Anemia in sleep-deprived rats receiving anticoagulants.

Independent groups of rats were deprived of sleep and treated with the anticoagulant drugs phenylindanedione or dicoumarol for 1 to 8 days. These animals developed an extremely severe anemia which was accelerated by p-chlorophenylalanine. The red cell count and amount of hemoglobin decreased to half of normal values. No decrease occurred in animals subjected to any one single treatment. Histological examination indicated hemolysis, hypoplasia of hemopoietic organs, slight hemorrhage, but no evidence of stress. The severity of the anemia was inversely related to the amount of sleep permitted during sleep deprivation. This new syndrome demonstrates marked effects of sleep deprivation on both maturation and destruction of red blood cells. Depletion of serotonin by injection of parachlorophenylalanine blocked the increase in amount of brain waves of the type commonly seen in slow wave sleep but did not eliminate the production of these waves. This result is at variance with the theory that serotonin is the neurochemical responsible for the "priming" of slow wave sleep.

Changes in protein levels in perfusates of freely moving cats: relation to behavioral state.

Perfusates from the brains of freely moving cats, obtained by means of a push-pull cannula, contain high concentrations of proteins. The levels vary in a cyclic fashion and are higher during rapid eye movement sleep than during the waking state. The proteins represent a distinctive class of tissue protein and their changing levels appear to reflect an alteration in the protein content of the extracellular space of brain related to behavioral state.

The anandamide membrane transporter inhibitor, VDM-11, modulates sleep and c-Fos expression in the rat brain.

Endogenous cannabinoids or endocannabinoids are lipid molecules that have a variety of biological actions, most notably via activation of the cannabinoid receptors. The family of endocannabinoids includes arachidonoylethanolamide (ANA) which modulates different behaviors, such as sleep. However, it is unknown whether pharmacological elevation of ANA endogenous levels might induce sleep. VDM 11 [(5 Z,8 Z,11 Z,14 Z)-N-(4-hydroxy-2-methylphenyl)-5,8,11,14-eicosatetraenamide] is commonly used as an inhibitor of ANA cellular uptake, and thereby to potentiate its actions. In this study we have examined whether VDM-11 exerts any effect on the sleep-wake cycle and c-Fos expression in brain areas. When assayed alone in rats, VDM-11 (10 or 20 microg/5 microL, i.c.v.) at the beginning of the lights-off period, reduced wakefulness and increased sleep. The CB(1) cannabinoid receptor antagonist, SR141716A, partially reversed the effects of VDM-11 on sleep. Additionally, VDM-11 enhanced c-Fos expression in sleep-related brain areas such as the anterior hypothalamic area, paraventricular thalamic nucleus, and pedunculopontine tegmental nucleus. It is concluded that VDM-11 displays sleep-inducing properties and these effects slightly, albeit significantly, are reversed using SR141716A. Furthermore, c-Fos data suggest a possible underlying neuroanatomical substrate of the sleep-inducing properties of VDM-11. We report evidence suggesting that VDM-11 might be considered for the development of new pharmacological and pharmaceutical approaches to treat sleep disorders such as insomnia.

[Neurogenesis as a therapeutic strategy to regenerate central nervous system]. / Neurogénesis como estrategia terapéutica para regenerar el sistema nervioso central.

INTRODUCTION: In the past few years, it has been demonstrated that the adult mammalian brain maintains the capacity to generate new neurons from neural stem/progenitor cells. These new neurons integrate into pre-existing systems through a process referred to as 'neurogenesis in the adult brain'. DEVELOPMENT: This discovery has modified our understanding of how the central nervous system functions in health and disease. Until today, a great effort has been made attempting to decipher the mechanisms regulating adult neurogenesis, which might help to induce neuronal endogenous cell replacement in various neurological diseases. CONCLUSIONS: In this revision, we will attempt to shed some light on the neurogenesis process with respect to diseases of the central nervous system and we will describe some therapeutic potentials in relation to neurodegenerative diseases.

[Neurogenesis in the adult brain]. / Neurogénesis en el cerebro adulto.

INTRODUCTION: The discovery that new neurons continue to be generated in the adult brain has modified the concept of brain plasticity and has brought to light new mechanisms that ensure the homeostasis of the nervous system. DEVELOPMENT: Neurogenesis, that is to say, the process involving the generation of new neurons, has been shown to occur in the hippocampus and in the olfactory bulb in adult mammals, which suggests that neuronal stem cells persist throughout the entire lifespan. The primary precursors have been identified in specialised regions called neurogenic niches. Interestingly, the cells that give rise to the new neurons in the adult brain express markers for glial cells, a cell lineage that is a long way from that of neurons. Studies conducted during the development of the brain have shown that radial glial cells not only give rise to astrocytes but also neurons, oligodendrocytes and ependymal cells. In addition, it is known that radial glial cells are also the precursors of neuronal stem cells in the adult brain. CONCLUSIONS: Overall, these data support the idea that stem cells develop from a neuroepithelial-glial radial-astrocytic lineage. Thus, identifying the primary precursors, both in the developing brain and in the adult brain, is essential to understand the functioning of the nervous system and, from there, to develop strategies for neuronal replacement in the adult brain when needed.

Endogenous and exogenous factors on sleep-wake cycle regulation.

A number of theories have proposed the involvement of different brain structures and neurotransmitters in order to explain the regulation of the sleep wake cycle. However, there is no clear consensus as to the mechanisms through which the brain structures and their various neurotransmitters interact to produce theses phases. Perhaps the problem is related to the fact sleep is a very fragile state, easily modified or influenced by a variety of substances or experimental manipulations. In this paper, we describe the evidence of two different groups of factors that induce important changes on the sleep wake cycle. The endogenous factors: neurotransmitters; hormone; peptides; and some substances of lipidic nature and exogenous factors: stress, food intake, learning, sleep deprivation, sensorial stimulation, exercise and temperature on the regulation the sleep-wake cycle. Likewise, we propose a hypothesis which attempts to reconcile the fact that endogenous and exogenous factors have similar effects.

Immunocytochemical, ultrastructural and neurochemical evidences on synaptogenesis and dopamine release of rat chromaffin cells co-cultured with striatal neurons.

The results reported herein address the question of synaptogenesis between adrenal chromaffin cells and striatal neurons. The release of dopamine from chromaffin cells in the presence of striatal neurons was also examined. Co-culture of newborn rat chromaffin cells and striatal neurons at 1:1 ratio was made. Cultures were examined morphologically using immunocytochemistry and ultrastructural techniques (transmission electron microscopy), while quantitation of dopamine in the culture media by HPLC-ECD was also determined. Neurite outgrowth from chromaffin cells was enhanced in the presence of striatal neurons and numerous synaptic-like contacts between these two cell types were observed. Higher concentration of dopamine was also present in the co-culture medium as compared with those containing only chromaffin cells. The development of synapses between these two types of cells may give support to the functionality of transplants in human cases of Parkinson disease (PD).

Delay in manifestations of aging by grafting NGF cultured chromaffin cells in adulthood.

Dopamine agonists or grafts compensate impaired motor functions in aged rats. However, there is no evidence showing whether grafting in adulthood retard aging manifestations. Motor performance of 13-month-old rats was tested on 2 meter-long wooden beams which had a 15 degree inclination and whose thickness varied from 3, 6, 12, 18, to 24 mm. Rats at 14 months were randomly assigned to 3 groups: sham graft (Group 1); intrastriatal graft of chromaffin cells cultured with NGF (Group 2); intrastriatal graft of chromaffin cells (Group 3). Motor performance was tested at monthly intervals up until rats were 26 months old. Two more groups were included: 26-month-old naive rats (Group 4); and 3- to 5-month-old naive rats (Group 5) both evaluated only once. At 26 months, the basal activity of ventral mesencephalic dopaminergic neurons was recorded. Results showed in Group 2 delay of motor detriments seen in aged rats, maintenance of basal firing rates of nigral cells compared to those of younger rats, and greater survival of substantia nigra cells. It is suggested that NGF cultured chromaffin cells produce a delay of motor detriments in aged rats, as a result of inducing survival and firing rates of nigral cells comparable to those seen in young rats.

Neuropsychological effects of brain autograft of adrenal medullary tissue for the treatment of Parkinson's disease.

We describe the pre- and postoperative neuropsychological profiles of seven patients who received an autograft of adrenal medullary tissue to the caudate nucleus for the treatment of Parkinson's Disease (PD). The preoperative neuropsychological evaluations revealed specific cognitive deficits of varying degree. The patients showed frontal lobe-type deficits with alterations in behavioral programming leading to difficulties in the organization of motor sequences and alternating programs. They also showed memory disorders and visuospatial and visuoperceptual deficiences such as a loss of figure-ground perspective and fragmentation. Postoperative evaluations, carried out 3 months after neurosurgery, revealed a significant amelioration of the frontal lobe-type symptoms and visuospatial deficits, as well as an improvement in memory tasks that require an active organization of the response. Immediate and delayed memory difficulties remained unchanged. These observations were compared to neuropsychological data obtained from neurologically intact subjects and from unoperated PD patients. The improvements of the operated PD patients resulted in performance levels close to normal values and clearly distinguishable from those of unoperated PD patients, and were unrelated to improved mood, increased alertness, or sustained attention. Autotransplantation of adrenal medullary tissue to the caudate nucleus of PD patients showing a decreased effective response to L-dopa therapy can partially restore motor functions and frontal-type cognitive symptoms.

The combination of VIP and atropine induces REM sleep in cats rendered insomniac by PCPA.

Twenty-four cats were implanted with electrodes for chronic sleep recordings. One week after the surgery, cats were treated with two intraperitoneal injections of parachlorophenylalanine (PCPA), an inhibitor of serotonin synthesis, to induce insomnia. Twenty-four hours after the second injection of PCPA, cats were at the peak of insomnia (strong reduction of both slow wave sleep 2 and rapid-eye movement [REM] sleep). During this period cats were divided into four groups (n = 6) and were injected with either atropine (0.5 mg/kg, IM [3.5 mmol/kg]), vasoactive intestinal peptide (VIP) (200 ng, ICV [60 pmol]) or atropine plus VIP (same doses and routes of administration). The control group received saline intramuscularly (IM) intracerebroventricularly and (ICV). Results showed that VIP and atropine injected alone and in combination increased mean total time of REM sleep in PCPA-treated animals. These findings are discussed in terms of a serotonin-acetylcholine interaction.

The effects of sensory stimulation on REM sleep duration.

Previous experiments have demonstrated that auditory (AS) and/or somatosensory (SS) stimulation can increase the duration of REM sleep periods in rats, cats and humans. The objectives of this study were to determine whether repeated AS stimulation causes habituation to the stimulus and whether any additive effects could be obtained with the simultaneous application of AS and SS. Three experimental procedures were used in this study. In experiment 1, animals were recorded for 4 consecutive days with AS, followed by a post-stimulus session. In experiment 2, they were recorded for 24 hours with AS applied at each REM period, followed by a subsequent 24-hours-post-stimulus recording. In experiment 3, animals underwent AS, SS stimulation, or simultaneous application of both in a random fashion at each REM period. The results of all experiments confirm previous findings showing that auditory or somatosensory stimuli significantly increase REM sleep period duration. In addition, AS--applied with different presentations during REM and throughout the sleep-wake cycle--are capable of increasing REM duration regardless of the manner in which they were presented. However, the effects of the stimuli were not additive. It is worth noting that although REM duration increased, REM period frequency decreased, resulting in no net change of total REM sleep through time. Furthermore, no changes were observed in other sleep-wake variables. These experiments clearly demonstrate that repeated auditory stimulation does not cause habituation, and there are no evident side effects on the sleep-wake cycle. These results confirm that the mechanisms involved in REM generation and maintenance can be modulated by sensory modalities.

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.

Vasoactive intestinal polypeptide induces REM recovery in insomniac forebrain lesioned cats.

Basal forebrain (BF) lesions in cats produces insomnia by reducing both slow wave sleep (SWS) and rapid-eye-movement (REM) sleep time. Recently it has been shown that vasoactive intestinal polypeptide (VIP) may be a specific REM inductor in the parachlorophenylalanine (PCPA) insomniac model. The purpose of this study was to test the hypnogenic properties of VIP in a nonpharmacological model of insomnia. Cats were rendered insomniac by delivering a DC current through stainless steel tripolar electrodes implanted in the basal forebrain area (BFA). Sleep-waking cycle recordings were done prior to lesions and on days 7, 9, 10, 11, 14, and 21 days after BF lesion. On day 10 after the lesion, 200 ng of VIP was injected into the 4th ventricle. Results showed that on postlesion days 7 and 9, SWS and REM sleep total times decreased, while waking time increased significantly. VIP restored REM sleep total time and frequency for almost 48 h, and SWS sleep total time for 24 h. On days 14 and 21 postlesion, insomnia was reestablished. Results are discussed in terms of the possible anatomical and neurochemical substrates whereby VIP can induce the recovery of sleep-waking control values.

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.

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.

Effects of biperiden on sleep at baseline and after 72 h of REM sleep deprivation in the cat.

We examined the effects of the muscarinic M1 antagonist biperiden in cats. In the first experiment a dose-response analysis was performed with intraventricular injection (IV ventricle) of biperiden. In the second experiment after REM sleep deprivation cats were injected with either biperiden (0.1 mg/kg) or saline. Biperiden produced a reduction in REM sleep percentage and an increase in REM sleep latency with these high doses. The 0.1 mg/kg biperiden dose, which did not suppress REM sleep at baseline, did reduce the REM sleep rebound. The present study suggests a modulatory role of biperiden on REM sleep regulatory processes. The fact that an effect of biperiden is noted only at the high doses suggests that at these doses the drug is influencing non-M1 receptors. Changes in the sensitivity of these receptors as a result of REM sleep deprivation might explain why a dose of biperiden will reduce REM sleep rebound, while being ineffective in suppressing REM sleep at baseline.

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.

The effects of various protein synthesis inhibitors on the sleep-wake cycle of rats.

The present investigation sought to determine the effects of Anisomycin (A), Chloramphenicol (ChA), Vincristine (V), and Penicilline G on the sleep-wake cycle of rats. It was found that both high and low doses of anisomycin decreased rapid eye movement (REM) sleep, while only high doses of ChA and V produced such a decrease. Slow wave sleep (SWS) was unaffected by these drugs. Penicilline G, on the other hand, had no effect on the sleep-wake cycle. It was further shown that the reduction of REM sleep was the result of a decrease in the number of REM periods rather than in the duration of each individual period. These results suggest that protein synthesis may participate in the mechanisms that trigger REM sleep.

Fetal substantia nigra and adrenal medullary grafts placed contralateral to the nigrostriatal lesion side induce a decrease in turning behavior but not in dopamine receptor density.

Motor asymmetries as well as changes in the density of postsynaptic dopamine receptors produced by unilateral denervation of the striatum have been reduced by both substantia nigra (SN) and adrenal medullary (AM) grafts. Since to this date all studies have placed the grafts on the side ipsilateral to the lesion, the purpose of this study was to determine whether similar effects can be obtained when grafts are placed contralateral to the denervated side. The results of this study showed that 6-hydroxydopamine-lesioned rats followed up to 150 days with contralaterally placed intraventricular fetal substantia nigra grafts and fetal adrenal medulla grafts have a reduction of turning behavior of 41% and 34% respectively. However, contrary to ipsilateral grafts no normalization of dopamine receptor density as measured by [3H]spiperone autoradiography was observed 6 months after SN grafts, however, after AM grafts normalization did occur except in the anterior portion of the striatum. These results suggest that the compensatory motor changes induced by the grafted tissues could be mediated by mechanisms unrelated to changes in receptor density.

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.