpidem were similar to those shown previously with benzodiazepines under similar conditions. The rates of self-injection of zolpidem were similar to those maintained by intermediate duration barbiturates (e.g., pentobarbital) and higher than those maintained by 11 benzodiazepines studied previously under similar conditions. Further research on the reinforcing effects of zolpidem may provide useful insights into mechanisms underlying the maintenance of behavior by compounds acting through the benzodiazepine receptor.

Animals↗
PubMed1992

Subjective and behavioral effects of diphenhydramine, lorazepam and methocarbamol: evaluation of abuse liability.

The effects of orally administered placebo, diphenhydramine, lorazepam, methocarbamol and placebo were studied in volunteers with histories of recreational substance abuse including sedative/hypnotics. Placebo, diphenhydramine (100, 200 and 400 mg), lorazepam (1 and 4 mg) and methocarbamol (2.25 and 9 g) were tested in a randomized, double-blind crossover study using 14 subjects. Psychomotor and cognitive performance and subject- and observer-rated responses were measured daily before and for 5.5 hr after drug administration. The results showed that each of the drugs exhibited a different profile of effects on the test battery. Lorazepam produced significant increases in subjects' ratings of drug effect and liking, increases in measures of sedation and impairment of psychomotor performance. Methocarbamol also produced significant increases in subjects' ratings of drug effect and liking and measures of sedation, but it produced only minor impairment of psychomotor and cognitive performance. Diphenhydramine increased subjects' and observers' ratings of drug effect and measures of sedation, but it produced less psychomotor performance impairment and liking than lorazepam. Diphenhydramine produced the most side effects. The present study clearly differentiated the behavioral and subjective profiles of diphenhydramine, lorazepam and methocarbamol. Consistent with its recognized low abuse liability, diphenhydramine produced fewer increases in measures of positive mood and more adverse effects. The considerable overlap in subjective effect measures of positive mood make further differentiation with respect to abuse liability difficult.

Adult↗
PubMed1991

Physical dependence on benzodiazepines: differences within the class.

Concern about physical dependence seems to be the major limiting factor in the long-term treatment with benzodiazepines (BZD). The severity of the withdrawal syndrome is determined by multiple factors, e.g. dose, duration of use, frequency of dose interval, mode of discontinuation, the pharmacologic characteristics of the BZD, personality and previous or concurrent use of cross-dependent drugs and/or alcohol. There is evidence that BZD with a short elimination half-life cause a more severe withdrawal syndrome than those with a long elimination half-life. Besides pharmacokinetic properties, pharmacodynamic factors such as potency may also covary with the liability of a BZD to induce physical dependence. There is an increasing body of literature indicating that quickly eliminated, high potency BZD such as alprazolam and lorazepam may be more likely to cause severe withdrawal reactions than slowly eliminated compounds such as diazepam or less potent derivatives such as oxazepam. Alprazolam seems to play an exceptional role, insofar as relatively soon after its introduction to the market a number of case reports of withdrawal psychoses, seizures and intense rebound anxiety were published. Data reviewed from the literature correspond well with the results of interviews conducted with 31 clinicians across the United States with experience in detoxifying patients dependent on BZD, 84% of these physicians mentioning alprazolam as especially problematic with respect to the intensity and/or duration of the withdrawal syndrome.

Anti-Anxiety Agents↗
PubMed1991

Behavioral effects of benzodiazepine ligands in non-dependent, diazepam-dependent and diazepam-withdrawn baboons.

Acute i.m. injections of benzodiazepine receptor ligands were administered to baboons before 1-h observational sessions. The agonist midazolam produced sedative effects, the antagonist flumazenil produced no behavioral effects, the inverse agonist FG7142 produced tremor and the inverse agonist 3-carboethoxy-beta-carboline hydrochloride (beta CCE) produced tremor, vomiting, jerks and seizures. Co-administration of these drugs (midazolam + beta CCE, midazolam + flumazenil or flumazenil + beta CCE) produced a mutual antagonism of these effects. Compared to the non-dependent condition, in the diazepam-dependent condition (baboons maintained on 20 mg/kg per day diazepam) and withdrawn condition (dependent baboons tested during withdrawal), midazolam produced decreased sedative effects, flumazenil produced increased effects (i.e., tremor, vomiting and jerks), and beta CCE produced increased frequency of seizures. Taken together, these data suggest that (1) benzodiazepine receptor ligands lie on a continuum of behavioral activity, and (2) chronic diazepam administration alters the behavioral effects of these benzodiazepine ligands, producing a shift in the direction of the inverse agonist.

Animals↗
PubMed1991

Self-injection of barbiturates, benzodiazepines and other sedative-anxiolytics in baboons.

Self-injection of 12 sedative-anxiolytics was examined in baboons. Intravenous injections and initiation of a 3-h time-out were dependent upon completion of a fixed-ratio schedule requirement, permitting eight injections per day. Before testing each dose of drug, self-injection performance was established with cocaine. Subsequently, a test dose was substituted for cocaine. At some doses, all five of the benzodiazepines examined (alprazolam, bromazepam, chlordiazepoxide, lorazepam, triazolam) maintained rates (number of injections per day) of drug self-injection above vehicle control in each of the baboons tested. Maximum rates of benzodiazepine self-injection were generally submaximal. Of the benzodiazepines examined, triazolam maintained the highest rates of self-injection. Among the three barbiturates tested, methohexital generally maintained high rates of self-injection in contrast to hexobarbital and phenobarbital, which only maintained low rates. Of the four non-benzodiazepine non-barbiturate sedatives examined, both chloral hydrate and methyprylon occasionally maintained high rates of self-injection. Although there were differences within and across animals, baclofen maintained intermediate rates of self-injection. The novel anxiolytic buspirone maintained only low rates of self-injection that were not different from vehicle. This study further validates the self-injection methodology for assessing sedative-anxiolytic abuse liability and provides new information about drug elimination rate as a determinant of drug self-administration.

Animals↗
PubMed1991

Comparison of the discriminative stimulus effects of midazolam after intracranial and peripheral administration in the rat.

Rats were trained in a two-lever drug discrimination paradigm to discriminate midazolam (0.32 mg/kg, i.p. or 1.0 mg/kg, i.p.) from the no-drug condition. After completion of i.p. and s.c. midazolam generalization gradients (0.032-1.0 mg/kg), rats were surgically implanted with unilateral cannulae into the lateral ventricles. Intracerebroventricular (i.c.v.) doses of 1.1-44.2 micrograms midazolam were delivered to unrestrained rats. Midazolam produced dose-dependent increases in drug-appropriate responding by all three routes of administration, but was 2.4- to 4.3-fold more potent when given i.c.v. than when given s.c. or i.p. Midazolam, over the dose range tested, did not produce substantial decreases in response rate by any route of administration. The discriminative-stimulus effect of i.c.v. midazolam was blocked by peripherally administered flumazenil, and such antagonism was surmounted by a 2- to 5-fold increase in the i.c.v. midazolam dose. Taken together, these data suggest that the discriminative-stimulus effects of midazolam are mediated via central benzodiazepine (BZ) receptors.

Animals↗
PubMed1991

Testing the abuse liability of anxiolytic and hypnotic drugs in humans.

This paper represents a comprehensive review of laboratory studies investigating the abuse liability of anxiolytic and hypnotic drugs in humans. The subjective effects of these drugs, most of which are either barbiturates or benzodiazepines, have been measured using various self-report questionnaires and their reinforcing effects have been studied using self-administration and choice procedures. Studies using both subjective and reinforcing effects reveal orderly relations between the two main chemical classes of anxiolytic/hypnotics (e.g. barbiturates are associated with higher abuse liability than benzodiazepines), between different doses of the drugs (e.g. higher doses are usually associated with higher abuse liability) and among different compounds within a class. The subjective and reinforcing effects of barbiturates and benzodiazepines depend critically upon the subject populations that are tested and it is argued that individuals with histories of drug abuse provide a more sensitive indicator of abuse liability than healthy volunteers. Several principles of abuse liability testing are discussed, including the selection of an appropriate subject population, the use of blind drug administration procedures, the comparison of a test compound to an appropriate standard, the inclusion of a placebo and a wide range of doses of the test drug and the use of multiple measures of likelihood of abuse.

Anti-Anxiety Agents↗
PubMed1991

Abuse liability assessment of anxiolytics/hypnotics: rationale and laboratory lore.

This paper describes the rationale, practical details, and laboratory lore relevant to conducting an acute dose-effect crossover evaluation for abuse liability of a novel anxiolytic/hypnotic compound relative to a standard compound. Basic principles underlying meaningful abuse liability assessments are presented and illustrated with examples from a comparative evaluation of the hypnotics zolpidem and triazolam. These principles include using a double-blind placebo-controlled design, selecting an appropriate comparison compound, evaluating a wide range of doses including supratherapeutic doses, using subjects with histories of sedative drug abuse, and using a range of dependent measures. The dose-effect crossover evaluation is proposed as a crucial first step in any rigorous drug abuse liability evaluation of a novel anxiolytic or hypnotic drug. Such a study can be expected to generate a broad data base which not only provides a prediction about the likelihood of abuse of the novel compound, but provides an assessment of some of the adverse consequences of recreational abuse. The crossover study also establishes parameters for subsequent studies such as direct assessment of reinforcing effects with drug self-administration testing.

Anti-Anxiety Agents↗
PubMed1990

Self-administration in baboons and the discriminative stimulus effects in rats of bupropion, nomifensine, diclofensine and imipramine.

The behavioral effects of the antidepressants nomifensine, diclofensine, bupropion, and imipramine were examined using a cocaine substitution drug self-administration procedure in baboons and a cocaine drug discrimination procedure in rats. Intravenous self-administration of the antidepressants was examined in baboons under conditions in which baseline responding was maintained by intravenous injections of cocaine HCl (0.32 mg/kg/injection). Drug was available under a fixed-ratio 80-response or 160-response schedule of intravenous injection. Each drug injection was followed by a 3-h time-out allowing a maximum of eight injections per day. The antidepressants or their vehicles were substituted for cocaine for a period of 15 days, followed by a return to the cocaine baseline. Nomifensine, diclofensine and bupropion all maintained self-administration behavior at levels above those maintained by their respective vehicles. Some doses of nomifensine, diclofensine, and bupropion maintained levels of behavior similar to those maintained under baseline cocaine conditions. High doses of imipramine maintained levels of behavior above those maintained by its vehicle, but the amount of behavior maintained under these conditions was extremely small. In a second experiment rats were trained to discriminate 32 mumol/kg cocaine (IP 10 min presession) from no drug in a two-lever food reinforced drug discrimination procedure in which responding on one lever was reinforced following ten consecutive responses when the session was preceded by cocaine administration, while responding on the other lever was similarly reinforced in the absence of cocaine pretreatment. Cocaine, nomifensine, diclofensine, and bupropion all dose-dependently occasioned cocaine-appropriate responding. Imipramine did not occasion cocaine-appropriate responding over a range of behaviorally active doses.

Animals↗
PubMed1990

Intravenous self-administration of 4-methylaminorex in primates.

The reinforcing effects of (+/-)-cis-2-Amino-4-methyl-5-phenyl-2-oxazoline (4-methylaminorex) were determined in two models of intravenous drug self-administration in primates. In baboons, lever pressing was maintained under a fixed-ratio (FR) 80- or 160-schedule of intravenous cocaine delivery (0.32 mg/kg per injection). Each drug injection was followed by a 3-h time-out allowing a maximum of 8 injections per day. Vehicle or 4-methylaminorex doses were substituted for cocaine for a period of 15 or more days. One of the two 4-methylaminorex doses evaluated (0.32 mg/kg per injection) maintained self-administration behavior above vehicle control levels in all four animals. This dose of 4-methylaminorex maintained cyclic patterns of self-injection behavior across days and produced signs of psychomotor stimulant toxicity. In rhesus monkeys, 4-methylaminorex (0.0003-0.1 mg/kg per injection) was made available to animals trained to self-administer cocaine (0.01 or 0.033 mg/kg per injection) under an FR 10 schedule of reinforcement during daily 1-h sessions. Each of the three monkeys self-administered at least two doses of 4-methylaminorex at rates exceeding those maintained by vehicle injections. Taken together with reports of recreational abuse of 4-methylaminorex, the present results indicate that this drug has a potential for abuse similar to that of other psychomotor stimulants.

Animals↗
PubMed1990

Relative abuse liability of different benzodiazepines in drug abusers.

There is a convergence of data from various sources suggesting that there are meaningful differences among the benzodiazepines with respect to their attractiveness as drugs of abuse for drug abusers. Laboratory studies of subjective and reinforcing effects in drug abusers, interviews with drug abusers, clinical judgment of medical professionals, and epidemiological studies all indicate that diazepam, in particular, has a greater abuse liability than many of the other benzodiazepines. Some of the available data also suggest that lorazepam and alprazolam are more diazepam-like in having relatively high abuse liability, while oxazepam, halazepam, and possibly chlordiazepoxide, are relatively low in this regard. These differences in abuse liability among benzodiazepines are analogous to the widely recognized differences in abuse liability within the barbiturate class that have proved to be important in helping guide clinicians' drug prescribing practices.

Anti-Anxiety Agents↗