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)     

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)     

Acute behavioral effects of triazolam and caffeine, alone and in combination, in humans.

The acute behavioral effects of triazolam (0, 0.375, and 0.75 mg/70 kg) and caffeine (0, 250, and 500 mg/70 kg), alone and in combination, were assessed in 9 male volunteers. Ss received all possible dose combinations according to a Latin square design. Triazolam administered alone dose dependently disrupted learning and performance on the Repeated Acquisition and Performance procedure and the Digit Symbol Substitution Test and increased S ratings of sedation. Caffeine administered alone did not significantly affect learning or performance measures, but it did dose dependently increase S ratings of drug strength. Caffeine significantly attenuated triazolam-induced decrements in learning and performance. Consistent with effects on learning and performance, caffeine offset triazolam-induced increases in S ratings of sedation. Combining caffeine and triazolam did not significantly alter increases in S ratings of drug strength observed with caffeine alone. These effects are qualitatively similar to those observed with other benzodiazepines (e.g., lorazepam) and document a high degree of consistency in the behavioral pharmacology of benzodiazepine-caffeine combinations in humans. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Discriminative and participant-rated effects of methylphenidate in children diagnosed with attention deficit hyperactivity disorder (ADHD)

Despite the demonstrated beneficial effects of methylphenidate and d-amphetamine for the treatment of attention-deficit hyperactivity disorder (ADHD), the discriminative and subjective effects of these compounds in children are not well understood. This study was designed to characterize such effects in children diagnosed with ADHD. In a series of 3 experiments, 17 children were examined to determine whether methylphenidate (n = 12) and d-amphetamine (n = 5) could be reliably discriminated at doses typically used in clinical practice. Under some conditions (e.g., when they were instructed to attend to the drug effects or when a wide range of doses was used), children discriminated methylphenidate (5.0-30.0 mg) from placebo. Children tested under a range of doses of d-amphetamine (2.5-20.0 mg) were unable to discriminate this drug from placebo reliably. Neither methylphenidate nor d-amphetamine produced reliable participant-rated effects.     

Comparison of the effects of methamphetamine, bupropion, and methylphenidate on the self-administration of methamphetamine by rhesus monkeys.

The effectiveness of methadone as a treatment for opioid abuse and nicotine preparations as treatments for tobacco smoking has led to an interest in developing a similar strategy for treating psychostimulant abuse. The current study investigated the effects of three such potential therapies on intravenous methamphetamine self-administration (1 – 30 μg/kg/injection) in rhesus monkeys. When given as a presession intramuscular injection, a high dose of methamphetamine (1.0 mg/kg) decreased intravenous methamphetamine self-administration but did not affect responding for a food reinforcer during the same sessions. However, the dose of intramuscular methamphetamine required to reduce intravenous methamphetamine self-administration exceeded the cumulative amount taken during a typical self-administration session, and pretreatment with a low dose of methamphetamine (0.3 mg/kg) actually increased self-administration in some monkeys at the lower self-administration dose. Like pretreatment with methamphetamine, pretreatment with bupropion (3.2 mg/kg) decreased methamphetamine self-administration but did not affect responding for food. Pretreatment with methylphenidate (0.56 mg/kg) did not significantly alter methamphetamine self-administration. These results suggest that some agonist-like agents can decrease methamphetamine self-administration. Although the most robust effects occurred with a high dose of methamphetamine, safety and abuse liability considerations suggest that bupropion should also be considered for further evaluation as a methamphetamine addiction treatment. (PsycINFO Database Record (c) 2011 APA, all rights reserved)     

Personality factors moderate subjective and psychophysiological responses to d-amphetamine in humans.

The aim of the present study was to examine the relationship between measures of novelty and sensation seeking and both psychophysiological and subjective measures of stimulation after a pharmacological challenge with an indirect dopamine agonist, d-amphetamine. Prepulse inhibition (PPI) of the startle reflex and subjective responses were assessed after the challenge. The results indicated that the Novelty Seeking scale of the Tridimensional Personality Questionnaire (TPQ; M. Zuckerman, 1994). TPQ was a significant predictor of lower PPI and greater subjective stimulation. The Disinhibition scale of the Sensation Seeking Scale (SSS; M. Zuckerman, S. B. G. Eysenck, & M. J. Eysenck, 1978) moderated the effects of amphetamine on stimulation and elation, whereas the Boredom Susceptibility and Experience Seeking subscales of the SSS moderated subjective stimulation. These findings indicate that higher scores on novelty and sensation seeking correspond to heightened sensitivity to the effects of a stimulant medication. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Tolerance to discriminative stimulus effects of d-amphetamine.

Chronic administration of high doses of d-amphetamine produced time-limited, surmountable tolerance to stimulus effects of d-amphetamine. 23 male Sprague-Dawley rats discriminated saline and 0.80 mg/kg d-amphetamine under fixed ratio (FR) schedules of food delivery. Suspending training and administering saline did not alter sensitivity to d-amphetamine, indicating that neither tolerance nor sensitization developed during regular training. Acute pretreatment with 3.2 mg/kg d-amphetamine did not alter the ED50 for stimulus effects of d-amphetamine. In contrast, administration of 3.2 or 6.4 mg/kg d-amphetamine, b.i.d., for 3 days or 2 weeks increased the ED50 for stimulus effects 3- to 4-fold but did not produce consistent tolerance to rate-altering effects. Tolerance to stimulus effects was surmountable, as higher doses of d-amphetamine produced full drug-lever selection in tolerant rats. Sensitivity recovered after chronic administration ended. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of d-Amphetamine and ethanol on a measure of behavioral inhibition in humans.

Little is known about the acute effects of psychoactive drugs on impulsivity and decision making in humans. This study examined the effects of d-amphetamine (AMP; 10 and 20 mg; N?=?20) and ethanol (EtOH; 0.2, 0.4, and 0.8 g/kg; N?=?17) on the stop task, a putative measure of behavioral inhibition and impulsivity in healthy human volunteers. The stop task provides a measure of the reaction time (RT) needed to inhibit a response (Stop RT [SRT]), relative to the time taken to execute a simple response (Go RT [GRT]). Healthy volunteers performed the stop task before and after receiving one of the drugs. AMP decreased SRT–that is, improved inhibition–only in participants with slow baseline SRTs. EtOH increased SRTs–that is, impaired inhibition–at doses that did not affect GRTs. These results suggest that AMP and EtOH have specific and distinctive effects on the ability to inhibit responses. Impairment in the ability to inhibit responses is thought to reflect a certain form of impulsivity. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of d-amphetamine on task performance and social behavior of humans in a residential laboratory.

Six healthy adult male volunteers lived for 11 days in a residential laboratory. Acute effects of d-amphetamine (0, 5, or 10 mg/70 kg) on performance of tasks, social interaction, and self-reports of drug effects were measured. Each day, participants engaged in a 6.5-hr work period and a 6.5-hr recreation period. Beverages containing d-amphetamine or placebo were consumed daily before the work period and before the recreation period. d-Amphetamine increased response rate without affecting accuracy on some tasks. d-Amphetamine increased the proportion of time spent engaging in verbal interaction during the first but not the second week of the study. No changes in self-reported drug effects were observed. Thus, d-amphetamine improved performance in the absence of stimulant-like subjective effects. This differentiation between performance and subjective effects confirms the importance of determining the effects of drugs on a range of behaviors. (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)     

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)     

The effects of triazolam on aggression in men.

To assess the effects of triazolam on human aggression, 46 male participants received either placebo or 0.25 mg triazolam using double-blind procedures. Approximately 60 min after drug ingestion, participants were given the opportunity to administer electric shocks to an increasingly provocative fictitious opponent during a competitive reaction time task. Aggression was defined as the level of shock the participant was willing to administer to the opponent. The results suggest that triazolam consumption was associated with increased levels of aggression. On average, participants who received triazolam set more intense levels of shock for the opponent, and selected the most extreme shock response available more frequently, than participants who received placebo. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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)     

Secobarbital in humans discriminating triazolam under two-response and novel-response procedures

The percentage of long-term survivors after intensive chemotherapy and the outcome of MDS patients who achieve partial remission (PR) with intensive chemotherapy (IC) are not known. Between 1981 and 1996 we treated 99 patients with de novo MDS who had high-risk MDS or progression to AML, with IC. 41 (41%) achieved CR, 16 (16%) achieved partial remission (PR), 26 (26%) had failure, and 16 (16%) died in aplasia. Eight of the patients who achieved CR were autografted, three were allografted and the remaining cases received moderate consolidation chemotherapy. After IC, the 16 PR patients fulfilled the criteria for RA in 15 cases and CMML in one case. Median PR duration was 17 months, and three PR were > 3 years (39, 50+, 82+ months). Median actuarial survival of patients who achieved PR and CR was 18 months and 20 months from the onset of IC, respectively (difference not significant). Of the 71 patients treated before 1993, with sufficient follow-up, 10 (14%) had survived > 4 years (long-term survivors). Four of them were alive in first CR after 49+ to 110+ months and probably cured, two were alive in PR after 50+ and 82+ months and four had died after 49-78 months. Long-term survivors were characterized by a significantly higher incidence of RAEB-T at diagnosis, and with normal or favourable cytogenetic findings. In patients with RAEB-T at diagnosis included before 1993, 8/23 (35%) cases who had no unfavourable karyotype had survived > 4 years. Our findings suggest that MDS patients who achieve PR with IC, and not only those who achieve CR, can benefit from this type of treatment. The percentage of long-term survivors remains low, however, and is almost restricted to patients with RAEB-T at diagnosis and no unfavourable karyotype.     

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)     

Nicotine-like discriminative stimulus effects of bupropion in rats.

Bupropion, a tobacco-cessation product, shares discriminative stimulus effects with cocaine and methamphetamine. The discriminative stimulus effects of these drugs, in turn, overlap with those of nicotine. This study investigated the overlap in discriminative stimulus effects of bupropion and nicotine. Rats were trained to discriminate 0.4 mg/kg (-)-nicotine from saline in 2-lever drug discrimination. Both nicotine and bupropion substituted for nicotine: however nicotine's effects were blocked by the nicotinic antagonist mecamylamine, whereas those of bupropion were not. These results suggest that bupropion may be producing its nicotine-like discriminative stimulus effect though a different mechanism that nicotine. Give bupropion's shared pharmacology with dopamine transport inhibitors, these effects may be produced in part through bupropion's actions on dopaminergic neurotransmission. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Role of dopamine in d-amphetamine-induced euphoria in normal, healthy volunteers.

The present study evaluated the role of dopamine in the euphorigenic effects of d-amphetamine in normal volunteers. d-Amphetamine (20 mg) was administered alone and after pretreatment with pimozide (4 mg), fluphenazine (3 or 6 mg), or prazosin (1 or 2 mg) in 3 separate groups of participants. Subjective effects were measured at regular intervals. It was hypothesized that pimozide and fluphenazine, but not prazosin, would attenuate the euphorigenic effects of d-amphetamine. In all studies, d-amphetamine produced robust stimulant-like effects (e.g., increased scores on measures of arousal and euphoria). Although none of the antagonists significantly attenuated subjective responses to d-amphetamine, there were trends for both dopamine antagonists to reduce some responses. Both dopamine antagonists also produced modest effects when administered alone. These findings are inconsistent with those of studies with laboratory animals, perhaps because of differing experimental conditions. Alternatively, these findings raise the possibility that separate processes mediate drug reinforcement and euphoria. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Sleepiness and the reinforcing and subjective effects of methylphenidate.

On 4 days, 6 volunteers received 10mg methylphenidate or placebo at 0900 after 4 or 8 hr time in bed (TIB) and then on 4 days after 4 or 8 hr TIB chose their preferred capsule. On sampling days, 4 hr TIB increased multiple sleep latency test (MSLT) scores and Fatigue scale scores on the Profile of Mood States (POMS). In both TIBs, the drug increased the MSLT and POMS Vigor and Tension scale scores. It reduced POMS Fatigue scores and improved divided attention performance to a greater extent after 4 versus 8 hr. Drug was chosen on 88% of days after 4 hr, but only 29% of days after 8 hr. Preference for the drug depends on sleepiness and is mediated by performance-enhancing and fatigue-altering effects. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Dose effects of triazolam and alcohol on cognitive performance in healthy volunteers.

Benzodiazepines and alcohol are widely used psychoactive substances that have performance-impairing effects. Research suggests that the impairment profiles for benzodiazepines and alcohol differ, although few cognitive psychopharmacological studies have directly compared these drugs. This double-blind, double-dummy, placebo-controlled, repeated measures study directly compared the acute dose effects of triazolam (0.125, 0.25 mg/70 kg) and alcohol (0.40, 0.80 g/kg) in 20 social drinkers. At doses that produced comparable psychomotor impairment, triazolam was more likely to impair several objective measures of cognitive performance (e.g., episodic memory, divided attention) and to slow performance across several measures. However, only alcohol impaired accuracy on the digit symbol substitution and semantic memory tasks. In addition to objective measures, both drugs impaired awareness of performance impairments (i.e., metacognition) such that participants overestimated impairment, and the magnitude of this effect was generally larger for alcohol. Only triazolam impaired other measures of metacognition (e.g., error detection on a choice reaction time task). Future research might examine the clinical implications of the performance impairments reported here given the widespread use of benzodiazepines and alcohol. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Posttrial d-amphetamine sulfate and one-trial learning in mice.

Conducted 3 experiments with a total of 216 male albino LACA mice to investigate the effect of dextroamphetamine sulfate on memory in such a way that (a) state-dependency learning effects were excluded, (b) the time of learning was known rather precisely, (c) the drug might be introduced rapidly after the learning trial if recovered, and (d) no previous learning experience or drug effects would be present to confound the interpretation of results. Results show that amphetamine (2 mg/Kg, iv) immediately after footshock on a 1-trial passive avoidance learning task impaired performance in retention tests 24 and 96 hrs later. When the injection was delayed by as little as 90 sec, no such impairment was seen. A similar injection immediately after the learning trial of a water-rewarded 1-trial appetitive task had no discernible effect on performance in retention trials 24 hrs and 6 wks later. It is argued that the effects of the amphetamines on learning behavior depend on whether reward or punishment is involved and, further, that all such effects could be accounted for in terms of the drugs' influence on memory mechanisms. (28 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)