Assessment of tolerance to the effects of methamphetamine on daytime and nighttime activity evaluated with actigraphy in rhesus monkeys.

RATIONALE: Methamphetamine is one of the most largely consumed illicit drugs, and its use is associated with abuse liability and several adverse health effects, such as sleep impairment. Importantly, sleep quality can influence addiction treatment outcomes. Evidence suggests that tolerance can develop to the sleep-disrupting effects of stimulant drugs. OBJECTIVE: The aim of the present study was to investigate the development of tolerance to the actigraphy-based sleep-disrupting and stimulant effects of methamphetamine self-administration in rhesus monkeys. METHODS: Methamphetamine (0.03 mg/kg/inf, i.v.) self-administration was carried out following three different protocols: 14 consecutive days of self-administration, 5 days/week for 3 weeks, with a 2-day interval between 5-day blocks of self-administration, and 3 days/week for 3 weeks, with a 4-day interval between 3-day blocks of self-administration. Daytime activity and activity-based sleep measures were evaluated with Actiwatch monitors a week before (baseline parameters) and throughout each protocol. RESULTS: Methamphetamine self-administration markedly disrupted sleep-like measures and increased daytime activity. Tolerance developed to those effects with repeated methamphetamine intake exceeding five consecutive days. Inclusion of washout periods (2 or 4 days) between blocks of methamphetamine self-administration attenuated the development of tolerance, with longer breaks from methamphetamine intake being more effective in maintaining the sleep-disrupting and stimulant effects of methamphetamine. CONCLUSIONS: Tolerance can develop to the stimulant and sleep-disrupting effects of methamphetamine self-administration. Interruption of drug intake extends the effects of methamphetamine on sleep-like measures and daytime activity.

Chronic escitalopram treatment attenuated the accelerated rapid eye movement sleep transitions after selective rapid eye movement sleep deprivation: a model-based analysis using Markov chains.

BACKGROUND: Shortened rapid eye movement (REM) sleep latency and increased REM sleep amount are presumed biological markers of depression. These sleep alterations are also observable in several animal models of depression as well as during the rebound sleep after selective REM sleep deprivation (RD). Furthermore, REM sleep fragmentation is typically associated with stress procedures and anxiety. The selective serotonin reuptake inhibitor (SSRI) antidepressants reduce REM sleep time and increase REM latency after acute dosing in normal condition and even during REM rebound following RD. However, their therapeutic outcome evolves only after weeks of treatment, and the effects of chronic treatment in REM-deprived animals have not been studied yet. RESULTS: Chronic escitalopram- (10 mg/kg/day, osmotic minipump for 24 days) or vehicle-treated rats were subjected to a 3-day-long RD on day 21 using the flower pot procedure or kept in home cage. On day 24, fronto-parietal electroencephalogram, electromyogram and motility were recorded in the first 2 h of the passive phase. The observed sleep patterns were characterized applying standard sleep metrics, by modelling the transitions between sleep phases using Markov chains and by spectral analysis. Based on Markov chain analysis, chronic escitalopram treatment attenuated the REM sleep fragmentation [accelerated transition rates between REM and non-REM (NREM) stages, decreased REM sleep residence time between two transitions] during the rebound sleep. Additionally, the antidepressant avoided the frequent awakenings during the first 30 min of recovery period. The spectral analysis showed that the SSRI prevented the RD-caused elevation in theta (5-9 Hz) power during slow-wave sleep. Conversely, based on the aggregate sleep metrics, escitalopram had only moderate effects and it did not significantly attenuate the REM rebound after RD. CONCLUSION: In conclusion, chronic SSRI treatment is capable of reducing several effects on sleep which might be the consequence of the sub-chronic stress caused by the flower pot method. These data might support the antidepressant activity of SSRIs, and may allude that investigating the rebound period following the flower pot protocol could be useful to detect antidepressant drug response. Markov analysis is a suitable method to study the sleep pattern.

Narcolepsy in the older adult: epidemiology, diagnosis and management.

Narcolepsy is a disorder of impaired expression of wakefulness and rapid-eye-movement (REM) sleep. This manifests as excessive daytime sleepiness and expression of individual physiological correlates of REM sleep that include cataplexy and sleep paralysis (REM sleep atonia intruding into wakefulness), impaired maintenance of REM sleep atonia (e.g. REM sleep behaviour disorder [RBD]), and dream imagery intruding into wakefulness (e.g. hypnagogic and hypnopompic hallucinations). Excessive sleepiness typically begins in the second or third decade followed by expression of auxiliary symptoms. Only cataplexy exhibits a high specificity for diagnosis of narcolepsy. While the natural history is poorly defined, narcolepsy appears to be lifelong but not progressive. Mild disease severity, misdiagnoses or long delays in cataplexy expression often cause long intervals between symptom onset, presentation and diagnosis. Only 15-30% of narcoleptic individuals are ever diagnosed or treated, and nearly half first present for diagnosis after the age of 40 years. Attention to periodic leg movements (PLM), sleep apnoea and RBD is particularly important in the management of the older narcoleptic patient, in whom these conditions are more likely to occur. Diagnosis requires nocturnal polysomnography (NPSG) followed by multiple sleep latency testing (MSLT). The NPSG of a narcoleptic patient may be totally normal, or demonstrate the patient has a short nocturnal REM sleep latency, exhibits unexplained arousals or PLM. The MSLT diagnostic criteria for narcolepsy include short sleep latencies (<8 minutes) and at least two naps with sleep-onset REM sleep. Treatment includes counselling as to the chronic nature of narcolepsy, the potential for developing further symptoms reflective of REM sleep dyscontrol, and the hazards associated with driving and operating machinery. Elderly narcoleptic patients, despite age-related decrements in sleep quality, are generally less sleepy and less likely to evidence REM sleep dyscontrol. Nonpharmacological management also includes maintenance of a strict wake-sleep schedule, good sleep hygiene, the benefits of afternoon naps and a programme of regular exercise. Thereafter, treatment is highly individualised, depending on the severity of daytime sleepiness, cataplexy and sleep disruption. Wake-promoting agents include the traditional psychostimulants. More recently, treatment with the 'activating' antidepressants and the novel wake-promoting agent modafinil has been advocated. Cataplexy is especially responsive to antidepressants which enhance synaptic levels of noradrenaline (norepinephrine) and/or serotonin. Obstructive sleep apnoea and PLMs are more common in narcolepsy and should be suspected when previously well controlled older narcolepsy patients exhibit a worsening of symptoms. The discovery that narcolepsy/cataplexy results from the absence of neuroexcitatory properties of the hypothalamic hypocretin-peptidergic system will significantly advance understanding and treatment of the symptom complex in the future.

Benzodiazepines promote the intermediate stage at the expense of paradoxical sleep in the rat.

The effects of diazepam, a long half-life benzodiazepine, midazolam and triazolam, two with short half-life, on the transitional stage between deep slow wave sleep and paradoxical sleep were studied in Wistar and WAG/Rij rats. This intermediate stage is characterized by the unusual association of cortical spindles and low frequency hippocampal theta rhythm. The main result was extension of the intermediate stage at the expense of paradoxical sleep by diazepam and triazolam by influencing only the duration of the intermediate stage and both the onset and maintenance of paradoxical sleep. Midazolam increased both intermediate stage and paradoxical sleep. Several differences in the qualitative modulation of the stage characteristics and between rat strains were found. In regard to the possible peculiar physiological significance of the intermediate stage, we conclude that benzodiazepines promote a transient pharmacological cerveau isolé-like stage during sleep in rats.

Objective assessment of sleep patterns resulting from benzodiazepines prescribed by general practitioners.

Fifteen general practitioners treated 21 newly diagnosed insomniac patients with benzodiazepines. In 15 cases, a short-acting benzodiazepine was prescribed without regard to the type, severity, duration and probable cause of insomnia. Sleep-wake ambulatory recordings were made at the respective homes of the patients before, 1 week and 4-6 weeks after the commencement of drug treatment and once after stopping the medication. In spite of the large variability in sleep complaint as well as in prescribed drug, statistically significant changes of sleep-wake patterns were discerned 1 week after drug intake: sleep onset was shorter, light sleep (NREM stage 2) was increased and sleep efficiency was increased. However, although the subjective complaint appeared to have disappeared, these effects could no longer be measured 4 weeks later or after cessation of medication.

Insomnia: I. Classification, assessment and pharmaceutical treatment.

Insomnia is a public health problem because of its high prevalence, the risk of hypnotic drug abuse, and self medication combined with alcohol and other nonprescription chemicals. Clinical experience has given rise to a descriptive classification of the insomnias many of which are secondary to medical disease. The information now available allows us to suggest a systematic approach to the assessment of insomnia emphasizing its history, events associated with sleep onset, observable behaviour and experience associated with interruptions in sleep. This paper attempts to organize the present state of knowledge in a format that can be taught to general physicians who deal with the most insomnia patients.

[Electroencephalographic assessment of dosage and sleep-profile in a hypnotic Triazolothienodiazepine (author's transl)]. / Elektroenzephalographische Dosis- und Schlafprofilbeurteilung eines Hypnotikums aus der Reihe der Triazolothienodiazepine.

We 941, a Triazolodiazepine, has satisfying hypnotic properties. The optimum dosage lies nearly at 0.3 mg. In this dosage the sleep-begin is shortened, the number of nightly wakeness is decreased and the total sleep-time is extended, while the sleep-profile remains unchanged. A normal cycling can be taken as a sign of qualitative good sleep. The REM-percentage is diminished insignificantly and increases again under the continuated therapy. The percentage of deep sleep increases by 0.3 mg. The subjective presentations confirm the melioration of sleep. In higher dosages troubles occur as decrease of deep-sleep stage and deteriorations of feeling. Remarkable is the withdrawal effect after 1.0 mg with an initial and a dissociated REM. However, such strong disturbances couldn't be observed in the carried on therapy with 0.3 mg.