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

This study was designed to develop a version of the stop task, a putative measure of behavioral inhibition, for use in rats and to assess the effects of d-amphetamine (AMP) and alcohol (ALC). The stop task provides a quantitative index of the ability to inhibit a response that has been initiated. Rats (N?=?11) were tested after intraperitoneal injections of AMP (0.125, 0.25, 0.5, 1.0 mg/kg) and ALC (250, 500, 750 mg/kg). AMP improved the ability to inhibit responses only in rats with relatively poor inhibitory performance at baseline. ALC impaired inhibition at doses that did not affect simple reaction time. The results support the sensitivity, reliability, and validity of the procedure as a measure of behavioral inhibition in rats and are highly concordant with a parallel study conducted with humans. (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)     

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)     

Separation of drug effects on timing and behavioral inhibition by increased stimulus control.

Impulsive behavior may represent, in part, a failure of behavioral inhibition (the ability to delay or inhibit a response). In this study, use of a multiple signaled–unsignaled differential-reinforcement-of-low-rates (DRL) 15-s schedule allowed examination of drug effects in conditions in which level of stimulus control differed. Results showed that whereas diazepam increased premature responding during signaled and unsignaled DRL components, amphetamine and Δ?-tetrahydrocannabinol increased premature responding primarily during unsignaled components when timing was necessary for efficient performance on the task. In contrast, primozide and desipramine increased long-delay responses across both components, resulting in longer mean interresponse times. Collectively, these results suggest that the use of different levels of stimulus control may aid in separation of drug effects on timing and other behavioral processes, including behavioral inhibition. (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.     

Dissociative antagonistic effects of caffeine on alcohol-induced impairment of behavioral control.

The present study examined the separate and combined effects of alcohol and caffeine on behavioral control in a context in which preliminary cues signaled the likelihood that a response should be executed or inhibited. Social drinkers (N = 12) performed a cued go/no-go task that measured control as the quick execution of responses to go targets and sudden suppression of responses to no-go targets. Performance was tested under 3 doses of caffeine (0.0 mg/kg, 2.0 mg/kg, and 4.0 mgl/g) in combination with 2 doses of alcohol (0.0 g/kg and 0.65 g/kg). Alcohol impaired both inhibitory and activational aspects of behavioral control. Caffeine antagonized alcohol effects on response execution but had no effect on inhibitory control. The findings highlight potential differences in how activational and inhibitory aspects of behavioral control respond to drug interactions. (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)     

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)     

Inhibitory Control in Rats Performing a Stop-Signal Reaction-Time Task: Effects of Lesions of the Medial Striatum and d-Amphetamine.

The stop-signal task measures the ability to inhibit a response that has already been initiated, that is, the ability to stop. Imaging studies have implicated frontostriatal circuitry in the mediation of this form of response control. The authors report inhibition functions of normal rats and those with medial striatal damage performing the stop-signal task. Excitotoxic lesions of the medial striatum produced significant deficits on task performance, including increased omissions on the go task and flattened inhibition function, possibly as a result of increased reaction-time mean and variability. Medial striatal lesions also significantly slowed stop-signal reaction time. Subsequent treatment with d-amphetamine removed (0.3 mg/kg) or exacerbated (1.0 mg/kg) this deficit. (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.     

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)     

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)     

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)     

Dissociating interference-control processes between memory and response.

The ability to mitigate interference is of central importance to cognition. Previous research has provided conflicting accounts about whether operations that resolve interference are singular in character or form a family of functions. Here, the authors examined the relationship between interference-resolution processes acting on working memory representations versus responses. The authors combined multiple forms of interference into a single paradigm by merging a directed-forgetting task, which induces proactive interference, with a stop-signal task, which taps response inhibition processes. The results demonstrated that proactive interference and response inhibition produced distinct behavioral signatures that did not interact. By contrast, combining two different measures of response inhibition by merging a go/no-go task variant and a stop signal produced overadditive behavioral interference, demonstrating that different forms of response inhibition tap the same processes. However, not all forms of response conflict interacted, suggesting that inhibition-related functions acting on response selection are dissociable from those acting on response inhibition. These results suggest that inhibition-related functions for memory and responses are dissociable. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

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.     

Effects of triazolam and ethanol on proactive interference: evidence for an impairment in retrieval inhibition

The effects of two memory-impairing drugs, ethanol and triazolam, on proactive interference (PI) in memory were studied. Following ingestion of either one of these drugs or a placebo, subjects studied an A-B list (e.g., BEE-WASP) of paired associates, followed by an A-C list (e.g., BEE-HONEY) on the interference trial, and a D-E list (e.g., KING-QUEEN) followed by an A-C list on the control trial. A PI effect was found in the data, such that subjects produced fewer correct second list targets on the interference trial than on the control trial. Neither ethanol nor triazolam was found to influence the size of the PI effect. However, both drugs were found to increase B intrusions on the test of the A-C list, to impair subjects' ability to produce more than one studied response for each cue word, and to impair the subjective experience of retrieved memory information. These data suggest that ethanol and triazolam impair an inhibitory process that normally operates as one component of intentional retrieval, playing an important role in the suppression of unwanted information during a memory task.     

Evaluation of genetic variability in the dopamine receptor D2 in relation to behavioral inhibition and impulsivity/sensation seeking: An exploratory study with d-amphetamine in healthy participants.

The dopamine D2 receptor (DRD2) appears to be involved in impulsive behaviors, and particularly in behavioral inhibition. We sought to determine whether inhibition and impulsivity were related to genetic polymorphisms in the DRD2 gene (DRD2) in healthy volunteers (N = 93). Participants received placebo or d-amphetamine in random order. They performed the stop task, measuring behavioral inhibition, and rated their mood states on each session. They also completed the Zuckerman–Kuhlman Personality Questionnaire, including an Impulsivity subscale. We investigated the association between 12 single nucleotide polymorphisms (SNPs) and haplotypes in DRD2 and stop task performance in the nondrug (i.e., placebo) session and on the personality measure of impulsivity. We secondarily evaluated the DRD2 SNPs in relation to response to d-amphetamine on stop task performance and mood ratings. Mood was not related to genotypes in either the drug free condition or in response to drug. However, 2 SNPs, rs4648317 and rs12364283, and a haplotype block consisting of those SNPs, were associated with better performance on the stop task in the drug free condition and lower scores on the Impulsivity subscale. We also found that rs12364283 was associated with effects of d-amphetamine on stop task performance: d-amphetamine decreased stop reaction time (RT) in the A/A group but increased stop RT in the combined A/G + G/G genotype. Of the SNPs we evaluated, rs12364283, which has been associated with DRD2 expression, was the most significantly associated with inhibition and impulsivity. The significant relationship between DRD2 genotype and both behavioral inhibition and impulsivity suggests a possible common genetic influence on behavioral and self-report measures of impulsivity. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Triazolam-induced changes in alcoholic thought processes

This study was designed to examine and contrast cognitive effects (explicit memory and access to semantic knowledge) of the benzodiazepine Halcion (triazolam) in ten normal volunteers and ten cognitively un-impaired detoxified alcoholics. The two groups were indistinguishable from one another under placebo conditions on all measures of cognitive functioning. Under Halcion test conditions (0.375 mg p.o.), both groups were about equally impaired in their recall of to-be-remembered information. However, alcoholics, were more likely to recall information that they were not asked to remember (intrusion errors) on all measures of explicit remembering. Alcoholics also generated relatively uncommon (low frequency) responses from semantic memory, rather than common, categorically related associations in response to stimuli such as types of vegetables, flowers, and fruit following the administration of Halcion, but were not different from normal volunteers in the types of responses generated under placebo conditions. These findings suggest that a drug challenge that simulates many of the effects of acute alcohol administration induces alcoholics to think and remember differently (qualitatively) from normal volunteers.     

Reduced electrodermal response to conflict, failure to inhibit dominant behaviors, and delinquency proneness.

Antisocial behavior patterns have been hypothesized to result in part from a reduced physiological component of fear, anxiety, and avoidance responses. The authors examined whether reduced electrodermal responses (EDR) of undersocialized individuals should be conceptualized in terms of reduced inhibitory control rather than in terms of reduced aversive processes and whether the reduced EDR actually relates to relevant behavior of undersocialized young adults. 90 male college students with high or low scores on the Socialization scale of the California Psychological Inventory performed a nonstressful response-conflict (or interference) task while the EDR was recorded. As predicted by the weak inhibitory control model, low-socialization Ss gave a larger EDR on response conflict than on control trials less frequently than did high-socialization Ss and, correspondingly, committed more errors by failing to inhibit a dominant behavioral response. (26 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of methylphenidate on cooperative responding in children with attention deficit-hyperactivity disorder.

The effects of methylphenidate on cooperative responding in children with attention deficit hyperactivity disorder were examined. During 1 of 2 alternating periods of a laboratory task, the child's button presses added points to a counter marked Your Earnings. During the 2nd period, cooperative and independent response options were available. Cooperative responses added points simultaneously to a counter marked Your Earnings and Other's Earnings. Concurrently available independent responses added points only to the counter marked Your Earnings. Time allocated to the cooperative response option was significantly decreased following acute administration of the 0.3 mg/kg and the 0.6 mg/kg methylphenidate doses as compared with placebo. Implications for understanding the behavioral mechanism of methylphenidate effects on social behavior are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)