Biomedical subjects

R R Griffiths

Publications and source records attributed to R R Griffiths.

At least 37 records · Page 2Linked to original sources

PubMed1999

Evaluation of the intravenous reinforcing effects of clonidine in baboons.

Clonidine HCl is an antihypertensive that is also sometimes used to alleviate symptoms of withdrawal during narcotics detoxification. Recently, there have been reports abuse of clonidine by methadone patients and opioid abusers. The present study evaluated the intravenous self-administration of clonidine in four baboons. Self-injections were available 24 h/day under a fixed-ratio (FR 120 or 160) schedule of injection with a 3-h timeout after each injection. Doses of clonidine (0.0001-0.056 mg/kg per injection) or its vehicle (saline) were substituted for cocaine (0.32 mg/kg) for at least 15 days. Food pellets were available continuously under a concurrent FR 30 schedule of pellet delivery. Clonidine maintained self-injection greater than its saline vehicle in all four baboons. Although self-injection of clonidine increased as a function of dose within each baboon, there were differences between baboons in the range of doses of clonidine that maintained self-injection. Doses of 0.032 or 0.056 mg/kg maintained peak mean levels of clonidine self-injection which ranged from low (3.2 injections/day) to high (> 6 injections/day) across baboons. Levels of self-injection were similar to vehicle at 0.01 mg/kg clonidine in two of four baboons. However, in the other two baboons, very low doses of clonidine (0.0001-0.001 mg/kg) maintained low to moderate levels of self-injection. Acute administration of clonidine produced signs of sedation including lip droop, drooling and sitting with eyes closed. At high doses, some toxicity was apparent: Baboons were pale and not responsive. Food intake was generally increased in a dose dependent manner. The present study indicates that clonidine functions as a positive reinforcer.

Animals↗

PubMed1999

Triazolam and zolpidem: effects on human memory and attentional processes.

RATIONALE: The imidazopyridine hypnotic zolpidem may produce less memory and cognitive impairment than classic benzodiazepines, due to its relatively low binding affinity for the benzodiazepine receptor subtypes found in areas of the brain which are involved in learning and memory. OBJECTIVES: The study was designed to compare the acute effects of single oral doses of zolpidem (5, 10, 20 mg/70 kg) and the benzodiazepine hypnotic triazolam (0.125, 0.25, and 0.5 mg/70 kg) on specific memory and attentional processes. METHODS: Drug effects on memory for target (i.e., focal) information and contextual information (i.e., peripheral details surrounding a target stimulus presentation) were evaluated using a source monitoring paradigm, and drug effects on selective attention mechanisms were evaluated using a negative priming paradigm, in 18 healthy volunteers in a double-blind, placebo-controlled, crossover design. RESULTS: Triazolam and zolpidem produced strikingly similar dose-related effects on memory for target information. Both triazolam and zolpidem impaired subjects' ability to remember whether a word stimulus had been presented to them on the computer screen or whether they had been asked to generate the stimulus based on an antonym cue (memory for the origin of a stimulus, which is one type of contextual information). The results suggested that triazolam, but not zolpidem, impaired memory for the screen location of picture stimuli (spatial contextual information). Although both triazolam and zolpidem increased overall reaction time in the negative priming task, only triazolam increased the magnitude of negative priming relative to placebo. CONCLUSIONS: The observed differences between triazolam and zolpidem have implications for the cognitive and pharmacological mechanisms underlying drug-induced deficits in specific memory and attentional processes, as well for the cognitive and brain mechanisms underlying these processes.

Adult↗

PubMed1999

Zaleplon and triazolam in humans: acute behavioral effects and abuse potential.

Zaleplon, a pyrazolopyrimidine that is under development as a hypnotic, produces its pharmacological effects at the benzodiazepine-recognition site on the GABA(A) benzodiazepine-receptor complex. Unlike most benzodiazepines, zaleplon binds selectively to the BZ1 (omega1) subtype of the benzodiazepine receptor. The present study compared the acute subject-rated effects, performance-impairing effects, and abuse potential of zaleplon and triazolam, a triazolobenzodiazepine hypnotic, in 14 healthy volunteers with histories of drug abuse. Zaleplon (25, 50, and 75 mg), triazolam (0.25, 0.5, and 0.75 mg) and placebo were administered orally in this double-blind, crossover study. Zaleplon and triazolam produced comparable dose-related effects on several subject-rated drug-effect questionnaires. Zaleplon and triazolam also produced comparable dose-dependent decrements on several performance tasks including balance, circular lights, digit-enter and recall, DSST, picture recall/recognition and repeated acquisition. Same-day and next-day subject-rated measures reflecting abuse potential (e.g., drug liking, good effects, and monetary street value) also suggest that zaleplon and triazolam were comparable. The only notable between-drug difference observed in the present study was that the time-action function of zaleplon differed from that of triazolam. The onset time, time to maximum drug effect, and duration of action were shorter with zaleplon than triazolam. Thus, despite its non-benzodiazepine structure and unique benzodiazepine-receptor binding profile, the behavioral pharmacological profile of zaleplon is similar to that of triazolam.

Acetamides↗

PubMed1999

A controlled study of flumazenil-precipitated withdrawal in chronic low-dose benzodiazepine users.

RATIONALE: Preclinical studies of the benzodiazepine antagonist flumazenil (Romazicon) have contributed to the understanding of the physical dependence associated with chronic benzodiazepine use; when administered to animals chronically pretreated with benzodiazepines, flumazenil precipitates a withdrawal syndrome. However, few controlled clinical studies have been conducted. OBJECTIVES: The objective was to characterize the effects of flumazenil in long-term users of therapeutic doses of benzodiazepines. METHODS: The acute physiological, participant-rated, and observer-rated effects of intravenously administered flumazenil (1 mg/70 kg) and caffeine (300 mg/70 kg; active drug control) were evaluated in an experimental group of 13 long-term users (mean 4.6 years) of low therapeutic doses (mean 11.2 mg/day diazepam equivalent) relative to a matched group of 13 volunteers without prior exposure to benzodiazepines in a double-blind, placebo-controlled, mixed design. RESULTS: Whereas the experimental group did not differ from the control group with respect to the effects of placebo, and both groups showed some changes in response to caffeine (e.g., increased blood pressure and anxiety scores), only the experimental group showed considerable changes in physiological measures, participant ratings (e.g., increased ratings of dizziness, blurred vision, heart pounding, feelings of unreality, pins and needles, nausea, sweatiness, noises louder than usual, jitteriness, things moving, sensitivity to touch), and observer ratings in response to flumazenil; in addition, four participants developed panic attacks. CONCLUSIONS: This study clearly demonstrates that flumazenil can precipitate symptoms commonly associated with benzodiazepine withdrawal in chronic low-dose benzodiazepine users.

Adult↗

PubMed1999

Evaluation of limited and unlimited food intake during withdrawal in triazolam-dependent baboons.

Chronic administration of benzodiazepine (BZ) agonists in baboons typically increases food intake, in a dose-dependent manner, during drug administration and suppresses food intake after termination of drug dosing. To determine if suppressed food intake after termination of chronic BZ administration (i.e. withdrawal) was related to increased food consumption during drug administration, the effects of chronic triazolam (1.0 mg/kg/day, intragastrically, for 30-34 days) and subsequent triazolam withdrawal on food intake was studied under two conditions in each of four baboons: (1) when the number of pellets was unlimited; and (2) when the number of pellets was limited so that pellet intake could not increase above the mean number of pellets per day obtained during a preceding vehicle condition. Pellets were available during daily 20-h sessions under a fixed-ratio 10 schedule of reinforcement. All baboons completed both pellet conditions, and the order of exposure was counterbalanced across subjects. During the unlimited pellet condition, pellets per day were increased during triazolam administration and then were suppressed in a time-limited manner when triazolam was discontinued in all four baboons. When pellet intake was limited during triazolam administration, pellet intake after triazolam discontinuation was suppressed in three of four baboons, and the magnitude and duration of suppression was generally less than during the unlimited pellet condition. Other behavioral signs of withdrawal (e.g., tremor/jerk, vomit/retch) were observed in all four baboons under both pellet conditions. These data suggest that the hyperphagic effects of triazolam appear to contribute to the subsequent suppression of food intake during triazolam withdrawal. However, these hyperphagic effects do not account for the entire phenomenon of suppressed food intake during BZ withdrawal.

Animals↗

PubMed1999

Selective effects of zolpidem on human memory functions.

Zolpidem is an imidazopyridine hypnotic with preferential binding affinity for the omega1-benzodiazepine (BZD) receptor. The present double-blind, placebo-controlled study evaluated the effects of orally administered zolpidem (15mg/70kg) on specific memory functions in 16 healthy volunteers using a battery of word and picture memory tasks. Relative to placebo, zolpidem significantly impaired memory for material presented after drug administration when memory was assessed directly by referring subjects back to the prior study episode (explicit memory: recall and recognition) but not when memory was assessed indirectly by evaluating subjects' ability to identify degraded versions of studied stimuli (implicit memory: fragment completion). Zolpidem did not impair explicit memory for material presented before drug administration or memory for previously acquired knowledge (semantic memory: categorization). There was evidence suggesting that zolpidem enhanced explicit and implicit memory for material presented before drug administration and that zolpidem produced a specific deficit in the acquisition of contextual information about material presented after drug administration. Despite zolpidem's unique pharmacological profile, the observed selectivity of zolpidem's memory-impairing effects for particular functions appears qualitatively similar to the selectivity observed with classic BZDs in previous studies.

Adult↗

PubMed1999

Caffeine withdrawal: a parametric analysis of caffeine dosing conditions.

Although caffeine is the most widely used behaviorally active drug in the world, caffeine physical dependence has been only moderately well characterized in humans. Four double-blind experiments were conducted in independent groups of healthy participants to assess the conditions under which withdrawal symptoms occur upon cessation of low to moderate doses of caffeine. In experiment 1, there was no evidence that the range or magnitude of caffeine withdrawal symptoms differed when 300 mg of caffeine was consumed as a single dose in the morning versus 100 mg at three time points across the day. In experiment 2, both the range and severity of withdrawal increased as a function of caffeine maintenance dose (100, 300, and 600 mg/day), with even the lowest dose (100 mg) producing significant caffeine withdrawal. Experiment 3 showed that when individuals were maintained on 300 mg caffeine/day and tested with a range of lower doses (200, 100, 50, 25, and 0 mg/day), a substantial reduction in caffeine consumption (</=100 mg/day) was necessary for the manifestation of caffeine withdrawal. Experiment 4 manipulated duration of exposure to caffeine (1, 3, 7, or 14 days of 300 mg/day) and showed that caffeine withdrawal occurred after as little as 3 days of caffeine exposure, with a somewhat increased severity of withdrawal observed after 7 or 14 days of exposure. As a whole, this set of experiments provides the most complete parametric characterization of caffeine withdrawal to date and suggests that caffeine physical dependence can occur under more modest conditions (i.e., fewer doses per day, lower daily dose, shorter duration of exposure) than previously recognized.

Adult↗

PubMed1999

Drug discrimination analysis of partial agonists at the benzodiazepine site. I. Differential effects of U-78875 across training conditions in baboons and rats.

The benzodiazepine receptor ligand U-78875 [3-(5-cyclopro pyl-1,2, 4-oxadiazol-3-yl)-5-(1-methylethyl)imidazol(1, 5-a)quinoxalin-4(5H)-o-ne] was studied in rats trained to discriminate i.p. 1.0 mg/kg lorazepam, 1.0 mg/kg diazepam, or 10 mg/kg pentobarbital, and baboons trained to discriminate oral 1.8 mg/kg lorazepam or 10 mg/kg pentobarbital. U-78875 doses were 0.01 to 10 mg/kg i.p. in rats and 0.32 to 56 mg/kg orally in baboons. U-78875 occasioned drug-appropriate responding in pentobarbital-trained (ED50 = 1.8 mg/kg) and diazepam-trained (ED50 = 0.056 mg/kg) rats, but it occurred in only one pentobarbital-trained baboon and not in the majority of lorazepam-trained baboons or rats. In baboons that generalized to U-78875, discriminative effects were antagonized by flumazenil. The interaction of U-78875 with pentobarbital, diazepam, and lorazepam revealed further differences in its behavioral effects. U-78875 potentiated the effects of pentobarbital, even in baboons that did not generalize to U-78875, but U-78875 had little effect in combination with diazepam. In lorazepam-trained animals that did not generalize to it, U-78875 antagonized lorazepam's effects, but U-78875 neither antagonized nor potentiated lorazepam in animals that did generalize to U-78875. Thus, although U-78875 generally functioned as a benzodiazepine agonist in pentobarbital- and diazepam-trained animals, its unique effects in lorazepam-trained animals appear to reflect its in vitro profile as a partial agonist.

Acoustic Stimulation↗

PubMed1999

Subjective and physiological effects of intravenous nicotine and cocaine in cigarette smoking cocaine abusers.

The subjective and physiological effects of intravenously administered cocaine and nicotine were compared in 10 cigarette-smoking cocaine abusers. Subjects abstained from smoking at least 8 h before each session. Under double blind conditions, subjects received placebo, cocaine (10, 20, and 40 mg/70 mg), or nicotine (0.75, 1.5, 3.0 mg/70 kg) in mixed order. Physiological and subjective data were collected before and repeatedly after each intravenous drug administration. Subjects also completed a drug versus money multiple-choice procedure in which they chose between that day's drug and 44 monetary values. Both drugs increased blood pressure and heart rate and decreased skin temperature. Nicotine showed a more rapid onset of subjective effects than cocaine. Overall, although both cocaine and nicotine increased subjective ratings of "drug effect", "rush", "good effects", "liking", "high", and "stimulated", only nicotine increased ratings of "bad effects" and "jittery". Although the highest nicotine dose produced greater effects than the highest cocaine dose on most subjective measures, the highest cocaine dose produced somewhat greater ratings of drug liking. At doses that produced comparable ratings of drug effect (40 mg/70 kg cocaine versus 1.5 mg/70 kg nicotine), cocaine produced significantly greater good effects, whereas nicotine produced greater bad effects. All three cocaine doses and the intermediate and high nicotine doses were frequently categorized as producing effects similar to those of cocaine or amphetamine. The drug versus money measure showed that the highest cocaine dose was worth twice as much as the highest nicotine dose. Thus, intravenous cocaine and nicotine can be differentiated by their subjective and reinforcing effects.

Adult↗

PubMed1998

Flunitrazepam and triazolam: a comparison of behavioral effects and abuse liability.

The performance, observer-rated, and participant-rated effects of orally administered placebo, and two benzodiazepines, flunitrazepam (2, 4 and 8 mg/70 kg) and triazolam (0.25, 0.5 and 1 mg/70 kg), were compared in 14 sedative drug abusers using a double-blind crossover design. Both flunitrazepam and triazolam produced dose-related decrements in memory and psychomotor/cognitive performance, and increases in many participant- and observer-rated measures. Effects of flunitrazepam had an earlier onset and a longer duration than those of triazolam. Although there was evidence that the flunitrazepam doses selected for study were somewhat higher overall relative to the selected triazolam doses, analysis of the participant-rated measures collected 24 h after drug administration (next-day) suggests that flunitrazepam may have a greater abuse liability than triazolam when abuse liability is assessed 24 h after drug administration. The highest flunitrazepam dose produced effects that were significantly greater than those of the highest triazolam dose on next-day ratings of good effects, take again, and worth; all tested flunitrazepam doses produced effects greater than any triazolam dose on next-day ratings of liking and take again. The highest flunitrazepam dose, but no triazolam dose, significantly increased the maximum dollar value at which participants chose drug over money in a Drug versus Money Choice Procedure.

Adult↗

PubMed1998

Stable low-rate midazolam self-injection with concurrent physical dependence under conditions of long-term continuous availability in baboons.

The current research was undertaken to characterize intravenous midazolam self-injection and the concurrent development of physical dependence under conditions of continuous drug availability. Baboons (n=6) i.v. self-injected midazolam under conditions of continuous availability under a fixed-ratio 30 schedule of lever-pull responses with a 5-min time-out after each injection. Midazolam (1.0 mg/kg) maintained an orderly spaced within-day pattern of injections and low, but stable, daily rates of self-injection over 30 or more days (e.g. <20 injections/day). Sequential substitution of saline and then midazolam produced rapid extinction and then reinstatement of responding at the same stable rate. In subsequent manipulations, a range of lower doses of midazolam (0.0156-0.25 mg/kg) were also shown to reinstate self-injection responding after extinction on saline; however, both chronic and acute dose manipulations indicated that dose-regulation was poor. Chronic self-injection of the high dose (1.0 mg/kg) but not lower doses produced a suppression in responding maintained by food pellet delivery. Chronic self-injection of 1.0 and 0.25 mg/kg midazolam produced physical dependence as reflected in classic benzodiazepine spontaneous and flumazenil-precipitated withdrawal syndromes, including tremor, vomiting and, in one instance, seizure. The stable, low-rate self-injection of midazolam, with concurrent development of physical dependence, demonstrated in the present study may provide a useful model system for investigating factors which contribute to long-term inappropriate use of benzodiazepines by physically dependent patients.

Animals↗

PubMed1998

Buspirone is differentiated from diazepam in humans using a three-response drug discrimination procedure.

The discriminative stimulus effects of buspirone and diazepam were examined in 12 healthy volunteers using a three-response drug discrimination procedure and a within-subject design. During an initial sampling phase, the training drug conditions (placebo, 15 mg/70 kg buspirone, and 10 mg/70 kg diazepam) were identified to subjects by letter codes before oral drug administration. During a subsequent training phase, subjects earned money for correct drug identifications made two hours after drug administration. Ten out of 12 subjects acquired the three-response discrimination. When lower doses of buspirone (3.75 and 7.5 mg/70 kg) and diazepam (2.5 and 5.0 mg/70 kg) were tested in a subsequent generalization testing phase, both buspirone and diazepam produced dose-related increases in appropriate drug identifications, without significant cross-generalization. Analyses of standardized and unstructured self report questionnaires revealed that buspirone and diazepam produced different profiles of effects, and that buspirone was associated with a number of "negative" subject-rated effects including tension, nausea, and dizziness. These results demonstrate a distinct profile of discriminative stimulus and subjective effects for buspirone relative to diazepam which is consistent with its distinct pharmacological profile, and provide evidence for the sensitivity of the three-response drug discrimination procedure.

Adult↗

PubMed1998

Physical dependence increases the relative reinforcing effects of caffeine versus placebo.

Using a within-subject cross-over design, this study examined the role of physical dependence in caffeine reinforcement by experimentally manipulating physical dependence. Each subject was exposed to two chronic drug phases (300 mg/70 kg/day caffeine and placebo) for 9-12 days, with order of phases counterbalanced across subjects. On 2 separate days immediately following each of the chronic drug exposures, subjects received acute doses of either caffeine (300 mg/70 kg) or placebo in counterbalanced order. The reinforcing effects of these drugs were then determined by using a multiple-choice procedure in which subjects made a series of discrete choices between receiving varying amounts of money or receiving the drug again, and a choice between the two drugs. To ensure that subjects completed the form carefully, following exposure to both of the acute drug administrations, one of the subject's previous choices from the multiple-choice form was randomly selected and the consequence of that choice was implemented. When subjects were maintained on chronic caffeine, they were willing to forfeit significantly more money and showed significant increases in typical withdrawal symptoms (e.g. fatigue, mood disturbance) after receiving placebo as compared to the other three conditions. When subjects were maintained on chronic caffeine, they also chose to receive caffeine over placebo twice as often than when they were maintained on chronic placebo. These findings provide the strongest evidence to date indicating that caffeine physical dependence increases the relative reinforcing effects of caffeine versus placebo.

Adult↗

PubMed1998

Zolpidem is differentiated from triazolam in humans using a three-response drug discrimination procedure.

The discriminative stimulus effects of the imidazopyridine hypnotic zolpidem and the classic benzodiazepine hypnotic triazolam were examined in seven healthy volunteers using a three-response drug discrimination procedure and a within-subject design. During an initial sampling phase, the training drug conditions (placebo, 20 mg/70 kg zolpidem, and 0.5 mg/70 kg triazolam) were identified to subjects by letter codes before oral drug administration. During a subsequent training phase, subjects earned money for correct drug identifications made 3.75 h after drug administration. Five out of seven subjects acquired the three-response discrimination. Analyses of standardized and unstructured self-report questionnaires revealed that zolpidem and triazolam produced different profiles of effects; zolpidem was associated with a number of negative somatic symptoms including nausea, blurred vision, visual images/hallucinations, and heavy limbs, whereas triazolam was associated with greater sedative effects. These results demonstrate a distinct profile of discriminative stimulus and subjective effects for zolpidem, relative to triazolam, which is consistent with its somewhat distinct pharmacological profile, and provide evidence for the sensitivity of the three-response drug discrimination procedure for detecting between-drug differences.

Adult↗

PubMed1998

Zolpidem physical dependence assessed across increasing doses under a once-daily dosing regimen in baboons.

The current study examined behavioral effects and possible development of physical dependence after once-daily doses of zolpidem (0, 1.0, 3.2, 10.0, 32.0 mg/kg intragastrically [i.g.]) in three baboons. Each dose was administered for 17 days and then the dose was increased; the 32.0 mg/kg dose was administered for 27 days. Baboons had access to food pellets for 20 hr/day beginning 15 min after dosing. Each day, baboons were presented with a fine motor task. Observation sessions were conducted 1 hr after dosing on days 1, 10, 12 and 14 of each dose condition and after termination of drug dosing. On days 10 and 14 of each dose condition, vehicle and flumazenil (5 mg/kg i.m.) were administered, respectively. Zolpidem increased the number of pellets obtained by two of three baboons. Vomit and/or retch and grimace (signs believed to be indicative of abdominal discomfort) were observed in one or two baboons during all zolpidem dose conditions (1.0-32.0 mg/kg). Time to complete the fine motor task increased dose-dependently in all three baboons, and incoordination was observed during the task in two baboons at 10.0 and 32.0 mg/kg. Analysis of blood plasma showed that measurable levels of zolpidem were present 24 hr after dosing in all drug conditions. The signs of flumazenil-precipitated withdrawal were summarized on a 9-point scale. Scores ranged from 1 to 5 in the 1.0 mg/kg condition, from 2 to 5 in the 3.2 and 10.0 mg/kg conditions and from 4 to 6 in the 32.0 mg/kg condition. Signs that were considered intermediate in severity were observed. Specifically, tremor, jerk and/or rigidly braced posture was observed in one baboon at 1.0 mg/kg, two baboons at the next two doses and all three baboons at 32.0 mg/kg. Vomit and/or retch also occurred in two baboons at dose conditions above 1.0 mg/kg. Discontinuation of zolpidem dosing after 78 to 79 days resulted in mild withdrawal signs (e.g., number of pellets obtained were lower and number of 1-min intervals increased in which eyes were closed, or in which lying down, head lower than torso posture and/or withdrawn posture were observed) on the first day in two baboons. The peak withdrawal scores were 4 or 5 on days 5 to 10; two baboons vomited and/or retched and all three baboons showed tremor, jerk and/or rigidly braced posture. Thus, zolpidem produced physical dependence under once-daily dosing conditions, and the severity of the withdrawal syndrome can be characterized as intermediate.

Animals↗

PubMed1998

Zolpidem self-injection with concurrent physical dependence under conditions of long-term continuous availability in baboons.

Intravenous zolpidem self-injection, and the concurrent development of physical dependence under conditions of continuous drug availability, was characterized in three baboons. Previously, under similar conditions, 1.0 mg/kg midazolam maintained low, but stable, daily rates of self-injection (e.g. less than 20 injections/day) over 30 or more days and resulted in the development of physical dependence in baboons. In the current experiments, saline and zolpidem (1.0 mg/kg) were available for self-injection under a fixed-ratio (FR-30) schedule of lever-pull responses with a 5 min time-out after each injection. Saline maintained only low levels of responding (i.e. less than five injections per day). Zolpidem maintained an orderly spaced within-day pattern of injections and daily rates of self-injection were higher than saline (i.e. 10 or more injections per day). Daily rates of zolpidem self-injection were relatively stable in two baboons, and increased over time in the third baboon. Substitution of saline for zolpidem produced a rapid decrease in responding that remained low (i.e. less than five injections per day) in all three baboons. Chronic self-injection of zolpidem produced an increase in responding maintained by food pellet delivery and an increase in body weights. Administration of flumazenil (0.1-1.0 mg/kg, i.v.) after at least 35 days of zolpidem self-injection produced postures and behavioral signs typical of a classic flumazenil-precipitated benzodiazepine withdrawal syndrome. Substitution of saline after chronic zolpidem self-injection produced a time-limited spontaneous withdrawal syndrome. Behavioral signs and postures were similar to those observed during flumazenil-precipitated withdrawal and were most prominent during the first 8 days after zolpidem was discontinued. Therefore, like midazolam, zolpidem maintained self-injection and physical dependence developed under conditions of long-term continuous availability.

Animals↗

PubMed1997

Caffeine reinforcement: the role of withdrawal.

This study examined caffeine's acute and withdrawal effects in moderate caffeine consumers (mean = 379 mg/day caffeine) to compare the relative contributions each might have to caffeine reinforcement. Subjects were caffeine restricted on the night before each of three sessions, which generally occurred at weekly intervals; these restrictions lasted until the session was completed approximately 19 h later. During the first two sessions, subjects received either placebo or caffeine (each subject's average daily intake). These two conditions occurred using a double-blind, quasi-random, crossover design. At the end of each session subjects completed the POMS, a caffeine withdrawal questionnaire, and a Multiple-Choice Form on which subjects made a series of discrete choices between receiving the drug again or receiving varying amounts of money. This form also included negative money amounts to assess how much subjects would forfeit to avoid placebo (e.g., withdrawal symptoms after placebo). During the third session, one of the previous choices was randomly selected and the consequence of that choice was implemented. Placebo increased self-reported feelings of "worn out," "headache," and "flu-like feelings," and decreased "alert," "upset stomach," "helpful," and "well-being" relative to caffeine. On the Multiple-Choice Forms, subjects chose to receive caffeine rather than an average of $0.38 and to forfeit $2.51 to avoid receiving placebo again. "Headache" was significantly correlated with amount of money forfeited to avoid placebo. These results suggest that, under these conditions, choice of caffeine is more potently controlled by avoiding withdrawal than it is by the positive effects of caffeine.

Adult↗

PubMed1997

Benzodiazepine self-administration in humans and laboratory animals--implications for problems of long-term use and abuse.

Drug reinforcement may represent the primary behavioral-pharmacological mechanism underlying two types of problematic use of benzodiazepines--recreational abuse by polydrug abusers and inappropriate chronic use by patients. High dose polydrug abuse for the purpose of getting high is readily recognized as a significant social problem. Inappropriate chronic benzodiazepine use is more subtle but relatively common: for anxiolytics, 36% of past-year users (3% of the adult population in the US) report using these drugs for 4 consecutive months or longer. The risks of such long-term use are much better documented than the benefits. This paper provides a current review of various problems that have been identified with the long-term use and the recreational abuse of benzodiazepines, including memory impairment, risk of accidents, falls and hip fractures in the elderly, a withdrawal syndrome, brain damage, overuse in the elderly, overuse by chronic pain patients, overuse by alcoholics and recreational abuse among alcoholics and polydrug abusers. A comprehensive review of the literature on benzodiazepine reinforcing effects in humans and laboratory animals is also provided. Drug self-administration studies in humans and laboratory animals provide models of both types of problematic benzodiazepine use. Recreational abuse of benzodiazepines has been modeled in human research with polydrug abusers and in laboratory animal studies, which show that the reinforcing effect of benzodiazepines is intermediate relative to other sedative compounds and is increased in subjects with histories of previous sedative drug self-administration. The problem of inappropriate long-term use of benzodiazepines by people without histories of drug abuse has been partially modeled in human studies showing that benzodiazepines function as reinforcers in subjects with anxiety, insomnia, and histories of moderate alcohol consumption, and in preclinical studies showing stable, low-rate benzodiazepine self-injection with concurrent physical dependence under conditions of continuous availability. Both human and animal research suggests that the drug history and current behavioral context may be important in the establishment of benzodiazepines as reinforcers. Limited human and animal research provides little support for the common belief that physical dependence enhances benzodiazepine reinforcement.

Animals↗