Ethanol and pentobarbital: Comparison of behavioral and subjective effects in sedative drug abusers.

The behavioral and subjective effects of acute oral doses of placebo, ethanol (0.5, 1.0, and 2.0 g/kg), and pentobarbital (150, 300, 600, and 750 mg/70 kg) were compared in 8 male volunteers with histories of sedative drug abuse using a double-blind, double-dummy, cross-over design. Ethanol and pentobarbital produced similar dose-related decrements in psychomotor and cognitive performance and exhibited a similar profile of effects on staff- and participant-rated measures. There was some evidence indicating that, at the highest dose, pentobarbital was perceived by participants as being more sedating than ethanol and that pentobarbital has a greater abuse liability than ethanol. In conjunction with the results of previous human laboratory studies comparing the effects of different types of sedative-hypnotic drugs, these results support a mostly barbituratelike rather than benzodiazepinelike profile of effects for ethanol. (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)     

The effects of transnasal butorphanol on mood and psychomotor functioning in healthy volunteers

Transnasal butorphanol is effective in relieving migraine and postoperative pain. The extent to which this drug preparation impacts on cognitive and psychomotor performance, as well as mood, has not been examined. Accordingly, the cognitive and psychomotor, subjective, and physiological effects of two clinically relevant doses of transnasal butorphanol (1 and 2 mg) were compared to that of placebo, and a common analgesic drug combination given for pain relief in ambulatory settings, 600 mg of acetaminophen and 60 mg of codeine, in healthy volunteers (n = 10). The larger transnasal butorphanol dose impaired psychomotor performance for up to 2 h, and produced subjective effects for up to 3 h. The smaller dose had no psychomotor-impairing effects, but had subjective effects (including increased ratings of "sleepy"). All three active drug conditions including miosis. These laboratory results suggest that patients should use caution when using the 1-mg dose of transnasal butorphanol, and should curtail certain activities if they administer the 2-mg dose of transnasal butorphanol for analgesia.     

Perception of alcohol intoxication shows acute tolerance while executive functions remain impaired.

Several psychological constructs (e.g., subjective perception of intoxication, visuomotor speed) display acute tolerance to alcohol, that is, show improvement at declining blood alcohol concentrations (BACs) relative to equivalent rising BACs. However, methodological challenges emerge when attempting to make such comparisons across limbs of the BAC curve, which have proven a barrier to advancing research on acute tolerance. To date, no studies have made multiple comparisons across the entire BAC trajectory. This study employs experimental procedures that overcome some of these difficulties, offering a clearer picture of recovery of impairment for subjective perception of intoxication and cognitive performance and the relationship between them. Twenty participants were assessed at multiple time points over 2 days. Continuous subjective perception of intoxication ratings and cognitive data derived from a computerized measure were paired with a novel analytic paradigm, which allowed comparisons at identified BACs. Results showed acute tolerance for individuals' subjective perception of intoxication and for performance on cognitive tasks measuring visuomotor speed and learning efficiency (recovery from impairment). In contrast, performance on measures of executive function and short-term memory showed no significant difference between limbs at exact concentrations (no recovery from impairment). Therefore, despite participants feeling less intoxicated over time, many cognitive functions remained impaired. The implication for these findings in terms of drunken driving behavior are substantial, suggesting that people may be likely to drive once they subjectively perceive that they have recovered from the acute intoxicating effects of alcohol, despite the persistence of “higher order” cognitive impairments. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Inhibition of prostaglandin synthesis and effects of ethanol and pentobarbital in humans

Results from animal research suggest that pretreatment with prostaglandin synthesis inhibitors (PGSIs) may inhibit physiological and behavioral effects of moderate ethanol ingestion. We examined the effects of ethanol and pentobarbital in humans with and without pretreatment with indomethacin, a potent PGSI. Ten male subjects with histories of recreational use of ethanol and sedative/hypnotics participated in this inpatient study. The effects of indomethacin alone (0.66 mg/kg), indomethacin (0, 0.17, 0.33, 0.66 and 1.33 mg/kg) in combination with ethanol (0 and 1 g/kg) and indomethacin (0 and 0.66 mg/kg) in combination with pentobarbital (0, 1.33 and 4 mg/kg) were tested. On test days, subjects swallowed capsules containing indomethacin or placebo. One hour later, they swallowed capsules that contained pentobarbital or placebo and a large drink (500 ml) of tonic water that contained ethanol or placebo (tonic water with 2 ml of ethanol floated on top). Both ethanol and pentobarbital affected subjective ratings, performance measures and heart rate. However, indomethacin pretreatment had no influence on drug-induced changes to ethanol and pentobarbital. The results of this study illustrate the relationship between depressant drugs and human performance, but they do not support the hypothesis that inhibition of prostaglandin synthesis diminishes the effects of ethanol and pentobarbital in humans.     

Sensitivity to low doses of ethanol and pentobarbital in mice selected for sensitivity to hypnotic doses of ethanol.

Assessed sensitivity to low doses of ethanol and pentobarbital in mice that had been selectively bred with respect to ethanol sleep time (the length of time an animal remains on its back following a hypnotic dose of ethanol). The hypothesis investigated was that short-sleep (SS) Ss might be more sensitive than long-sleep (LS) Ss to excitatory effects produced by low doses of depressants. In support of this hypothesis, SS Ss were more active in an open-field test after ethanol than were LS Ss. Two experiments were conducted, using 88 LS and 88 SS Ss. The lines did not differ in performance on a rotating-rod apparatus after these same doses of ethanol, suggesting that the difference in open-field activity was not attributable to a greater impairment of locomotor activity in LS Ss. A similar difference in the open-field activity of the selected lines was observed with pentobarbital. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Stress controllability influences the ataxic properties of both ethanol and midazolam in the rat.

Rats were administered either 80 escapable shocks or yoked inescapable shocks, were then injected with saline or several ataxic doses of either ethanol or midazolam, and then had their motoric impairment assessed by Rotarod performance. No motoric impairment was observed following saline injection. However, inescapable shock impaired Rotarod performance in response to both ethanol and midazolam at 2 hr, but not immediately poststress. Conversely, escapable shock reduced the ataxic potency of ethanol, although it had no influence on midazolam-induced ataxia. These results indicate functional alterations in behavioral reactivity to low doses of several classes of central nervous system depressants by psychological dynamics of stress exposure. Our findings demonstrate the impact of stress controllability on behavioral reactivity to two classes of drugs of abuse. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Effects of phencyclidine, pentobarbital, and d-amphetamine on the acquisition and performance of conditional discriminations in monkeys

In each of two components of a multiple schedule, monkeys were required to respond on a right or left lever depending upon the stimulus combination (a color and a geometric form) presented. Reinforcement of a response in the presence of one stimulus (the form) was therefore conditioned upon the other stimulus (the color). The completion of a two-member chain of discriminations produced a food pellet. Errors produced a brief timeout. One composition of the multiple schedule was a repeated-acquisition task where the discriminative stimuli for left- or right-lever responses changed each session (learning). In the other component, the discriminative stimuli for left- or right-lever responses were the same each session (performance). Phencyclidine, pentobarbital, and d-amphetamine each produced dose-related decreases in the overall rate of responding in both components of the multiple schedule. At high doses each drug increased the percent errors in each component. At lower doses, however, the three drugs produced selective effects on accuracy. Errors were increased in the learning component at lower doses than those required to disrupt the discrimination in the performance component. A signal detection analysis of the data revealed that none of the drugs tested increased errors by selectively affecting either discriminability or bias.     

Ethanol and spatial localization.

Water (Exp 1) and radial maze (Exp 2) tasks permitted an evaluation of the relative degree of impairment imposed by ethanol (0, 0.75, 1.5, and 2.0 g/kg) on cognitive mapping vs. cued place learning. The tasks did not require working memory. A strong tendency emerged for ethanol-treated rats to persist in cognitive mapping strategies after the strategies were no longer useful, but there was no indication of a mapping impairment per se. When performance deficits appeared, they were equivalent across mapping and cued place tasks and may have reflected motivational effects of ethanol. In most instances neither mapping nor cued place tasks were difficult for ethanol-treated animals unless the tasks required abandoning one strategy for another. The tenacity of ethanol-treated rats to use cognitive mapping strategies, particularly rats receiving the highest dose, proved consistent and theoretically decisive. The behavioral invariance of ethanol-treated rats is not caused by a cognitive mapping deficit. Rather, mapping is another domain in which ethanol reduces flexibility. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Carbamazepine and lamotrigine in healthy volunteers: relevance to early tolerance and clinical trial dosage

This study was conducted to examine the effects of acute doses of lamotrigine (LTG) and carbamazepine (CBZ) in healthy subjects and determine whether the low tendency to impairment with LTG observed in animals applied to humans. Twelve healthy men participated in a placebo-controlled, balanced, double-blind comparison of the drugs on a series of psychomotor, autonomic, sensory, and subjective variables. Variables were analyzed by analysis of variance, and p < 0.05 was considered significant. Adaptive tracking and body sway were impaired by CBZ 600 mg. CBZ 400 and 600 mg impaired smooth pursuit eye movements and also reduced mean peak saccadic velocity. No differences from placebo occurred after LTG. CBZ 600 mg increased heart rate (HR), but no drug-related changes were noted in pupil size, salivary secretion, visual near point, or subjective effects. During the controlled study, mean plasma CBZ concentrations at 2 and 6.5 h after the 600-mg dose were 5.28 and 5.36 micrograms/ml; after LTG 300 mg, they were 3.16 and 3.00 micrograms/ml. Increased CBZ saliva concentrations were significantly associated (p < 0.01) with impaired adaptive tracking, smooth and saccadic eye movements and increased HR, and plasma concentrations were associated with impaired eye movements and body sway.     

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)     

Comparing the subjective, psychomotor and physiological effects of intravenous nalbuphine and morphine in healthy volunteers

The purposes of this study were to characterize the subjective, psychomotor and physiological effects of nalbuphine in healthy non-drug abusing volunteers and to compare and contrast the effects of equianalgesic doses of nalbuphine and morphine. Subjects (12 males, 4 females) without histories of opiate dependence were injected in an upper extremity vein with 0, 2.5, 5.0 or 10 mg/70 kg nalbuphine, or with 10 mg/70 kg morphine, using a randomized, double-blind, crossover design. The 10-mg doses of nalbuphine and morphine are considered equianalgesic and are doses commonly given for relief of postoperative pain. Subjective effects of nalbuphine included increased scores on the Pentobarbital-Chlorpromazine-Alcohol Group scale and the Lysergic Acid Diethylamide scale of the Addiction Research Center Inventory; increased adjective checklist ratings of "nodding," "numb" and "sweating"; increased visual analog scale ratings of "coasting or spaced out," "high" and "sleepy" and increased "feel drug effect" and drug-liking ratings. Ten milligrams of nalbuphine had subjective effects similar, and similar in magnitude, to those of 10 mg of morphine. Nalbuphine produced exophoria and impairment on the Digit Symbol Substitution Test in a dose-related fashion. Ten milligrams of morphine produced exophoria but did not affect performance on the Digit Symbol Substitution Test. Both nalbuphine and morphine induced miosis and decreases in respiration rate. The results of the present study demonstrate that 2.5 to 10 mg nalbuphine had orderly, dose-related effects on subjective, psychomotor and physiological variables. The results also indicate that 10 mg of nalbuphine produces a profile of subjective, psychomotor and physiological effects similar to that of an equianalgesic dose of morphine (10 mg). The similarity in profiles between drugs at this dose is consistent with both infrahuman studies, which suggests that nalbuphine is a mu agonist, and studies with nondependent opioid abusers, in which relatively low doses of nalbuphine (such as 10 mg) produce morphine-like effects.     

Alprazolam and DN-2327 (Pazinaclone) in humans: Psychomotor, memory, subjective, and reinforcing effects.

The psychomotor, memory, subjective, and reinforcing effects of DN-2327 (DN), a novel partial agonist at benzodiazepine receptors, were compared with those of alprazolam (AL) in 14 men with histories of sedative drug abuse. Placebo, DN (8, 16, and 32 mg), and AL (0.5, 1.0, and 2.0 mg) were administered orally in a randomized, double-blind, cross-over design. DN and AL produced similar maximal impairment on psychomotor and memory performance. AL produced greater increases in participant ratings of sedation and a variety of somatic symptoms that were absent following DN. Abuse liability measures showed both drugs increased liking and good effects and were categorized by participants as sedative-hypnotics; however, 2 of 3 indirect and 1 direct measure of drug reinforcement were greater with AL than with DN. The dissociation between psychomotor-memory performance effects and various subjective effects demonstrates a novel pharmacological profile of DN. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Subjective cognitive complaints and longitudinal changes in memory and brain function.

Objective: Subjective cognitive complaints are often used in the diagnosis of memory and other cognitive impairment. This study examined whether cognitive complaints are associated with longitudinal changes in cognition and cross-sectional differences in regional brain function during memory performance in 98 participants with a mean age of 75. Method: The Cognitive Failures Questionnaire (CFQ) assessed cognitive complaints and mixed effects regression models were used to determine whether mean CFQ scores predicted rates of change in cognitive function over a period of 11.5 years. Results: Higher CFQ scores, reflecting increased subjective complaints, were associated with steeper rates of decline in immediate and delayed recall on the California Verbal Learning Test. Voxel-based regression analysis was used to determine the cross-sectional relationship between CFQ scores and regional cerebral blood flow measured by PET during a resting condition and during verbal and figural memory tasks. Higher levels of cognitive complaints were associated with increased activity in insular, lingual and cerebellar areas during memory tasks. Conclusions: These findings offer some support for the validity of subjective cognitive complaints as markers of age related changes in memory and brain activity. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Mood and performance changes in women with premenstrual dysphoric disorder: acute effects of alprazolam

This study determined if women with premenstrual dysphoric disorder (PMS) showed impaired mood and performance when they were experiencing their premenstrual symptoms, and if the effects of alprazolam varied as a function of menstrual cycle phase. Under double-blind conditions, the acute effects of placebo and alprazolam (0.25, 0.50, 0.75 mg) were tested during both luteal and follicular phases. Women with confirmed PMS experienced substantial changes in mood as a function of menstrual cycle phase. However, under controlled laboratory conditions, acute doses of alprazolam did not improve negative premenstrual mood, but rather increased negative mood in the follicular phase. Alprazolam impaired task performance, although this impairment was generally similar in both phases when baseline phase differences were taken into consideration. Consistent with the failure of alprazolam to improve mood premenstrually, subjective measures indicative of abuse liability were not increased following alprazolam. Taken together, these data suggest that acute administration of alprazolam doses are not clinically useful for the treatment of PMS.     

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)     

Working memory and control of attention in persons with Alzheimer's disease and mild cognitive impairment.

The goal of the present study was to assess 3 attentional control processes--divided attention, manipulation capacities, and inhibition--in persons with mild cognitive impairment (MCI) and with mild Alzheimer's disease (AD). Manipulation capacities were tested by comparing immediate serial recall with alphabetical-order recall of words. Divided attention was tested with the Brown-Peterson procedure, in which participants divide their attention between simple addition tasks and consonant trigrams over delays. Inhibition was tested with the Hayling procedure, in which participants complete sentences with words irrelevant to their context. Persons with AD showed severe impairment on the 3 attentional control components. Persons with MCI exhibited impaired performance on the Brown-Peterson procedure but normal performance on the other 2 tasks. With AD and MCI participants, there was a negative correlation between general cognitive deficits and impairment on attentional control tasks, indicating that attentional control deficits increase in the MCI/AD continuum. When separating MCI with and without significant subsequent decline, those with subsequent decline showed impaired performance on both the Brown-Peterson procedure and manipulation task. These data suggest that control of attention tasks can track AD at a preclinical stage and that impairment increases gradually during the preclinical phase of AD. (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)     

Prenatal cocaine exposure impairs selective attention: Evidence from serial reversal and extradimensional shift tasks.

This study assessed the effects of prenatal cocaine exposure on cognitive functioning, using an intravenous (IV) rodent model that closely mimics the pharmacokinetics seen in humans after smoking or IV injection and that avoids maternal stress and undernutrition. Cocaine-exposed males were significantly impaired on a 3-choice, but not 2-choice, olfactory serial reversal learning task. Both male and female cocaine-exposed rats were significantly impaired on extradimensional shift tasks that required shifting from olfactory to spatial cues; however, they showed no impairment when required to shift from spatial to olfactory cues. In-depth analyses of discrete learning phases implicated deficient selective attention as the basis of impairment in both tasks. These data provide clear evidence that prenatal cocaine exposure produces long-lasting cognitive dysfunction, but they also underscore the specificity of the impairment. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Buprenorphine dose self-selection: Effects of an alternative reinforcer, behavioral economic analysis of demand, and examination of subjective drug effects.

Buprenorphine (BUP)-maintained patients were first exposed to various BUP doses and then chose between BUP doses and money. In the choice phase, they had 10 units exchangeable for units of BUP (constant at 3 mg/unit) or money (varied from $0.30 to $20/unit). They chose BUP exclusively (30 mg) when the money alternative was low. As available money increased, they selected lower daily BUP doses (down to 3 mg). An economic analysis indicated demand for BUP was inelastic; changes in drug intake were proportionally lower than changes in price. Subjective reports of agonist and withdrawal effects increased >200% when high and low BUP doses, respectively, were given during the exposure phase. In the choice phase, subjective drug effects were constant regardless of the BUP dose selected. Thus, BUP dose selection varies with the magnitude of alternative reinforcers, and subjective drug effects depend on whether doses are self- or experimenter-selected. (PsycINFO Database Record (c) 2010 APA, all rights reserved)