Discriminative-stimulus effects of zolpidem, triazolam, pentobarbital, and caffeine in zolpidem-trained humans.

Six non-drug-abusing humans were trained to discriminate 15 mg zolpidem in the present experiment. After participants acquired discrimination, a range of doses of zolpidem (2.5–15.0 mg), triazolam (0.0625–0.3750 mg), pentobarbital (25–150 mg), caffeine (100–600 mg), and placebo were tested to determine whether they shared discriminative-stimulus effects with 15 mg zolpidem. The participant-rated and performance-impairing effects of zolpidem, triazolam, pentobarbital, and caffeine were assessed concurrently. Triazolam and pentobarbital dose dependently increased zolpidem-appropriate responding. Caffeine occasioned low levels of zolpidem-appropriate responding. Zolpidem, triazolam, and pentobarbital, but not caffeine, generally produced a similar constellation of participant-rated drug effects (e.g., increased scores for the Pentobarbital, Chlorpromazine, and Alcohol Group subscale on the Addiction Research Center Inventory) and dose dependently impaired performance. These results suggest that humans can reliably discriminate zolpidem. Despite its unique benzodiazepine-receptor binding profile, the discriminative-stimulus, participant-rated, and performance-impairing effects of zolpidem are similar to those of the barbiturates and benzodiazepines. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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 mg/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-rated 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. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The Baby K case: a search for the elusive standard of medical care

The present study compared the acute subject-rated and performance-impairing effects of trazodone and triazolam in seven healthy humans. Trazodone (50, 100 and 200 mg), triazolam (0.125, 0.25, 0.50 mg) and placebo were administered orally in a double-blind, crossover design. Drug effects were measured approximately 30 min before drug administration and repeatedly afterwards for 6 h. Trazodone and triazolam produced dose-related increases in subject-ratings of drug effect and sedation. The absolute magnitude of trazodone's and triazolam's effects was comparable across these measures, which suggests the doses tested were equivalent on some behavioral dimension. By contrast, triazolam, but not trazodone, increased subject ratings of "dizzy", "excited", "nervous", "restless", "stomach turning" and "itchy skin". Triazolam, but not trazodone, significantly impaired learning, recall and performance. The present findings suggest trazodone may be a viable alternative to benzodiazepine hypnotics like triazolam, especially when needing to minimize drug-induced impairment. Future research could extend the present findings by replicating them in a clinically relevant population such as individuals with histories of drug abuse.     

Discriminative-stimulus and participant-rated effects of methylphenidate, bupropion, and triazolam in d-amphetamine-trained humans.

The discriminative-stimulus and participant-rated effects of a range of doses of d-amphetamine (2.5–20 mg), methylphenidate (5–40 mg), bupropion (50–400 mg), and triazolam (0.0625–0.5 mg) were tested in 5 humans trained to discriminate between oral d-amphetamine (20 mg) and placebo. d-Amphetamine and methylphenidate generally dose dependently increased drug-appropriate responding. Bupropion and triazolam on average occasioned less than or equal to 40% drug-appropriate responding. d-Amphetamine, methylphenidate, and bupropion produced stimulant-like participant-rated effects, while triazolam produced sedative-like effects. These results further demonstrate that the acute behavioral effects of d-amphetamine and methylphenidate overlap extensively in humans, which is concordant with preclinical studies. Bupropion produced some d-amphetamine-like, participant-rated drug effects but did not occasion significant levels of d-amphetamine-appropriate responding. These findings are concordant with previous findings of a dissociation between the discriminative-stimulus and participant-rated effects of drugs. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of oral caffeine pretreatment on response to intravenous nicotine and cocaine.

Previous research suggests that under conditions of chronic daily caffeine administration, caffeine increases the effects of nicotine. Little is known about the effects of caffeine pretreatment on response to nicotine under infrequent caffeine administration conditions. The present study examined whether infrequent (not on consecutive days) acute oral caffeine administration alters subject-rated, physiological, and monetary value effects of intravenous nicotine in regular users of caffeine, tobacco, and cocaine. To determine the specificity of effects of caffeine on response to nicotine, the effects of caffeine administration on response to intravenous cocaine (another short-acting stimulant) were also studied. Fourteen (1 woman) volunteers participated in this 3–4 week, double-blind, inpatient study. Volunteers participated in 10 experimental conditions in pseudo-randomized order, in which oral caffeine (250 mg/70 kg) or placebo was administered 1 hr before an intravenous injection, consisting of nicotine (1 or 2 mg/70 kg), cocaine (15 or 30 mg/70 kg), or saline. Infrequent acute caffeine pretreatment attenuated the increase resulting from 2 mg/70 kg nicotine administration on ratings of “rush,” “good effects,” “liking,” “high,” and “drowsy/sleepy.” Caffeine had no significant effect on physiological response to nicotine. Caffeine had no significant effect on subject-rated and physiological response to cocaine, with the exception that caffeine significantly augmented blood pressure response to cocaine. In contrast to the previous research using chronic caffeine maintenance, these data suggest that infrequent acute caffeine administration may attenuate nicotine effects. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A follow-up study of the acute behavioral effects of benzodiazepine-receptor ligands in humans: Comparison of quazepam and triazolam.

Quazepam, a trifluoroethylbenzodiazepine hypnotic, and triazolam, a triazolobenzodiazepine hypnotic, differ in terms of their benzodiazepine-receptor binding profile. Previous studies have suggested that quazepam produces less performance impairment than triazolam. Whether these effects are due to differences between quazepam and triazolam in terms of their benzodiazepine-receptor binding profile or to the testing of insufficient doses is unknown. The present study compared the acute behavioral effects of triazolam, quazepam, and placebo in 12 healthy humans using a within-subjects, placebo-controlled, crossover design. Quazepam and triazolam produced comparable dose-dependent performance impairment and increased ratings of drug effect and drowsy. Quazepam increased ratings of dizzy/light-headed, performance impaired, and sleepy. Triazolam increased ratings of high. Thus, across a sufficient range of doses, the performance-impairing effects of quazepam were similar to those of triazolam. By contrast, quazepam and triazolam produced somewhat different constellations of participant-rated drug effects. These differential drug effects may be attributable to differences between quazepam and triazolam in terms of their benzodiazepine-receptor binding profile. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Medium-intensity light produces circadian rhythm adaptation to simulated night-shift work

The study presented here compared the acute performance-impairing, subject-rated, and observer-rated effects of quazepam (15, 30, and 45 mg), triazolam (0.1875, 0.375, and 0.5625 mg), zolpidem (7.5, 15, and 22.5 mg), and placebo in nine healthy, non-drug-abusing humans. Quazepam, a trifluoroethylbenzodiazepine, was chosen for study because, when compared with triazolam, a triazolobenzodiazepine, it is a relatively weak benzodiazepine-receptor ligand, and it may bind selectively to the BZ1 benzodiazepine-receptor subtype. Zolpidem, an imidazopyridine, is the most commonly prescribed hypnotic and was chosen for study because it is biochemically distinct from benzodiazepine hypnotics and also purportedly binds selectively to the BZ1 benzodiazepine-receptor subtype. Triazolam was chosen as the reference compound because it binds nonselectively to BZ1 and BZ2 benzodiazepine-receptor subtypes. Triazolam, zolpidem, quazepam, and placebo were administered orally in a double-blind, crossover design. Triazolam and zolpidem produced orderly dose- and time-related impairment of learning, performance, and recall, and produced sedative-like subject- and observer-rated drug effects. The behavioral pharmacologic profile of zolpidem and triazolam was indistinguishable in that at peak effect, the absolute magnitude of drug effect was comparable across the various measures. Quazepam, by contrast, did not impair performance on any task to a statistically significant degree, nor did it produce significant sedation as measured by subject- and observer-rated drug-effect questionnaires. Whether these effects are a result of the unique benzodiazepine-receptor binding profile of quazepam or the testing of insufficient dosages is unknown. Future research could extend the findings presented here by testing higher dosages of quazepam.     

Reinforcing effects of caffeine, ephedrine, and their binary combination in rats

The reinforcing effects of caffeine, ephedrine, and caffeine + ephedrine combinations were tested in rats maintained to self-administer 0.5 mg/kg/injection of cocaine in daily 4 h limited access periods. The dose-response relationship for cocaine demonstrated a a typical inverted U-shaped function. The dose-dependent administration of cocaine was stable over the 3-day substitution epochs. Similar to earlier reports, neither caffeine nor ephedrine engendered stable patterns of self-injections. Combinations of caffeine + ephedrine produced biphasic patterns of administration only on the first day of substitution. Days 2 and 3 of the caffeine-ephedrine substitution periods engendered variable and inconsistent reinforcer deliveries that did not significantly differ from saline substitution tests. These reduced patterns of self-administered caffeine-ephedrine combinations were not attributed to behavioral toxicity. Progressive-ratio tests demonstrated rank ordered break points of: food > cocaine > caffeine ephedrine combination = caffeine = ephedrine = saline. Caffeine-ephedrine pretreatments failed to show any significant change in the administration of the maintenance dose of cocaine except at the highest combination dose tested. Although previous data from this laboratory demonstrated symmetrical crossgeneralization between the discriminative effects of caffeine-ephedrine combinations and cocaine, the present data suggest limited reinforcing effects of these combinations in rats.     

Acute behavioral effects of estazolam and triazolam in non-drug-abusing volunteers.

The present study compared the acute behavioral, participant-rated and observer-rated effects of estazolam and triazolam in 7 healthy, non–drug-abusing humans. Placebo, estazolam (1, 2, and 4 mg), and triazolam (0.125, 0.25, and 0.50 mg) were administered orally in a double-blind, crossover design. Estazolam and triazolam produced orderly dose- and time-related impairment of learning and performance and produced sedative-like participant-rated and observer-rated effects. The absolute magnitude of estazolam's and triazolam's effects at peak effect was comparable across these measures. Triazolam, but not estazolam, impaired immediate and delayed picture recall. The greater effects of triazolam than of estazolam on immediate and delayed picture recall should be viewed cautiously because subtle differences between these drugs in terms of time-to-peak plasma levels may be a confound. Future research should attempt to more thoroughly establish the time–action function of estazolam and triazolam on tasks like picture recall and recognition and determine if the drugs differ at peak effect. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Interaction of buprenorphine with cocaine-morphine combinations.

Sixteen nonheroin dependent drug abusers, who identified intravenous cocaine and heroin as their drug combination of choice, participated in a study assessing the efficacy of buprenorphine in altering the subjective and cardiovascular effects of such combinations. A sublingual dose of buprenorphine (none, 2, or 4 mg) was administered 50 min before the intravenous administration of morphine sulfate (0, 5, or 10 mg/70 kg) in combination with cocaine hydrochloride (0, 8, or 32 mg/70 kg). Buprenorphine had minimal effects on the response to cocaine alone but decreased cardiovascular activity produced by morphine alone. Buprenorphine decreased ratings of drug liking when given before combinations of 32 mg of cocaine and morphine. The greater effect of buprenorphine on cocaine-morphine combinations suggests that buprenorphine may be effective as a treatment medication for individuals who use such combinations. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Subjective effects of caffeine among introverts and extraverts in the morning and evening.

In previous studies of psychomotor performance, the stimulant effects of caffeine differed by personality characteristics. For example, caffeine improved the task performance of extraverts but overaroused introverts and thus impaired their performance. The present study compared the effects of caffeine on subjective arousal among introverts and extraverts. Seventeen introverts and 19 extraverts drank coffee that contained doses of 0, 2, and 4 mg/kg caffeine during morning and evening sessions in a within-subjects, randomized, double-blind, crossover design. At 30-min intervals for 180 min after drinking, participants completed the Profile of Mood States, a battery of self-report visual analog scales, and the Digit Symbol Substitution Test (DSST). Caffeine effects on mood and task performance did not significantly interact with extraversion, except for nonsignificant trends for caffeine to increase happiness and vigor more among extraverts than introverts. No 3-way interactions of group, time, and dose were found on any scales or on the DSST. Results do not support the hypothesis that caffeine differentially affects extraverts and introverts, particularly at different times of the day. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Full and partial 5-HT1A receptor agonists disrupt learning and performance in rats

As a means of characterizing the role of 5-hydroxytryptamine (5-HT1A) receptors in learning, a full 5-HT1A receptor agonist, 8-hydroxy-dipropylaminotetralin (8-OH-DPAT), was administered both alone and in combination with two partial agonists (buspirone and 1-(2-methoxyphenyl)-4-[4-(2-phthalimido)butyl] piperazine hydrobromide (NAN-190)) and a 5-HT1A receptor antagonist (p-MPPI) to rats responding under a multiple schedule of repeated acquisition and performance of response sequences. In addition, the effects of another 5-HT1A receptor agonist, (LY228729), were also studied under this same procedure. When administered alone, both 8-OH-DPAT (0.1-3. 2 mg/kg) and LY228729 (0.32-3.2 mg/kg) dose dependently decreased overall response rate and increased the percentage of errors in the acquisition and performance components. At the doses of each drug tested, both buspirone (0.32 or 1 mg/kg) and NAN-190 (1 or 3.2 mg/kg) also decreased overall response rate and increased the percentage of errors. However, the effects of these drugs differed across behavioral components and dependent measures. The effects of buspirone and NAN-190 on rate and accuracy were also different when they were administered in combination with 8-OH-DPAT. In contrast, p-MPPI (3.2 or 10 mg/kg) had little or no effect when administered alone and antagonized the effects of 8-OH-DPAT; shifting the dose-effect curves for both response rate and the percentage of errors in both components to the right. Taken together, these results indicate that complex behaviors in rats are sensitive to disruption by drugs with both full and partial 5-HT1A receptor agonist properties, and that the effects of partial 5-HT1A receptor agonists on learning may be different depending on their efficacy at pre- and postsynaptic 5-HT1A receptors.     

Cardiovascular reactivity, mood, and task performance in deprived and nondeprived coffee drinkers.

40 habitual, heavy coffee drinkers (aged 18–48 yrs; mean consumption of 5.7 cups/day) were deprived of their morning coffee for 1 experimental session and not deprived of the other. During each session, Ss consumed 12 oz of caffeinated coffee, decaffeinated coffee, or caffeine-free herbal tea. Measurements of heart rate, blood pressure, mood, and catecholamine response to deprivation and consumption of the beverage, alone and in combination with challenging tasks, were made. Caffeine continues to cause blood pressure increases with chronic, heavy consumption and these effects do not appear to habituate with regular use. Ss reacted to behavioral challenge with fewer negative mood effects if they had consumed caffeine or coffee. Mild caffeine deprivation was associated with symptoms of stress. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Discriminative-stimulus, self-reported, performance, and cardiovascular effects of atomoxetine in methylphenidate-trained humans.

Atomoxetine is marketed as a nonstimulant medication indicated for the treatment of attention-deficit/hyperactivity disorder in adults. Previous laboratory research suggests that atomoxetine has limited abuse potential but that some of its behavioral effects might overlap with traditional psychomotor stimulants like methylphenidate and d-amphetamine. A drug with this profile might be useful for the treatment of stimulant dependence. The aim of this experiment was to compare the discriminative-stimulus and self-reported effects of atomoxetine with methylphenidate, damphetamine, and triazolam in humans who had acquired a methylphenidate (30 mg) discrimination. Six healthy subjects with a recent history of nontherapeutic stimulant use were enrolled in this outpatient study. After subjects acquired the methylphenidate discrimination, a range of doses of methylphenidate (5-30 mg), atomoxetine (15-90 mg), d-amphetamine (2.5-15 mg), triazolam (0.06-0.375 mg), and placebo were tested. To more fully characterize the behavioral effects of atomoxetine, a battery of self-reported drug-effect questionnaires, a performance task, and cardiovascular assessments were also included. Methylphenidate and d-amphetamine increased drug-appropriate responding and produced typical stimulant-like effects (e.g., increased ratings of "Active, Alert, Energetic"). Atomoxetine partially substituted for methylphenidate (i.e., 33%-50%) and produced some dose-dependent, stimulant-like, subject-rated drug effects, although the magnitude of these effects was less than d-amphetamine and methylphenidate and generally did not attain statistical significance. These data suggest that the behavioral effects of atomoxetine overlap to a small degree with psychomotor stimulants and that it has low abuse potential. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Diazepam alters caffeine-induced effects on beta-endorphin levels in specific rat brain regions

The present study was conducted to evaluate the effects of caffeine and the benzodiazepine agonist diazepam, and a combination of both on beta-endorphin (beta-EN) levels in specific rat brain regions. Male Sprague-Dawley rats (150-200 g) adapted to a 12-hour light: 12-hour dark illumination cycle were used in this study. Caffeine (10 mg/kg), diazepam (2 mg/kg) or a combination of caffeine (10 mg/kg) and diazepam (2 mg/kg) were administered intraperitoneally to rats at 11:00 hr. Control animals were injected with saline. Animals were sacrificed by decapitation 1 h after injection, the brains were immediately removed; the cortex, hippocampus, hypothalamus and midbrain were dissected and their B-EN levels measured by radioimmunoassay. Caffeine administration significantly increased B-EN levels in the cortex. Similarly, administration of diazepam alone resulted in a significant increase of B-EN levels in cortex. However, concurrent administration of diazepam and caffeine resulted in higher increase of B-EN levels in cortex. No significant changes in B-EN levels were detected in hippocampus and midbrain after administration of either caffeine or diazepam alone. On the other hand, when diazepam and caffeine were concurrently administered a significant increase of B-EN levels were observed in the midbrain. Moreover, administration of diazepam alone resulted in a significant increase of B-EN levels in hypothalamus. This increase was still observed following concurrent administration of diazepam and caffeine. These results clearly indicate that diazepam alters caffeine-induced effects on B-EN in specific rat brain regions.     

Discriminative and reinforcing stimulus effects of nicotine, cocaine, and cocaine + nicotine combinations in rhesus monkeys.

Concurrent cigarette smoking and cocaine use is well documented. However, the behavioral pharmacology of cocaine and nicotine combinations is poorly understood, and there is a need for animal models to examine this form of polydrug abuse. The purpose of this study was twofold: first to assess the effects of nicotine on the discriminative stimulus effects of cocaine, and second, to study self-administration of nicotine/cocaine combinations in a novel polydrug abuse model. In drug discrimination experiments, nicotine increased the discriminative stimulus effects of low cocaine doses in two of three monkeys, but nicotine did not substitute for cocaine in any monkey. Self-administration of cocaine and nicotine alone, and cocaine + nicotine combinations was studied under a second-order fixed ratio 2, variable ratio 16 (FR2[VR16:S]) schedule of reinforcement. Cocaine and nicotine alone were self-administered in a dose-dependent manner. The combination of marginally reinforcing doses of cocaine and nicotine increased drug self-administration behavior above levels observed with the same dose of either cocaine or nicotine alone. These findings indicate that nicotine may increase cocaine's discriminative stimulus and reinforcing effects in rhesus monkeys, and illustrate the feasibility of combining cocaine and nicotine in a preclinical model of polydrug abuse. Further studies of the behavioral effects of nicotine + cocaine combinations will contribute to our understanding the pharmacology of dual nicotine and cocaine dependence, and will be useful for evaluation of new treatment medications. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Phylogenetic relationships inferred from the sequence and secondary structure of ITS1 rRNA in Albinaria and putative Isabellaria species (Gastropoda, Pulmonata, Clausiliidae)

It has been suggested that liking for the taste, flavour and aroma of, for example, coffee and tea is acquired through the process of classical conditioning, involving association of these orosensory cues with the psychopharmacological consequences of caffeine ingestion. Accordingly, this study investigated caffeine reinforcement by assessing changes in preference for a novel drink consumed with or without caffeine. Particular care was taken to use "ecologically valid" procedures; that is, overnight caffeine abstinence followed by a cup-of-coffee equivalent dose of caffeine (70 mg) at breakfast. Caffeine had no significant effects on drink preference or mood in subjects with habitually low intakes of caffeine. In contrast, moderate users of caffeine developed a relative dislike for the drink lacking caffeine and showed somewhat lowered mood following overnight caffeine abstinence (e.g., less lively, clearheaded and cheerful), which was significantly improved by caffeine. These together with other recent results strongly suggest that, in everyday life, caffeine reinforcement can occur as the result of the alleviation by caffeine of the adverse effects of overnight caffeine abstinence (negative reinforcement). They also demonstrate the utility of this flavour-conditioning procedure, which could be applied in the wider investigation of the reinforcing properties of drugs.     

Dose effects of triazolam and scopolamine on metamemory.

The present study compared the acute dose effects of the benzodiazepine triazolam and the anticholinergic scopolamine on metamemory (knowledge and awareness of one’s own memory) in a two-phase paradigm designed to assess effects on both monitoring and control components of metamemory in both semantic (general knowledge) and episodic memory (cued-recall) tasks. Placebo and 2 doses each of triazolam (0.125, 0.25 mg/70 kg, oral) and scopolamine (0.25, 0.50 mg/70 kg, subcutaneous) were administered to 80 healthy volunteers (16 per group) in a double-blind, double-dummy, independent groups design. Both triazolam and scopolamine impaired episodic memory (quantity and accuracy) but not semantic memory. Results suggested that both drugs impaired monitoring as reflected in absolute accuracy measures (impaired calibration in the direction of overconfidence) and control sensitivity (the relationship between confidence and behavior). Overall, the results did not provide evidence for differences between triazolam and scopolamine in memory or metamemory. In addition to the clinical relevance of the observed effects, this study adds to the accumulating body of cognitive psychopharmacological research illustrating the usefulness of drug-induced amnesia as a vehicle to explore memory and metamemory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Enhanced mood and psychomotor performance by a caffeine-containing energy capsule in fatigued individuals.

Caffeine produces mild psychostimulant effects that may be particularly evident in individuals whose mood or performance is impaired by sleep restriction or caffeine withdrawal. Caffeinated energy drinks have been shown to improve energy and cognition but expectancy effects cannot be ruled out in these studies. Very few studies have examined the effects of caffeine-containing energy capsules upon behavioral and subjective measures. This study compared the effects of a caffeine-containing (200 mg) supplement (CAF) or placebo in capsule form after prolonged wakefulness, in participants who varied in their level of habitual caffeine use. Thirty-five healthy volunteers (16 male, 19 female) participated in two experimental sessions in which they remained awake between 5 p.m. and 5 a.m. At 3:30 a.m. they consumed CAF or placebo in random order under double-blind conditions. Participants completed subjective effects questionnaires and performed computerized attention tasks before and after consuming capsules. Heart rate and blood pressure were monitored at regular intervals. Compared to measures at 5 p.m., participants reported more tiredness and mood disturbance at 3 a.m., and exhibited longer reaction times and more attentional lapses. Heavier caffeine consumers exhibited the greatest decreases in Profile of Mood States (POMS) Vigor. CAF produced stimulant-like effects and significantly improved mood and reaction times upon the tasks. These effects did not vary with level of habitual caffeine consumption. These findings indicate that consumption of a caffeine-containing food supplement improves subjective state and cognitive performance in fatigued individuals that is likely a result of its caffeine content. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Acute effects of caffeine on several operant behaviors in rhesus monkeys

The acute effects of 1,3-trimethylxanthine (caffeine) were assessed using an operant test battery (OTB) of complex food-reinforced tasks that are thought to depend upon relatively specific brain functions, such as motivation to work for food (progressive ratio, PR), learning (incremental repeated acquisition, IRA), color and position discrimination (conditioned position responding, CPR), time estimation (temporal response differentiation, TRD), and short-term memory and attention (delayed matching-to-sample, DMTS). Endpoints included response rates (RR), accuracies (ACC), and percent task completed (PTC). Caffeine sulfate (0.175-20.0 mg/kg, IV), given 15 min pretesting, produced significant dose-dependent decreases in TRD percent task completed and accuracy at doses > or = 5.6 mg/kg. Caffeine produced no systematic effects on either DMTS or PR responding, but low doses tended to enhance performance in both IRA and CPR tasks. Thus, in monkeys, performance of an operant task designed to model time estimation is more sensitive to the disruptive effects of caffeine than is performance of the other tasks in the OTB.