Paulo Jose Forcina Martins

Endocrinological and catecholaminergic alterations during sleep deprivation and recovery in male rats

Since previous data of our group showed increased concentrations in HPA axis hormones in sleep deprived rats, we hypothesized that this augmentation could produce effects in other hormonal systems, particularly in the sexual system. Considering that little is known about how the hormonal system changes during the recovery period after sleep deprivation (SD), our objective was to examine from what point SD alters sexual and stress‐related hormones along with plasma catecholamine concentrations during 4 days. We also sought to verify the time course of their recovery after an equivalent period of recovery sleep. Rats were deprived of sleep by the platform technique for 1–4 days and were allowed to recover for the same period. Plasma catecholamines [dopamine (DA) and noradrenaline (NOR)], testosterone, estrone, progesterone, prolactin, corticosterone and adrenocorticotropic hormone (ACTH) concentrations were measured. Comparisons between groups showed that the SD procedure used in the present study produced marked alterations in almost all studied hormones from 24 h of SD, except for estrone and prolactin (which required 96 h of SD to become altered). Testosterone and estrone decreased, whereas progesterone, prolactin, corticosterone, ACTH, DA and NOR increased. During recovery period, progesterone, prolactin and corticosterone concentrations returned to control levels, whereas testosterone, estrone, NOR and DA did not. In addition, after 48 h of recovery ACTH and NOR decreased below control concentrations, remaining low until 96 h of sleep recovery. Thus, SD showed long lasting, differential effects upon these neurochemicals suggesting that each has its own pattern of responses to SD as well as variable periods of recovery.

Increased hypocretin-1 (orexin-a) levels in cerebrospinal fluid of rats after short-term forced activity

The hypocretins (orexins) are recently discovered neuropeptides initially associated with feeding behavior and sleep regulation. However, the normal function of these peptides is unclear and a number of studies have reported a role in energy homeostasis and locomotor activity. Exercise (or physical activity) is the most powerful way of challenging the internal homeostatic process. This study examines the circadian differences in response to forced activity and homeostatic challenges on hypocretin-1 (Hcrt-1) levels in the cerebrospinal fluid (CSF) of rats. Hcrt-1 levels were decreased after long-term immobilization at the end of active phase (zeigeber time-0, ZT-0) and increased after short-term forced swimming in the rest phase (ZT-8). Nevertheless, no effects were observed after short-term immobilization, total sleep deprivation or cold exposure. We concluded that despite the relation between hypocretins, stress and sleep regulation reported in the literature, short-term total sleep deprivation, immobilization and cold exposure did not induce increases in CSF Hcrt-1 levels at ZT-0 and ZT-8. On the other hand, the relationship between hypocretinergic system activation and motor activation is reinforced by decrease in Hcr-1 levels after long-term immobilization at ZT-0 and its increased levels after short-term forced swimming at ZT-8 in CSF of rats.

Long term treatment with ACE inhibitor enalapril decreases body weight gain and increases life span in rats.

Renin-angiotensin system is involved in homeostasis processes linked to renal and cardiovascular system and recently has been linked to metabolic syndrome. We analyzed the influence of long term angiotensin I converting enzyme (ACE) inhibitor enalapril treatment in normotensive adult Wistar rats fed with standard or palatable hyperlipidic diets. Our results show that long term enalapril treatment decreases absolute food intake, serum leptin concentration and body weight gain. Moreover, in adipose tissue, enalapril treatment led to decreased ACE activity, enhanced the expression of peroxisome proliferator activated receptor gamma, adiponectin, hormone-sensitive lipase, fatty acid synthase, catalase and superoxide dismutase resulting in prolonged life span. On the other hand, the ACE inhibitor was not able to improve the transport of leptin through the blood brain barrier or to alter the sensitivity of this hormone in the central nervous system. The effect of enalapril in decreasing body weight gain was also observed in older rats. In summary, these results extend our previous findings and corroborate data from the literature regarding the beneficial metabolic effects of enalapril and show for the first time that this ACE inhibitor prolongs life span in rats also fed with palatable hyperlipidic diet, an action probably correlated with adipose tissue metabolic modulation and body weight reduction.

OREXIN ACTIVATION PRECEDES INCREASED NPY EXPRESSION, HYPERPHAGIA AND METABOLIC CHANGES IN RESPONSE TO SLEEP DEPRIVATION

Several pieces of evidence support that sleep duration plays a role in body weight control. Nevertheless, it has been assumed that, after the identification of orexins (hypocretins), the molecular basis of the interaction between sleep and energy homeostasis has been provided. However, no study has verified the relationship between neuropeptide Y (NPY) and orexin changes during hyperphagia induced by sleep deprivation. In the current study we aimed to establish the time course of changes in metabolite, endocrine, and hypothalamic neuropeptide expression of Wistar rats sleep deprived by the platform method for a distinct period (from 24 to 96 h) or sleep restricted for 21 days (SR-21d). Despite changes in the stress hormones, we found no changes in food intake and body weight in the SR-21d group. However, sleep-deprived rats had a 25-35% increase in their food intake from 72 h accompanied by slight weight loss. Such changes were associated with increased hypothalamus mRNA levels of prepro-orexin (PPO) at 24 h followed by NPY at 48 h of sleep deprivation. Conversely, sleep recovery reduced the expression of both PPO and NPY, which rapidly brought the animals to a hypophagic condition. Our data also support that sleep deprivation rapidly increases energy expenditure and therefore leads to a negative energy balance and a reduction in liver glycogen and serum triacylglycerol levels despite the hyperphagia. Interestingly, such changes were associated with increased serum levels of glucagon, corticosterone, and norepinephrine, but no effects on leptin, insulin, or ghrelin were observed. In conclusion, orexin activation accounts for the myriad changes induced by sleep deprivation, especially the hyperphagia induced under stress and a negative energy balance.

Increased hypocretin-1 levels in cerebrospinal fluid after REM sleep deprivation

Rat cisternal (CSF) hypocretin-1 in cerebrospinal fluid was measured after 6 or 96 h of REM sleep deprivation and following 24 h of REM sleep rebound. REM deprivation was found to increase CSF hypocretin-1 collected at zeitgeber time (ZT) 8 but not ZT0. Decreased CSF hypocretin levels were also observed at ZT8 after 24 h of REM sleep rebound. These results suggest that REM sleep deprivation activates and REM sleep rebound inhibits the hypocretin system. Increased hypocretin tone during REM deprivation may be important in mediating some of the effects of REM sleep deprivation such as antidepressant effects, hyperphagia and increased sympathetic activity.

Effects of paradoxical sleep deprivation on blood parameters associated with cardiovascular risk in aged rats

The effects of 96 h of paradoxical sleep deprivation (PSD) on blood parameters associated with cardiovascular risk were studied in young (3-month old) and aged (22-month old) rats. In general, aging was associated with an overall increase in most measures, irrespective of sleep deprivation condition. The latter manipulation also had significant effects on blood variables, but not in a consistent pattern. Thus, PSD significantly reduced triglyceride levels in both young and aged rats; it reduced blood viscosity in aged but not in young rats, and had no effect on the increased cholesterol levels observed in aged controls. Examinations of cholesterol fractions revealed significant increases in low density lipoprotein and high density lipoprotein in aged PSD rats compared to respective controls, whereas very low density lipoprotein was significant decreased after PSD in both young and aged animals. PSD increased vitamin B(12) levels in aged rats, and significantly decreased homocysteine levels in young but not in aged rats which in turn were already reduced. Folate levels were the only variable that was unaffected by aging and/or PSD. These results indicate that PSD has significant but heterogeneous physiological effects in aged rats and may intensify certain aging-related effects which contribute to cardiovascular disease risk while attenuating others.

Exercício e sono

.Porem, efetivamente, a prescricao de exercicios fisicos comessa finalidade ainda e reduzida, possivelmente como umreflexo da falta de conhecimento por parte de professorese medicos dos beneficios dos exercicios nessa area.O objetivo desta revisao e discutir os principais aspectosdo ciclo sono-vigilia, enfatizando as caracteristicas do pa-drao de sono e as influencias do exercicio no ciclo sono-vigilia. Desta forma, pontuamos fatores como: horario,aptidao fisica, relacao entre a duracao e intensidade doexercicio que se relacionam com as teorias pelas quais setenta justificar os efeitos do exercicio sobre o sono. Porultimo, sugerimos alguns metodos que possam auxiliar, emespecial os atletas, a minimizar os problemas de sono quepodem prejudicar tanto as atividades diarias como os trei-namentos.SONOApesar do interesse sobre o sono existir desde aproxi-madamente 1.000 a.C., ainda hoje nao se conhece a funcaodeste fenomeno. Apesar das inumeras teorias propostas,ainda nao existe uma que inspire confianca em que a es-sencia do sono tenha sido totalmente capturada

Sleep deprivation-induced gnawing—relationship to changes in feeding behavior in rats

We have recently reported that food spillage increases during sleep deprivation in rats, which may lead to an overestimation of food intake in this condition. The objective of this study was to verify whether sleep deprivation induces an increase in gnawing behavior that could account for increased food spillage and apparent increase in food intake. We introduced wood blocks as objects for gnawing and determined the effects of their availability on food consumption and food spillage during sleep deprivation. Wood block availability reduced the amount of food removed from hoppers and decreased the amount of food spilled. However, weight loss still occurred during the sleep deprivation period, especially in the first 24 h, and it was related to a reduction in food intake. Sleep deprivation causes an increase in stereotyped gnawing behavior which largely accounts for increased food spillage observed during deprivation. Specifically, the observed increase in food removed from feeders seems to be due to an increase in gnawing and not to increased hunger. However, even when appropriately corrected for spillage, food intake decreased in the first 24 h of sleep deprivation, which accounted for most of the body weight loss seen during the 96 h of sleep deprivation.

Effects of paradoxical sleep deprivation and cocaine on genital reflexes in hyperlipidic-fed rats

The present study was designed to investigate the effects of a hyperlipidic diet (HD) on penile erection (PE) and ejaculation (EJ) induced by cocaine in paradoxical sleep deprived (PSD) rats. Secondly, we aimed to verify the influence of HD cafeteria diet on steroid hormone levels. Twenty-one day-old male Wistar rats were randomly assigned into two groups: rats fed with commercial chow diet and rats fed with a palatable HD containing chow mixed with peanuts, milk chocolate and sweet cookies in the proportion of 3:2:2:1. After nine weeks of treatment, the animals were submitted to PSD or maintained as home cage control group for 96 h and challenged with cocaine (7 mg/kg, i.p.). Results showed that the HD led to a reduction in the frequency of erection in the PSD+cocaine group when compared to the PSD+cocaine fed with standard diet. Regardless of the diet, testosterone concentrations were significantly lower and progesterone was higher in the PSD rats than in the respective home-cage control rats. Although there were no hormonal alterations, the findings showed that a long-term HD might modify the stimulating effects of cocaine in potentiating genital reflexes in PSD rats.

Neonatal arthritis disturbs sleep and behaviour of adult rat offspring and their dams.

This study aims to evaluate the impact of neonatal arthritis on adult pain threshold, sleep and general behaviours in rats and their lactating dams. Male pups were injected in the hind paw with complete Freunds adjuvant or saline on postnatal day (PN) 1. After weaning, dams were tested for anxiety, sleep recording or hormone profiling (ACTH, corticosterone and prolactin) and brain sampling (pineal melatonin and hippocampus serotonin). At adulthood (PN90), distinct subgroups of neonatal arthritic (AR) and control rats (CR) were also assessed for anxiety and pain thresholds, sleep recording, and blood/brain sampling. Compared to their respective controls at PN12, dams of arthritic rats (DAR) showed a longer latency in expressing pup retrieval and dam–pup interaction. DAR and AR showed a lower pain threshold, anxiety‐like behaviour, and sleep fragmentation. Compared to controls, DAR displayed longer sleep latency, reduced paradoxical sleep latency and sleep efficiency, a decrease in prolactin and serotonin levels and increased melatonin levels. This model of unilateral hindpaw inflammation has a wide range of long‐term effects in both lactating dams and their adult offspring.