Stimulant Drug Effects on Performance and Behavior After Prolonged Sleep Deprivation: A Comparison of Amphetamine,Nicotine, and Deprenyl

Normal male subjects (N = 102) underwent total sleep deprivation in a laboratory environment for 48 hr. In separate dose-response, double-blind, placebo-controlled experiments, 36 subjects received single doses of d- amphetamine, 35 received intravenous nicotine, and 31 received l-deprenyl. All were deprived of sleep for an additional 12 hr. Amphetamine reversed the effects of sleep loss in a dose-related way, but the pattern and persistence of the reversal varied across measures. Neither nicotine nor I-deprenyl produced substantial persistent reversal of sleep deprivation effects. We conclude that these latter two agents are unlikely to be useful for the acute remediation of the effects of severe sleep loss. Although amphetamine is acutely effective, its usefulness in the treatment or prophylaxis of sleep loss requires further study.     

Effect of sulpiride on amphetamine-induced activity and stereotyped locomotion

To investigate the hypothesis that sulpiride potentiates stereotyped locomotion at an intermediate dose of amphetamine, rats were assigned to one of four treatment groups (n=7 per group): vehicle + saline; 20 mg/kg sulpiride + saline; vehicle + 3.5mg/kg amphetamine; 20 mg/kg sulpiride + 3.5 mg/kg amphetamine. An automated tracking system was used to record distance moved and sequences of movements between quadrants in a circular open-field. The results showed that amphetamine increased horizontal distance moved, and increased the number and proportion of thigmotaxic trips around the perimeter of the apparatus. Sulpiride reduced amphetamine-induced hyperactivity and the number of perimeter trips, but had no effect on the proportion and maximum run length of perimeter trips. Thus sulpiride reduces the hyperactivity produced by an intermediate dose of amphetamine, but does not appear to affect the stereotyped nature of locomotion under the drug.     

Trait-anger enhances effects of caffeine on psychomotor vigilance performance

This study examined the combined effects of caffeine and the personality attribute of trait-anger on the speed of psychomotor vigilance performance during sleep deprivation. 23 young adult soldiers (19 male) were administered the State-Trait Anger Expression Inventory-2 when well-rested. Participants were then sleep deprived for three consecutive nights (77 hours total) during which they completed repeated psychomotor vigilance testing. Half of the participants received four doses of oral caffeine (200 mg every 2 hr.; 800 mg total) each night, while the other half were administered a placebo. For the first night, higher scores on trait-anger, outward anger expression, and intensity of anger expression predicted better sustained overnight vigilance performance, but only for those volunteers receiving caffeine. These correlations were not significant for the subsequent nights. Findings suggest a possible synergistic effect between personality traits associated with arousal of the central nervous system and vigilance-promoting effects of caffeine.     

Recovery of performance during sleep following sleep deprivation in older normal and insomniac adult males

Groups of 12 normal and insomniac male subjects aged 55 to 71 yr. were sleep deprived for 64 hr. In both groups, the sleep loss was preceded by four baseline sleep nights and followed by four recovery nights. Reaction time, immediate recall, sleepiness, and body temperature were measured at approximately 2300, 0115, 0330, 0530, and 0800 during baseline, deprivation and recovery nights. Significant performance or mood differences were not found between the normal and insomniac males on any measure or at any testing period throughout the study. Performance of both groups declined characteristically during sleep loss while subjective sleepiness increased. As in young adults, degraded performance was restored by 8 hr. of recovery sleep. However, subjective sleepiness did not return to baseline levels until early in the second recovery night. It was concluded that chronic insomnia does not result in group performance deficits similar to those seen after chronic sleep loss; and the restorative function of sleep operates as efficiently in older insomniac subjects (who apparently have reduced need to sleep) as in older normal subjects.     

Effects of acute sleep restriction on behavior, sustained attention, and response inhibition in children.

This study examined the effects of acute sleep restriction on the day-time behavior and performance of healthy children and adolescents. 82 participants (8 to 15 years of age) completed 5 nights of baseline sleep and were randomly assigned to Optimized (10 hr.) or Restricted (4 hr.) sleep for an overnight lab visit. Behavior, performance, and sleepiness were assessed the following day. Sleep restriction was associated with shorter daytime sleep latency, increased subjective sleepiness, and increased sleepy and inattentive behaviors but was not associated with increased hyperactive-impulsive behavior or impaired performance on tests of response inhibition and sustained attention. Results are discussed in terms of current theories regarding effects of inadequate or disturbed sleep among children and adolescents.     

Melatonin and sleep qualities in healthy adults: pharmacological and expectancy effects

The impact of expectancy on melatonin's effects on sleep qualities was investigated. Both the pharmacological dose of 6 mg of melatonin and the expectation of receiving melatonin were predicted to improve subjective ratings of sleep qualities. The balanced placebo design varied 2 factors within-subjects: actual treatment and expected treatment. Adults (N = 53; 21 men and 32 women) between the ages of 26 and 71 years were administered either 6 mg of melatonin or a placebo for 8 nights. An instructional manipulation directed participants' expectations. Participants rated their nightly sleep experiences. Results revealed that feelings upon awakening differed between genders and that expecting melatonin increased ratings of sleep continuity. Most important, high ratings of "grogginess/tiredness" were associated with receiving melatonin, regardless of expectancy, as well as with receiving placebo when melatonin was expected. Overall, the findings underscore the need to consider expectancy and gender differences in research on melatonin and sleep experiences.     

Three consecutive nights of sleep loss: Effects of morning caffeine consumption on subjective sleepiness/alertness,reaction time and simulated driving performance

Caffeinated products are often consumed as a popular countermeasure to the effects of sleep loss. However, the efficacy of caffeine to exert these effects after consecutive nights of sleep loss is poorly understood. The aim of this study was to investigate the effects of three consecutive nights of restricted sleep and morning caffeine consumption on subjective ratings of sleepiness/alertness, reaction time, and simulated driving performance. Twenty healthy, habitual caffeine consumers (11 females; age: 23.3 ± 5.7 y; BMI: 22.3 ± 3.5 kg⋅m⁻²; caffeine intake: 204 ± 89 mg⋅day⁻¹; Mean ± SD) who had normal sleeping patterns (≥8 h⋅night⁻¹) participated in this double-blind, placebo-controlled, randomised study. Following one night of normal sleep (≥8 h time in bed (TIB)), participants underwent three consecutive nights of restricted sleep (5 h TIB). Participants received caffeine (200 mg; n = 10) or placebo (n = 10) capsules each morning and all participants received caffeine (100 mg) capsules each afternoon. Subjective ratings of alertness, concentration and tiredness were measured before and 1 h after morning capsule administration. Choice Reaction Time (CRT) was examined 1 h after morning capsule administration, with response speed and accuracy as outcome variables. Driving performance was assessed using a 30 min simulated driving task, with lateral (standard deviation of lane position [SDLP]; total number of line crossings [LC]) and longitudinal (standard deviation of speed [SDSP]) measures of vehicle control as outcome variables. Alertness and concentration significantly decreased, and tiredness increased across the three days of sleep loss. Caffeine only marginally alleviated these effects. No differences were observed between treatments or across trial days for response speed and accuracy on the CRT task. Likewise, no significant differences were observed between groups or across trial days for any measures of simulated driving performance. Overall, results from this study indicate that three consecutive days of sleep loss influence subjective ratings of alertness, concentration and tiredness, but does not alter CRT or simulated driving performance. Caffeine may alleviate some of the negative subjective effects imposed by restricted sleep, but the efficacy of caffeine to attenuate performance changes in CRT and driving performance were unable to be observed.     

Methylphenidate enhances extinction of contextual fear

Methylphenidate (MPH, Ritalin) is a norepinephrine and dopamine transporter blocker that is widely used in humans for treatment of attention deficit disorder and narcolepsy. Although there is some evidence that targeted microinjections of MPH may enhance fear acquisition, little is known about the effect of MPH on fear extinction. Here, we show that MPH, administered before or immediately following extinction of contextual fear, will enhance extinction retention in C57BL/6 mice. Animals that received MPH (2.5-10 mg/kg) before an extinction session showed decreased freezing response during extinction, and the effect of the 10 mg/kg dose on freezing persisted to the next day. When MPH (2.5-40 mg/kg) was administered immediately following an extinction session, mice that received MPH showed dose-dependent decreases in freezing during subsequent tests. MPH administered immediately after a 3-min extinction session or 4 h following the first extinction session did not cause significant differences in freezing. Together, these findings demonstrate that MPH can enhance extinction of fear and that this effect is sensitive to dose, time of injection, and duration of the extinction session. Because MPH is widely used in clinical treatments, these experiments suggest that the drug could be used in combination with behavioral therapies for patients with fear disorders.     

Changes in cis(Z)-flupentixol-induced dopamine blockade produce contrast effects in rats

Two groups of rats were trained under a 45-sec variable-interval schedule. The magnitude of reinforcement used in each test session alternated daily between one and four 45-mg food pellets, the magnitude of reinforcement available at any time being signalled by lights in the operant chamber. Testing took place over two consecutive 11-day phases. During the first phase one group of rats was injected with 0.06 mg/kg of cis(Z)-flupentixol prior to testing; the other group received vehicle injections. In the second phase drug conditions were reversed. The change in drug conditions between phases produced both positive and negative successive contrast effects, consistent with the hypothesis that dopamine blockade attenuated the hedonic impact of reinforcement. Embedded within each session were two short signalled probe periods during which the reinforcement magnitude was switched to that used on the alternate days. No contrast effects were found during these brief daily probe periods.     

Predictors of Adherence to a Brief Behavioral Insomnia Intervention: Daily Process Analysis

Behavioral interventions for insomnia are effective in improving sleep, yet adherence is variable, and predictors of adherence have not been consistently replicated. The relationships between daily variations in state factors at the initiation of treatment and adherence have not been investigated. Using 2-week, self-report online logs, this study determined, among 53 college students with probable insomnia, the associations of pretreatment factors and daily factors during treatment on daily variations in adherence to one session of behavioral treatments for insomnia. These treatments included stimulus control therapy (SCT), sleep restriction therapy (SRT), and sleep hygiene (SH). Low self-efficacy was associated with poorer SCT and SH adherence. Participants with a “bed partner or pet” at least some of the time had better SCT adherence. Greater total sleep time and poorer sleep quality were associated with poor SCT and SRT adherence the following night. Greater sleep efficiency was related to greater next night SCT and SRT adherence. Alcohol consumption was related to poorer SRT and SH adherence the following night. Future studies should test the replicability of these findings. Adherence trials may want to test whether discouraging alcohol intake, enhancing treatment-related self-efficacy, and monitoring and providing feedback on sleep, early in treatment, affects adherence.     

REM periodicity under ultrashort sleep/wake cycle in narcoleptic patients

Six narcoleptic patients were tested three times on the 13-min waking/7-min resisting sleep paradigm each time after a night of sleep in the laboratory. The three experiments were conducted after 10 days without any antinarcoleptic treatment or after 2 weeks of daily treatment with either methyl-phenidate or aniracetam. The results showed that patients had pronounced levels of diurnal sleepiness in all three experimental conditions with a midafternoon peak at around 1300-1500 hr and a nadir at around 1800 hr. Methyl-phenidate significantly reduced REM sleep and marginally reduced total sleep in comparison with the no-treatment and aniracetam conditions. REM sleep in the 7/13 paradigm appeared cyclically with a dominant periodicity of 80 min/cycle. The cycles tended to be synchronized across patients and were unrelated to the temporal structure of total sleep. The present results support the continuation of the REM oscillator during brief periods of waking, but suggest that the REM periodicity is unrelated to Kleitman's BRAC model of arousal.     

Reduction in paradoxical sleep after L-dopa administration in rats

The EEG and EMG activity of two groups of rats (N = 8 each) was recorded during one experimental and 5 control days. On the experimental day, one group received 125.0 mg/kg L-dopa preceded by 50.0 mg/kg benserazide hydrochloride. The other group received 1.0 mg/kg haloperidol, immediately before the recording session. After L-dopa plus benserazide administration the total time and the number of episodes of paradoxical sleep and slow wave sleep decreased significantly compared to control sessions.     

Melatonin and Sleep Qualities in Healthy Adults: Pharmacological and Expectancy Effects

The impact of expectancy on melatonin's effects on sleep qualities was investigated. Both the pharmacological dose of 6 mg of melatonin and the expectation of receiving melatonin were predicted to improve subjective ratings of sleep qualities. The balanced placebo design varied 2 factors within-subjects: actual treatment and expected treatment. Adults (N = 53; 21 men and 32 women) between the ages of 26 and 71 years were administered either 6 mg of melatonin or a placebo for 8 nights. An instructional manipulation directed participants' expectations. Participants rated their nightly sleep experiences. Results revealed that feelings upon awakening differed between genders and that expecting melatonin increased ratings of sleep continuity. Most important, high ratings of “grogginess/tiredness” were associated with receiving melatonin, regardless of expectancy, as well as with receiving placebo when melatonin was expected. Overall, the findings underscore the need to consider expectancy and gender differences in research on melatonin and sleep experiences.     

Discriminative stimulus effects of diazepam and buspirone in normal volunteers.

A within-subject design was used to characterize the effects of dose manipulations on discriminative and self-reported effects of oral diazepam and buspirone. Subjects were trained to discriminate diazepam (10 mg) versus placebo (n = 10), or buspirone (10 or 15 mg) versus placebo (n = 9). The compounds were identified to subjects by letter code before discrimination training began. In later sessions, correct identifications at 2 hr after the oral administration of drug earned money. All subjects showed accurate discrimination performance during the test-of-acquisition phase. In a low-dose generalization phase, diazepam and buspirone produced dose-related increases in drug identifications across a four-fold range of doses. In a subsequent low-dose training phase, in which subjects were trained to discriminate progressively lower drug doses, the median lowest discriminable dose of diazepam and buspirone was 2.5 and 7.5 mg, respectively. Dose-response functions for drug identifications were shifted leftward in the low-dose training phase relative to the low-dose generalization phase, suggesting that reinforcement of progressively lower doses enhances drug discriminability. The self-reported effects of diazepam and buspirone were similar (e.g., both drugs increased ratings of drug strength and clumsy/uncoordinated) and different (e.g., diazepam but not buspirone increased ratings of drowsy/sleepy; buspirone but not diazepam increased ratings of tense/nervous). This study demonstrates discriminative and self-reported effects of diazepam and buspirone at doses lower than previously shown to be behaviorally active, and suggests that at commonly used clinical doses, diazepam is relatively more discriminable than buspirone.     

Combined action of diazepam and d-amphetamine on fixed-interval performance in cats

Cats trained under a fixed-interval 5-min schedule of milk presentation were injected with diazepam, amphetamine, and combinations of amphetamine and diazepam. Diazepam increased overall response rate as a function of the dose and disrupted the temporal pattern of responding. Low doses of amphetamine (0.5 mg/kg) usually increased the response rate; higher doses (1 to 2 mg/kg) either decreased the response rate or had little effect. Amphetamine always disrupted the temporal pattern of responding, even though it did not affect the overall rate. When doses of amphetamine that increased the response rate or left it unchanged were combined with diazepam, a potentiated increase in response rate occurred. When doses of amphetamine that decreased the response rate were combined with diazepam, the amphetamine-induced rate decreases were reversed at least partially. Less clear potentiation of disruption of the temporal pattern of responding was observed when amphetamine and diazepam were combined.     

Forgetting as a function of sleep at different times of day

The experiment studied the separate effects of sleep and time period of retention interval on forgetting. A free recall task was given to independent groups of subjects either at night or in the morning, and a second recall demanded 5 h later, after an intervening period of sleeping or waking activity. Oral body temperatures (BT) were measured at each session. The data were analysed in terms of (a) immediate recall at test 1, and (b) amount forgotten from test 1 to test 2. Immediate recall was higher for morning groups, in agreement with previous findings, serial position analysis indicating that the effect is confined to enhancement of the primary memory component. Long-term retention was higher over the night interval, irrespective of sleeping conditions, though having slept at night produced better retention than having stayed awake. Sleep during the morning was not effective in reducing forgetting. BT showed a marked drop for both night groups and rise for day groups over the retention interval. Alternative explanations for the classical sleep/memory findings are suggested in terms of (a) differential effects of sleep stages on memory, and (b) the underlying diurnal variation in BT and other processes.     

Retention deficit after d-amphetamine treatment: memory defect or performance change?

Retention deficits in discrete trial delayed alternation and delayed matching to sample tasks following administration of d-amphetamine have been interpreted to support the view that arousal facilitates the decay of information from shortterm memory (STM) (Kesner, 1973). But since amphetamine causes numerous changes in performance, alternative explanations of the deficit are also plausible. In an attempt to separate drug effects on memory from those on performance, the effects of d-amphetamine on spatial memory in the radial maze were studied in rats. The unusually long span of accurate working memory in this setting permits drug administration within the retention interval as well as prior to the to-be-remembered event (TBRE). In rats tested at a 5-hr retention interval d-amphetamine (2 mg/kg) disrupted retention when given 0.5 hr before or 4.5 hr after the TBRE, but the same treatment 0 or 2 hr after the TBRE or 3 hr before the TBRE was without effect. At a 5-hr retention interval 3 mg/kg d-amphetamine impaired performance if given 2 hr after the TBRE, but not when given 0 hr after the TBRE or 3 hr before the TBRE. However, when the retention interval was lengthened to 7 hr, administering 3 mg/kg d-amphetamine 2 hr after the TBRE did not disrupt performance. The effects of d-amphetamine on spatial memory are best explained in terms of the well established effects of the drug on motor activity and appetite. Similar changes in performance may account for the "memory" impairments observed after amphetamine treatment in other tasks.     

Reversible Verbal Memory Integration Deficits in Obstructive Sleep Apnoea

When presented with novel but semantically related elements after learning verbal material, healthy participants tend to endorse these items as previously learned. This reflects the normal integration and association of novel verbal information into long-term memory. How obstructive sleep apnoea (OSA) negatively impacts verbal memory performance, and whether deficits are reversible following positive airway pressure (PAP) treatment, remain elusive. We investigated immediate and delayed OSA- and PAP treatment-related effects on verbal memory integration, using a false memory paradigm. Twenty-three patients with OSA learned lists of words semantically related to target non-presented words (1) at baseline after a polysomnography diagnosis night, (2) after a consecutive polysomnography night under PAP titration, and (3) after three months of compliant PAP treatment. At each session, participants learned 10 different lists of words, each list comprising 15 semantically related items. They had then to recognize 15 minutes later (after an intermediate vigilance task) previously learned words within a list including studied words (learned), unstudied but semantically related items (lures), and non-related unstudied items (controls). Sleep quality and fatigue questionnaires, and psychomotor vigilance tests (PVT) were administered at each session. PAP treatment led to OSA remission and improvement in objective and subjective sleep quality. Crucially, recognition of learned and lure words increased after the first night under treatment and remained stable three months later, suggesting successful memory integration and restoration of semantic processes. No treatment-related outcome was found on PVT performance. OSA exerts a detrimental but PAP-reversible effect on verbal learning and semantic memory integration mechanisms underlying the acquisition of novel memory representations.     

Effects of amphetamine-CNS depressant combinations and of other CNS stimulants in four-choice drug discriminations

Three pigeons were trained to discriminate among 5 mg/kg pentobarbital, 2 mg/kg amphetamine, a combination of these two drugs at these doses, and saline using a four-choice procedure (amphetamine-pentobarbital group). Three other pigeons were trained to discriminate among 5 mg/kg morphine, 2 mg/kg methamphetamine, a combination of these two drugs at these doses, and saline (methamphetamine-morphine group). After 10 to 13 months of training, the pigeons averaged more than 90% of their responses on the appropriate key during training sessions. In subsequent testing, dose-response curves were determined for the individual drugs, for a wide range of dose combinations of the training drugs, and for two drugs to which the pigeons had not been exposed previously (pseudoephedrine and nicotine). After low test doses of the training drugs, pigeons responded on the saline key. As the dose increased, responding on the key associated with that drug during training sessions increased. When training drugs were combined at doses that were not discriminable when given alone, responding occurred on the saline key. When a discriminable dose of one training drug was combined with a nondiscriminable dose of the other training drug, responding occurred on the key associated with the discriminable dose. When both drugs were given at discriminable doses, responding almost always occurred on the drug-combination key. The response-rate decreasing effects of pentobarbital and amphetamine were mutually antagonized when the drugs were combined, but the rate-decreasing effects of morphine and methamphetamine were not. After low doses of pseudoephedrine and nicotine, pigeons in both groups responded on the saline key. After higher doses of pseudoephedrine and nicotine, responding in the amphetamine-pentobarbital group occurred primarily on the amphetamine key. In the methamphetamine-morphine group, higher doses of pseudoephedrine and especially nicotine engendered more responding on the combination key than had occurred in the other group. The four-choice procedure can reveal subtle effects in the discrimination of individual drugs and drug combinations that are not apparent with procedures offering fewer response alternatives.     

Further evaluation of morphine aversion: maintenance of a taste aversion using a low, nonaversive morphine dose

Previously, in an investigation of morphine-conditioned taste aversion (CTA), we found that limited preexposure to a low, nonaversive (non-CTA-inducing) dose of morphine (2.5 mg/kg) was as effective as preexposure to a higher, CTA-inducing dose (15 mg/kg) in blocking the formation of a subsequent morphine CTA. In the present study, we examined the capacity of this low, 2.5-mg/kg morphine dose to maintain a CTA initially induced by the 15-mg/kg dose. A standard CTA procedure was used. Results indicated that rats given three initial taste-drug pairings with 15 mg/kg morphine followed on subsequent pairing days by treatment with the low, non-CTA-inducing, 2.5-mg/kg dose continued to exhibit a strong CTA over 8 pairing days. A similar pattern was observed for animals continuing to receive taste-drug pairings with the 15-mg/kg dose. Animals receiving only one taste-drug pairing with the 15-mg/kg dose, followed on subsequent pairing days by 2.5-mg/kg conditioning, failed to show such a pattern of CTA. An intermediate CTA pattern was seen with animals conditioned with 15, 10, 5, and repeated 2.5-mg/kg doses over consecutive pairing days. These data suggest that exposure to a low dose of morphine, with no apparent CTA-inducing properties, is sufficient to maintain a previously established morphine taste aversion. Potential implications for understanding the apparent discriminative complexity of morphine's motivational properties are discussed.