Hipersomnia relacionada con un exceso de cafeína: estudio de un caso / Hypersomnolence related to high dose of caffeine: a clinical case

La cafeína tiene un efecto promotor de la vigilia, sin embargo en algunas personas se ha observado un efecto paradójico. Se informa de un caso de una paciente que desarrolló tolerancia a la ingesta de altas dosis de cafeína, cuyas principales manifestaciones clínicas fueron somnolencia excesiva diurna. Se trató de una mujer de 23 años de edad, estudiante de medicina, con somnolencia importante desde hacía 3 años, incluso durante los períodos vacacionales. Al momento de la primera entrevista en la clínica de sueño ella manifestó consumir entre 5 y 7 cápsulas de cafeína (200 mg por cápsula), de 10 a 15 tazas de café o refrescos de soda (100 a 500 mg de cafeína entre cada dosis). Todo lo anterior con la finalidad de mantenerse alerta. Se programó un registro nocturno sin ningún cambio en su patrón de ingesta de cafeína, seguido de 4 siestas, diurnas a las 10, 12, 14 y 16 h, en lo que se conoce como test de latencias múltiples del sueño (TLMS). Se le determinaron exámenes clínicos sistemáticos y la determinación del antígeno de histocompatibilidad HLA-DR2. Se observó un porcentaje elevado de sueño en el índice de eficiencia de sueño durante la noche. Las latencias a sueño total, lo mismo que a sueño de movimientos oculares rápidos (MOR), fueron cortas. No se detectaron otras anormalidades en sueño nocturno. El TLMS mostró una latencia a sueño promedio de 3 min, sin ningún ingreso a sueño MOR durante las 4 siestas. Los exámenes de laboratorio fueron normales y el antígeno HLA-DR2, negativo. Se siguió la observación de la paciente por 6 meses, bajando la cantidad de cafeína ingerida, y con metilfenidato 2 g repartido en 2 tomas. Se recuperó de la somnolencia excesiva al cabo de ese tiempo. La cafeína en exceso puede estar relacionada con somnolencia excesiva, debido a una fragmentación del sueño nocturno, y al desarrollo de tolerancia al efecto de alertamiento (AU)

Caffeine awakening effects could be the opposite in some people that abuse it. The present case report is an example of both tolerance and sleep fragmentation of caffeine that may result in a daytime hypersomnia. A 23 year old, medical student with all day sleepiness that lasted even when she was on holidays. All the clinical manifestations started about 3 years previous to the first consultation. At the moment of the first interview she admitted taking several capsules of caffeine (200 mg each); ten to fifteen cups of regular coffee (100 to 150 mg each) and soda containing caffeine. All of this, in order to keep her awake during daytime. A sleep recording night followed by a multiple sleep latency test the day after were performed. Also laboratory examinations including HLA-DR2 antigen were done. It could be observed a high percentage of sleep efficiency above 95%, during the night. She had very short sleep latency and short REM sleep latency. Other than that no major sleep abnormalities in sleep stages were found. The following day MSLT showed and average sleep latency of 3 min, without any appearance of REM sleep what so ever. All laboratory tests were normal and HLA-DR2 antigen was negative. After six months with a slow reduction in caffeine intake plus 2 mg of metylphenidate, a full recovery was observed in terms of excessive sleepiness. Caffeine excessive intake could produce somnolence through a tolerance to the awakening effect as well as sleep fragmentation during night time (AU)

[Hypocretins and adenosine in the regulation of sleep]. / Hipocretinas y adenosina en la regulación del sueño.

OBJECTIVES: To review the recent discovery of hypocretins (orexins) and their link to the pathophysiology of narcolepsy and the role of adenosine in the integration of brain metabolism and sleep. DEVELOPMENT: The importance of the functions carried out by the hypothalamus in the regulation of sleep and the waking state has been consolidated by the discovery of hypocretins and the role played by cerebral adenosine. Hypocretins are two peptides made up of 33 and 28 amino acids whose neurons are located predominantly in the lateral hypothalamus and surrounding regions. In the Doberman canine narcolepsy model, in which this disease is presented with an autosomal recessive pattern, a mutation was detected in one of the receptors involved in the hypocretin system, namely the hypocretin-2 receptor. Failures in the hypocretin system have been confirmed as a key factor in narcolepsy by other findings in laboratory animals and humans. Adenosine, on the other hand, is accumulated during the waking state as a result of neuronal metabolism and this in turn is related to drowsiness. Sleep episodes lower the levels of this substance in the brain. Adenosine receptor antagonists increase wakefulness (e.g. caffeine), while the agonists promote slow-wave sleep. CONCLUSIONS: Hypocretins and adenosine from the hypothalamus perform functions involving the regulation of sleep and wakefulness. Understanding these two systems can have repercussions on clinical problems such as insomnia, hypersomnia and other neuropsychiatric disorders.

The diurnal rhythm of adenosine levels in the basal forebrain of young and old rats.

There are significant decrements in sleep with age. These include fragmentation of sleep, increased wake time, decrease in the length of sleep bouts, decrease in the amplitude of the diurnal rhythm of sleep, decrease in rapid eye movement sleep and a profound decrease in electroencephalogram Delta power (0.3-4 Hz). Old rats also have less sleep in response to 12 h-prolonged wakefulness (W) indicating a reduction in sleep drive with age. The mechanism contributing to the decline in sleep with aging is not known but cannot be attributed to loss of neurons implicated in sleep since the numbers of neurons in the ventral lateral preoptic area, a region implicated in generating sleep, is similar between young (3.5 months) and old (21.5 months) rats. One possibility for the reduced sleep drive with age is that sleep-wake active neurons may be stimulated less as a result of a decline in endogenous sleep factors. Here, we test this hypothesis by focusing on the purine, adenosine (AD), one such sleep factor that increases after prolonged W. In experiment 1, microdialysis measurements of AD in the basal forebrain at 1 h intervals reveal that old (21.5 months) rats have more extracellular levels of AD compared with young rats across the 24 h diurnal cycle. In experiment 2, old rats kept awake for 6 h (first half of lights-on period) accumulated more AD compared with young rats. If old rats have more AD then why do they sleep less? To investigate whether changes in sensitivity of the AD receptor contribute to the decline in sleep, experiments 3 and 4 determined that for the same concentration of AD or the AD receptor 1 agonist, cyclohexyladenosine, old rats have less sleep compared with young rats. We conclude that even though old rats have more AD, a reduction in the sensitivity of the AD receptor to the ligand does not transduce the AD signal at the same strength as in young rats and may be a contributing factor to the decline in sleep drive in the elderly.

Extracellular serotonin levels in the medullary reticular formation during normal sleep and after REM sleep deprivation.

Rapid eye movement (REM) sleep is hypothesized to result from the activity of REM sleep-generating and REM sleep-inhibiting neurons. The serotoninergic (5-HT) neurons of the dorsal raphe nucleus (DRN) represents one such population of REM-sleep inhibiting neurons since they are silent during REM sleep. Consistent with the decrease in activity of 5-HT neurons, the brain extracellular levels of 5-HT are lower during REM sleep compared to wakefulness. It is not known whether serotonin release is also reduced as a consequence of REM sleep rebound. Using microdialysis sampling coupled to HPLC-ECD, we measured the extracellular levels of 5-HT and its metabolite (5-HIAA) in the medial medullary reticular formation (mMRF) of freely behaving rats during normal sleep, REM sleep deprivation as well as during REM sleep rebound. We found that the levels 5-HT and 5-HIAA were significantly decreased by REM sleep deprivation. The reduction of 5-HT release was maintained during REM sleep rebound but the extracellular level of its main metabolite was increased. In addition, even during REM sleep rebound, 5-HT release during sleep was low compared to wakefulness. Taken together these data support the permissive role of 5-HT neurotransmission for REM sleep expression.

The role of the hypothalamic neuropeptides hypocretin/orexin in the sleep-wake cycle.

The novel neuropeptides hypocretin/orexin have recently been located on the lateral hypothalamus cells. This system has been linked to the regulation of both feeding and sleep, and recent studies have found an association between a defect in these neuropeptides and narcolepsy. We conducted a MEDLINE review of all the articles published since the discovery of hypocretin/orexin peptides, narrowing the field to the relationship between these neuropeptides and sleep. The finding of a deletion in the transcription of the hypocretin receptor 2 gene in narcoleptic Doberman pinschers and the development of a knockout of the hypocretin gene in mice pointed to the relevance of this system in the sleep-wake cycle. We provide further evidence of the role of the hypocretin/orexin system in narcolepsy and in sleep regulation and present an integrative model of the pathophysiology of narcolepsy. The discovery of the link between these peptides and narcolepsy opens new avenues to both the understanding of sleep mechanisms and therapeutic implications for sleep disorders.

Changes in sleep after acute and repeated administration of nicotine in the rat.

RATIONALE: Acetylcholine clearly plays a role in regulating sleep. This influence may involve nicotinic systems because several studies have demonstrated that nicotine treatment alters sleep. However, the literature that suggests an effect of nicotine treatment on sleep is contradictory, perhaps because different doses and routes of administration were used. OBJECTIVE: The studies reported here evaluated the effects of several doses of nicotine on REM sleep in the rat. METHODS: Male Wistar rats were prepared with a set of sleep recording electrodes and, following habituation to the test chamber, were used in one of three studies: a) a dose-response analysis of an acute dose of nicotine on REM sleep measured during the first 4 h after injection; b) a chronic treatment experiment; or c) a mecamylamine blockade experiment. RESULTS: Acute nicotine administration decreased REM sleep in a dose-dependent fashion; significant effects were observed following injection with the 0.5 and 1.0 mg/kg doses. A decrease in slow wave sleep and an increase in wakefulness were also observed. Mecamylamine by itself did not affect REM sleep, but it blocked the effects on sleep produced by nicotine when given 30 min before a 1 mg/kg dose of nicotine. Rats that had been injected once daily with a 0.1 mg/kg dose of nicotine showed an increase in REM sleep after the third injection, whereas rats that had been chronically treated with a higher dose (0.5 mg/kg) displayed a reduction in REM and total sleep time. CONCLUSION: These findings argue that the effects of both acute and chronic nicotine treatment on sleep are influenced by the dose of nicotine used.

Olanzapine acute administration in schizophrenic patients increases delta sleep and sleep efficiency.

BACKGROUND: A delta sleep deficit has been observed in schizophrenic patients. Olanzapine is a novel atypical antipsychotic agent with affinity at dopaminergic, serotonergic, muscarinic, adrenergic and histaminergic binding sites. The present study was designed to analyze a sleep promoting effect reported for olanzapine. METHODS: Twenty schizophrenic patients (DSM-IV) were studied, who were drug free and inpatients. Patients slept for 5 consecutive nights in the sleep unit as follows: one acclimatization night; two baseline nights (the first for sleep disorder screenings); and two olanzapine nights (10 mg olanzapine, one hour before sleep onset). RESULTS: Sleep continuity variables and total sleep time showed an overall improvement with olanzapine. Waking time was reduced since the first night of olanzapine administration. The main sleep architecture changes were: reduction in sleep stage 1, while sleep stage 2 and delta were significantly enhanced. Rapid eye movement density was also increased by the second olanzapine night. CONCLUSIONS: Total sleep improvement was due to the increase in sleep stages 2 and delta sleep. This may be related to serotonergic antagonistic properties of olanzapine. Olanzapine seems to have a sleep promoting effect in schizophrenic patients.

A novel effect of nicotine on mood and sleep in major depression.

The role of repeated nicotine administration on sleep and major depression was studied. Six non-smoking normal volunteers (NV) and six non-smoking major depressed patients (MD) with a Hamilton Rating Scale for Depression > 18 served as subjects. All subjects underwent the following sleep procedures: acclimatization, control night, four nicotine nights (17.5 mg, transdermal patches) and one withdrawal night (WN). Nicotine increased REM sleep time in both groups and also on the WN. Hamilton scores showed an average reduction of 43.9% in the depressed patients. These findings suggest that nicotine receptor activation may be important in major depression and shows for the first time that nicotine patches may be useful in the treatment of depression.

Decrease in muscarinic M2 receptors from synaptosomes in the pons and hippocampus after REM sleep deprivation in rats.

The effects of both REM sleep deprivation and its recovery on pontine and hippocampus muscarinic M2 receptors were investigated in synaptosomes using [3H]-AF-DX 384 as a ligand. Animals were divided into three groups: REM sleep deprivation group (small platforms 6.5 cm of diameter); stress group (large platforms 14 cm of diameter) and cage control group. In a second experiment REM sleep-deprived animals were allowed 48 h of recovery. REM sleep-deprived rats showed a reduction in M2 receptors compared with both intact and stress groups. Changes in M2 receptors were also observed after 48 h of recovery from REM sleep deprivation only in hippocampus. The enhancement of acetylcholine release during both REM sleep deprivation and recovery could explain the present findings.

Sleep changes after 4 consecutive days of venlafaxine administration in normal volunteers.

BACKGROUND: The purpose was to examine the effect of the antidepressant drug venlafaxine on sleep architecture and periodic leg movements of sleep (PLMS) in normal volunteers. METHOD: Eight normal volunteers were studied under laboratory sleep conditions as follows: 1 acclimatization night, 1 baseline night, and 4 consecutive nights of venlafaxine p.o. administration (75 mg during the first 2 nights and 150 mg the last 2 nights). RESULTS: Venlafaxine increased both wake time and sleep stage I. Sleep stages II and III were reduced. REM sleep time was reduced after the first venlafaxine dose, and, by the fourth night, REM sleep was completely suppressed in all volunteers. Six of the eight volunteers showed PLMS at a frequency above 25 per hour. CONCLUSION: Venlafaxine produces several sleep disturbances, which include abnormal leg movements.

Repeated REM sleep deprivation after chronic haloperidol administration in the rat.

Repeated haloperidol administration produces up-regulation of dopamine (DA) receptors. REM sleep deprivation (REMSD) does also, but in addition, has been shown to produce REM sleep rebound. Should DA receptor up-regulation play a role in REM sleep rebound, haloperidol could conceivably have effects similar to those observed following REMSD. This is the central question investigated in this study. Male Wistar rats were prepared for sleep recordings. They were randomly assigned to the following groups: group 1, REMSD by small platforms (40 h REMSD + 8 h recording); group 2, was the large platform control group (40 h in large platforms + 8 h of recording); group 3, received 2-week daily administration of haloperidol (3 mg/kg, i.p.) plus REMSD (40 h REMSD + 8 h of recording); group 4, 2-week administration of haloperidol (3 mg/kg) without sleep manipulation and at the end 40 h were allowed to elapse, following which 8 h of sleep recordings was carried out. In each group the sleep manipulation and/or sleep recordings were repeated five consecutive times. Repeated REMSD produced increases of REM sleep time after each recovery in group 1. Large platforms did not produce increases of REM sleep during the recovery trials. The 2-week administration of haloperidol plus REMSD prevented REM sleep rebound (group 3). The 2-week administration of haloperidol without sleep manipulation (group 4) produced a REM sleep reduction. Dopamine modulation seems not to be important for REM sleep rebound. Hypersensitivity of DA receptors developed after REMSD may be an epiphenomenon associated with this sleep manipulation, but seems not to participate in REM sleep enhancement after REMSD.

Effects of venlafaxine in the sleep architecture of rats.

Different venlafaxine doses (1, 5, and 10 mg/kg) and saline solution were administered to ten male Wistar rats (Latin-Square design). Compared with saline, venlafaxine produced a dose-related suppression of REM sleep and an increase in wake time while slow wave sleep was reduced. This effect is similar to the one that has been reported with some tricyclic antidepressants.

Differences in sleep variables, blood adenosine, and body temperature between hypothyroid and euthyroid rats before and after REM sleep deprivation.

Sleep deprivation causes an increase in energy expenditure in animals. Thyroid gland function has been related to metabolic function, and this may be compromised in sleep manipulations. The objectives of the present study were the following: 1) to develop a model of hypothyroid rats by surgical removal of thyroid glands without extirpation of the parathyroid; 2) to observe the sleep architecture in euthyroid (Etx) and hypothyroid (Htx) rats, both before and after rapid eye movement (REM) sleep deprivation (96 hours); 3) to challenge both groups (i.e. Etx and Htx) with REM sleep deprivation (96 hours) and then evaluate the effects on temperature; and 4) to measure the levels of adenosine and thyroid hormones in blood. One-month-old Wistar male rats (weight 90-100 g) were studied. The thyroid gland was removed, and the parathyroid glands were reimplanted within the neck muscle (Htx) under halothane anesthesia. A sham-operated group was also included (Etx). Four months later, the animals were studied according to the following protocols. Protocol 1: Animals of both groups (i.e. Etx and Htx) were implanted for sleep recordings. After a baseline polysomnography, these animals were REM sleep deprived by the platform method (96 hours). Protocol 2. An intraperitoneal temperature transducer was placed into animals of both groups under deep halothane anesthesia. They were studied at baseline, during 96 hours of REM sleep deprivation, and on the rebound period. Protocol 3: Plasma thyroid hormones [T3, T4, and thyroid-stimulating hormone (TSH)] and plasma adenosine were determined in both groups. Results of protocol 1 indicated that the main difference observed in Htx rats during the baseline sleep was an increase in delta sleep (slow-wave sleep 2) and a reduction in waking time compared with Etx animals. REM sleep rebound after 96 hours of REM sleep deprivation was similar in both groups. In protocol 2, the main finding was that Htx animals had reduced body temperature. A significant difference in body temperature between Etx and Htx animals was found mainly during lights-on period. REM sleep deprivation in the Etx group produced an increase in body temperature. Htx animals showed the opposite effect, with a reduction in body temperature during and after REM sleep deprivation. In protocol 3, the main findings were that Htx animals exhibited a significant reduction in blood thyroid hormones (T3, T4), and that they also had high levels of plasma adenosine. REM sleep deprivation produces changes in temperature regulation. The increase in body temperature during REM sleep deprivation may require thyroid integrity. Absence of the thyroid gland does not seem to influence REM sleep recovery after its deprivation. The high plasma adenosine levels found in the Htx group may explain the increase in delta sleep in this group.

Transdermal nicotine on sleep and PGO spikes.

There is conflicting evidence for the role of nicotine in sleep regulation. This study was undertaken to determine the effects of transdermal nicotine at doses of 17.5, 35 and 52.5 mg on sleep and PGO spike activity. Minor effects were observed on sleep with a general increase in waking. PGO spike activity was abolished by all patches. The results are discussed in terms of the mechanisms involved in the disappearance of PGO spikes as a result of nicotine.

Antidepressant effect of transdermal nicotine patches in nonsmoking patients with major depression.

BACKGROUND: A high frequency of cigarette smoking has been reported among individuals with major depression. In a previous study, transdermal nicotine produced short-term improvement in the mood of depressed patients. This study was undertaken to determine the effects of 4 days' administration of transdermal nicotine on mood in nonsmoking patients with major depression. METHOD: The effects of nicotine patches (17.5 mg) on 12 nonmedicated outpatients with major depression (DSM-III-R) were studied for 4 continuous days. Patients had to score 18 points or more on the Hamilton Rating Scale for Depression (HAM-D) (21 items) for admission into the study. The HAM-D (10 items), a visual analog scale, and a side effects scale were scored daily during the trial (baseline, 4 days of nicotine patches, and 4 days of follow-up). RESULTS: Two patients dropped out of the study owing to nausea and vomiting. Results of the visual analog scale and HAM-D (10 items) showed a significant (p < .01) improvement in depression after the second day of nicotine patches. Patients relapsed 3 or 4 days after the last nicotine dose. The side effects observed were an increase in saliva production, nausea, loss of appetite, and mild insomnia. CONCLUSION: Nicotine patches produced short-term improvement of depression with minor side effects. Because of nicotine's high risk to health, nicotine patches are not recommended for clinical use in depression. Analogue drugs may be developed in the future that may help improve depression without the risk of other major health problems.

Rapid eye movement (REM) sleep deprivation in 6-OHDA nigro-striatal lesioned rats with and without transplants of dissociated chromaffin cells.

Since both REM sleep deprivation and unilateral 6-OHDA lesions induce supersensitivity of DA receptors, the purpose of this study was to determine whether the response of rats with such lesions would be modified by REM sleep deprivation. In addition, the effect of grafts of dissociated chromaffin cells was also tested. Rats with 6-OHDA lesions were subjected to 24 or 72 h of REM sleep deprivation and tested with various doses of apomorphine to determine turning behavior frequencies. At end of those experiments, the animals were transplanted with dissociated chromaffin cells and turning behavior was tested again. The results showed that REM sleep deprivation nearly doubled the turning behavior frequency, that chromaffin cell grafts decreased it, but that REM deprivation in grafted animals still seemed to produce an increase of post-synaptic supersensitivity independent of denervation. The results were discussed in terms of the possible relationship of sleep with Parkinson's disease through the DA system.

Effects of transderman nicotine on mood and sleep in nonsmoking major depressed patients.

The role of nicotine as an indirect cholinergic agent in sleep has been studied in normal subjects. There are no studies of its effects on sleep in depressed patients. Nicotine transdermal patches (17.5 mg), were studied in eight depressed patients (DSM-III-R) and eight normal volunteers. Subjects wore placebo and nicotine patches for 24 h. Depressed patients showed increased REM sleep without changes in other sleep variables. They also showed a short term improvement of mood. Normal volunteers had sleep fragmentation, and reduction of REM sleep time. No major side effects were reported in either group.

Vesamicol, an acetylcholine uptake blocker in presynaptic vesicles, suppresses rapid eye movement (REM) sleep in the rat.

Vesamicol inhibits acetylcholine uptake in presynaptic vesicles and reduce its release. The present study was performed in order to test the effects of this drug in a cholinergic related function as rapid eye movement (REM) sleep. Wistar male rats were implanted for sleep recordings. In addition, a stainless steel cannula was implanted into the left lateral ventricle for intracerebroventricular (ICV) injections. In experiment 1, a dose-response curve was performed. Saline or vesamicol (20, 40, 80 and 100 micrograms) were injected. Following the ICV injections, animals' sleep was recorded for 8 h. In experiment 2, after adaptation and baseline recordings, animals received 50 micrograms vesamicol ICV at 1000 hours. every 24 h for 2 consecutive days. After each injection an 8-h sleep recording session was performed. Two subsequent recovery recordings were allowed. Results obtained in experiment 1 showed a dose-response reduction of REM sleep with significant values at 80 micrograms and 100 micrograms of vesamicol. The main findings in experiment 2 were a reduction in REM sleep time and an increase in REM sleep latency. On the recovery days, a dramatic rebound of REM sleep was observed. Vesamicol behaved as an anticholinergic drug. It produced a reduction in REM sleep time and a rebound of this sleep stage after its withdrawal.

Administration of auditory stimulation during recovery after REM sleep deprivation.

Rapid eye movement (REM) sleep deprivation and auditory stimulation (ADS), separately, increase REM sleep in rats, cats and humans. The main goal of the present study was to test whether administration of ADS during REM sleep rebound has a synergistic effect on REM sleep elicitation. Male Wistar rats were implanted with standard sleep recording electrodes. Following the recovery period, animals were randomly assigned to the following conditions: undeprived (i.e. control) and 24, 48, 96 and 120 hours of REM sleep deprivation by the platform method. Undeprived and REM sleep-deprived animals were divided into two groups, with and without ADS. ADS was a "beep" of 80 dB and 2,000 Hz, lasting 20 msec every 10 seconds. This stimulus was applied for the first 4 hours of sleep recordings after deprivation. After that, animals were recorded for another 4 hours. In the undeprived situation, the group that received ADS increased REM sleep approximately 70% above the group that did not receive ADS, as has been reported previously (REM sleep without ADS: 38.1 +/- 13.84 vs. with ADS: 64.6 +/- 11.8, p < 0.005). No synergistic effect was observed between REM sleep deprivation and ADS for any REM sleep-deprivation schedule. This result may be explained as an increase in the excitability pattern of pontine neurons and/or changes in the cholinergic system due to REM sleep deprivation that could not be further increased by ADS.

Development of tolerance after repeated administration of a selective muscarinic M1 antagonist biperiden in healthy human volunteers.

The muscarinic antagonist biperiden produces a dose-dependent inhibition of (REM) sleep on acute administration. The present study addressed the possibility of pharmacological tolerance after repeated biperiden administration. Six healthy volunteers were studied under sleep laboratory conditions in the following situations: one acclimatization, night, two baseline (that were averaged), 4 nights of biperiden administration, and 4 nights of placebo recovery administration. Six milligrams of biperiden and placebo were administered in identical capsules. Volunteers and technicians were blind to the order of the administration of the capsules. REM sleep time was reduced during the first and the second night, but was not significantly different in comparison with baseline by the third night. During placebo recovery nights, REM sleep time was not different from baseline. REM sleep latency was increased during the first and second nights of biperiden administration, but tolerance to this effect was observed by the third night. On placebo nights a dramatic shortening of REM latency was observed. The present findings support the hypothesis that anticholinergic drugs, even a selective M1 antagonist such as biperiden, induce tolerance soon after administration. A similar effect has been reported with scopolamine, a nonselective muscarinic antagonist, but the main difference is that biperiden withdrawal was not followed by an REM sleep rebound. The observed effect on REM sleep latency during placebo administration may be related to a supersensitivity to muscarinic M-1 receptors that trigger the first REM sleep period. Because short REM latency has been the main finding in the sleep of depressed patients, some implications of the present findings are discussed.