Reyes Haro

Modafinil enhances extracellular levels of dopamine in the nucleus accumbens and increases wakefulness in rats

Modafinil (MOD) is a wakefulness-promoting drug that improves the alertness levels in narcolepsy; however, the molecular mechanism of action remains to be elucidated. We found that after a single icv injection of MOD (10 microg/5 microl) the extracellular levels of dopamine (DA) and l-DOPA collected from the nucleus accumbens were increased and decreased, respectively. Separately, the icv administration of MOD (10 microg/5 microl) to rats enhanced wakefulness (W) whereas diminished sleep during 4h. Lastly, the alertness induced by MOD was partially antagonized by the sleep-inducing endocannabinoid anandamide (ANA). We conclude that MOD enhances the extracellular levels of DA, promotes W and its effects on sleep are partially blocked by ANA.

Mechanisms of sleep-wake cycle modulation.

Regulation of the sleep-waking cycle is complex, involving multiple neurological circuits and diverse endogenous molecules. Interplay among assorted neuroanatomical and neurochemical systems such as acetylcholine, dopamine, noradrenaline, serotonin, histamine, and hypocretin maintain the waking (W) state. The sleep-onset is governed by the interacting forces of the sleep drive, which steadily increases with duration of W, and circadian fluctuations. Sleep-promoting neurons located in the anterior hypothalamus release GABA and inhibit wake-promoting regions in the hypothalamus and brainstem and participate in the generation of slow wave sleep (SWS). During rapid eye movement (REM) sleep, brainstem regions typically inhibited during W and SWS become active. In this regard, ascending projections from cholinergic neurons in the brainstem activate the thalamus which in turn increases the firing of the neurons in the cortex. Finally, sleep-promoting substances that accumulate in the brain during natural or prolonged W implicate a further complexity in the mechanism of modulation of the sleep-wake cycle. This review provides a broad understanding of our present knowledge in the field of sleep research.

How is the Epworth Sleepiness Scale related with subjective sleep quality and polysomnographic features in patients with sleep-disordered breathing?

PurposeTo determine the relationship between the Epworth Sleepiness Scale (ESS) and the Subjective Sleep Quality (SSQ) or polysomnographic (PSG) features in patients with sleep-disordered breathing (SDB).MethodsThis is a retrospective study that included 646 untreated patients with a PSG diagnosis of primary snoring (PS) or obstructive sleep apnea syndrome. Patients with SDB were grouped into four categories according to ESS scores: no diurnal sleepiness (DS) = 0-6; mild DS = 7–12; moderate DS = 13–18, and severe DS = ≥19. Analyses of variance were performed to compare SSQ or PSG features among the four ESS severity categories.ResultsWe found a significant increase in subjective sleep time in the group of patients with severe DS. With regard to PSG data, we also identified increases in total sleep time (TST) and rapid eye movement (REM) in the group of patients with severe DS.ConclusionUnexpectedly, DS severity was related with increases in TST and REM sleep. As has been described in SDB patients, a change in muscular tonus throughout sleep onset (and depth) is a causal factor of SDB features and DS impairment. Therefore, we propose that increases in TST and REM are worsening factors of SDB and consequently, also in DS.

Association of narcolepsy-cataplexy with HLA-DRB1 and DQB1 in Mexican patients: A relationship between HLA and gender is suggested

BackgroundNarcolepsy-cataplexy is characterized by excessive daytime sleepiness with recurrent episodes of irresistible sleep, cataplexy, hallucinations and sleep paralysis. Its aetiology is unknown, but it is positively associated with the human leukocyte antigens (HLA) in all studied populations. The purpose of the present study was to investigate the association of HLA class II DRB1/DQB1 alleles with narcolepsy-cataplexy in Mexican Mestizo patients.MethodsThis is a case-control study of consecutive patients and ethnically matched controls. We included 32 patients diagnosed with typical narcolepsy-cataplexy, of the National Institute of Neurology, of the Institute of Psychiatry and at the Center of Narcolepsy at Stanford University. As healthy controls, 203 Mexican Mestizos were included. DRB1 alleles were identified using sequence based typing. A PCR-SSOP reverse dot blot was used for DQB1 typing. Allele frequency was calculated by direct counting and the significance of the differences was assessed using the Yates Chi square. Odds ratio and confidence intervals were evaluated.ResultsHLA-DRB1*1501 (OR = 8.2; pc < 0.0001) and DQB1*0602 (OR = 8.4; pc < 0.0001) were found positively associated with narcolepsy. When deleting DQB1*0602+ patients from the analysis, DQB1*0301 was also found increased (OR = 2.7; p = 0.035; pc = NS). DQB1*0602/DQB1*0301 genotype was present in 15.6% of the cases (OR = 11.5; p = 0.00035), conferring a high risk. DRB1*0407 (OR = 0.2; p = 0.016 pc = NS) and DQB1*0302(OR = 0.4; p = 0.017, pc = NS) were found decreased in the patients. The gender stratification analysis showed a higher risk in females carrying DRB1*1501 (OR = 15.8, pc < 0.0001) and DQB1*0602 (OR = 19.8, pc < 0.0001) than in males (OR = 5.0 for both alleles; p = 0.012, pc = NS for DRB1 & p = 0.0012, pc = 0.017 for DQB1). The susceptibility alleles found in Mexicans with narcolepsy are also present in Japanese and Caucasians; DRB1*04 linked protection has also been shown in Koreans. A stronger HLA association is suggested in females, in accordance with the sexual dimorphism claimed previously.ConclusionThis knowledge may contribute to a better understanding of the disease pathogenesis in different populations. The evaluation of the risk to develop narcolepsy-cataplexy in carriers of the described alleles/genotypes may also be possible. A larger sample should be analysed in Mexican and in other Hispanic patients to confirm these results.

Mexican Version of the Epworth Sleepiness Scale

The Epworth Sleepiness Scale (ESS) has been reputed as a quick, valid, and reliable method to assess Daytime sleepiness (DS). Since its publication, it has been translated into a number of languages. Our aim was to determine valid- ity and reliability indicators of an Spanish language version ESS for Mexican population. Considering that in developing countries the majority of persons use public transportation, validity and reliability indicators were also assessed utilizing the ESS without item 8. ESS was applied to a Group of college students (GCS), a selected group of Healthy subjects (HS), and a Group of patients with Sleep disorders (GPSD). We made an ESS comparison among the 3 groups, calculated the correlation between the ESS and the Multiple Sleep Latency Test (MSLT) and determined construct validity and internal consistency. GCS and GHS had lower ESS scores than GPSD. Regarding convergence validity, we obtained a negative correlation between the ESS and the MSLT; we also found a rise in the ESS score associated with an increase in the Ap- nea-hypopnea index (AHI). With respect to construct validity (employing main component analysis and varimax rotation), we found that one factor explains 52.01% of variance. We determined that the ESS internal consistency was 0.85. When item eight was suppressed, validity and reliability remained acceptable. The present ESS Spanish-language exhibited suit- able levels of validity and reliability. Use of the ESS, suppressing item eight, allows assessment of DS more accurately in individuals who do not travel by automobile on a regular basis.

Effects of ozone exposure during pregnancy on ontogeny of sleep in rats.

Few studies regarding the effects of ozone exposure in the central nervous system (CNS), during the early stages of development have been reported. The study of sleep on newborn rats represents a model to understand the effects of this gas on the CNS. We studied the sleep organization in rats whose mothers were exposed to 1 part per million (ppm) ozone during pregnancy. We found severe sleep disturbances such as a decrease in paradoxical sleep duration and inversion of the light-dark cycle or a circadian phase-shift of vigilance states. These results suggest that ozone exposure during pregnancy may affect the generating mechanisms of paradoxical sleep, and the regulation of circadian rhythms in rats.

Infusion of modafinil into anterior hypothalamus or pedunculopontine tegmental nucleus at different time-points enhances waking and blocks the expression of recovery sleep in rats after sleep deprivation.

Clinical studies have indicated that the primary pharmacological activity of modafinil (MOD) is inducing wakefulness; however, the brain targets that underlie its wake-promoting activity have not been described. In the present study, we show that MOD injected into sleep-wake related brain areas promoted alertness. If administered (10, 20, or 30 μg/1 μL) into either anterior hypothalamus (AH) or pedunculopontine tegmental nucleus (PPTg) at 08:00, 12:00 or 16:00 h, MOD enhanced wakefulness whereas diminished slow wave sleep as well as rapid eye movement sleep. In addition, microinjection of MOD (10, 20, or 30 μg/1 μL) either into AH or PPTg after total sleep deprivation prevented the sleep rebound. Taken together, these observations suggest that AH and PPTg play a key role in the wake-inducing effects of MOD and encourage further experimentation to draw a possible mechanism of action.

CORRELATIONS BETWEEN SUBJECTIVE AND OBJECTIVE FEATURES OF NOCTURNAL SLEEP AND EXCESSIVE DIURNAL SLEEPINESS IN PATIENTS WITH NARCOLEPSY

OBJECTIVE To determine the correlations between excessive daytime sleepiness (EDS), assessed by the Epworth sleepiness scale (ESS), and the multiple sleep latency test (MSLT) and nocturnal sleep architecture features, clinical symptoms of narcolepsy (CSN) and subjective sleep quality (SSQ) in patients with narcolepsy. METHOD Twenty three untreated patients were studied and compared with a matched control group. Diagnosis of narcolepsy was carried out employing a clinical interview, a polysomnographic (PSG) record, and an MSLT. RESULTS Subjective number of awakenings was the SSQ indicator that best correlated with EDS (ESS and MSLT). Regarding clinical features, diurnal tiredness and sleep paralysis correlated with ESS values. Increase in ESS was related with decrease in total sleep time, SWS, and sleep onset latency. On the other hand, increase in MSLT was related with decrease in SWS. CONCLUSION These data suggest that EDS in patients with narcolepsy could be impaired by disturbed nocturnal sleep.

Promoting of wakefulness by administrations of modafinil into anterior hypothalamus and into the pedunculopontine tegmental nucleus in rats

We investigated whether administration of MOD in rats during the lights-on period into wake-promoting areas, such as anterior hypothalamus (AH) or into the pedunculopontine tegmental nucleus (PPTg) would enhance waking. Results showed that microinjections of 1 microL of MOD (10, 20, or 30 microg) into both brain areas increased the total time of alertness and decreased sleep. Additionally, MOD-treated rats showed an enhancement in alpha power spectra but delta power spectra was diminished. Finally, c-Fos expression was found increased into either AH or the PPTg. Collectively, these results suggest that MOD induces waking via the activity of two wake-related brain areas such as AH and the PPTg.

Prolonged waking reduces human immunodeficiency virus glycoprotein 120- or tumor necrosis factor alpha-induced apoptosis in the cerebral cortex of rats.

The human immunodeficiency virus (HIV) induces neuronal death, presumably by apoptosis. This effect may be triggered by the glycoprotein 120 (HIVgp120) released by HIV when infecting a cell, and mediated by tumor necrosis factor alpha (TNFalpha), a pro-inflammatory cytokine. Both molecules, HIVgp120 and TNFalpha, increase sleep when administered acutely in the brain. On the other hand, sleep deprivation increases the levels of several growth factors. In this context, we challenged rats with HIVgp120 or TNFalpha simultaneously with sleep deprivation. Our results indicate that both HIVgp120 and TNFalpha increase neuronal death in the rat cerebral cortex, but not hippocampus, and that this effect is completely prevented by total deprivation of sleep. These results suggest that acute total deprivation of sleep protects against the HIVgp120 and TNFalpha deleterious effects.