Inflammatory markers are associated with inhibitory avoidance memory deficit induced by sleep deprivation in rats.

Sleep deprivation (SD) causes detrimental effects to the body, such as memory impairment and weight loss. SD also changes the concentration of inflammatory mediators such as cytokines, which, in turn, can affect cognitive functioning. Thus, the objective of this study was to investigate the involvement of these inflammatory mediators in inhibitory avoidance memory deficit in sleep-deprived rats. Male Wistar rats were deprived of sleep by the modified multiple platform method for 96 h, while their respective controls remained in their housing cages. To assess memory after SD, all animals underwent training, followed by the inhibitory avoidance task test 24h later. Also, the weight of each animal was recorded daily. In the first experiment, animals received an acute administration of lipopolysaccharide (LPS, 50 or 75 µg/kg i.p.) 3h before the inhibitory avoidance training. In the experiment 2, the animals received acute or chronic administration of anti-IL-6 antibody (Ab, 2 µg/kg i.p.). The acute administration was performed 3h before the inhibitory avoidance training, while the chronic treatment administrations were performed daily during the SD period. The 75 µg/kg dose of LPS, but not the 50 µg/kg dose, caused a significant attenuation of memory impairment in the sleep-deprived animals. Although the treatments with the anti-IL-6 Ab did not produce any significant changes in cognitive performance, the Ab attenuated weight loss in sleep-deprived animals. Taken together, these results suggest the involvement of inflammatory mediators in the modulation of memory deficit and weight loss that are observed in sleep-deprived rats.

Effects on prolactin secretion and binding to dopaminergic receptors in sleep-deprived lupus-prone mice.

Sleep disturbances have far-reaching effects on the neuroendocrine and immune systems and may be linked to disease manifestation. Sleep deprivation can accelerate the onset of lupus in NZB/NZWF(1) mice, an animal model of severe systemic lupus erythematosus. High prolactin (PRL) concentrations are involved in the pathogenesis of systemic lupus erythematosus in human beings, as well as in NZB/NZWF(1) mice. We hypothesized that PRL could be involved in the earlier onset of the disease in sleep-deprived NZB/NZWF(1) mice. We also investigated its binding to dopaminergic receptors, since PRL secretion is mainly controlled by dopamine. Female NZB/NZWF(1) mice aged 9 weeks were deprived of sleep using the multiple platform method. Blood samples were taken for the determination of PRL concentrations and quantitative receptor autoradiography was used to map binding of the tritiated dopaminergic receptor ligands [3H]-SCH23390, [3H]-raclopride and [3H]-WIN35,428 to D(1) and D(2) dopaminergic receptors and dopamine transporter sites throughout the brain, respectively. Sleep deprivation induced a significant decrease in plasma PRL secretion (2.58 +/- 0.95 ng/mL) compared with the control group (25.25 +/- 9.18 ng/mL). The binding to D(1) and D(2) binding sites was not significantly affected by sleep deprivation; however, dopamine transporter binding was significantly increased in subdivisions of the caudate-putamen--posterior (16.52 +/- 0.5 vs 14.44 +/- 0.6), dorsolateral (18.84 +/- 0.7 vs 15.97 +/- 0.7) and ventrolateral (24.99 +/- 0.5 vs 22.54 +/- 0.7 microCi/g), in the sleep-deprived mice when compared to the control group. These results suggest that PRL is not the main mechanism involved in the earlier onset of the disease observed in sleep-deprived NZB/NZWF(1) mice and the reduction of PRL concentrations after sleep deprivation may be mediated by modifications in the dopamine transporter sites of the caudate-putamen.

Effects on prolactin secretion and binding to dopaminergic receptors in sleep-deprived lupus-prone mice

Sleep disturbances have far-reaching effects on the neuroendocrine and immune systems and may be linked to disease manifestation. Sleep deprivation can accelerate the onset of lupus in NZB/NZWF1 mice, an animal model of severe systemic lupus erythematosus. High prolactin (PRL) concentrations are involved in the pathogenesis of systemic lupus erythematosus in human beings, as well as in NZB/NZWF1 mice. We hypothesized that PRL could be involved in the earlier onset of the disease in sleep-deprived NZB/NZWF1 mice. We also investigated its binding to dopaminergic receptors, since PRL secretion is mainly controlled by dopamine. Female NZB/NZWF1 mice aged 9 weeks were deprived of sleep using the multiple platform method. Blood samples were taken for the determination of PRL concentrations and quantitative receptor autoradiography was used to map binding of the tritiated dopaminergic receptor ligands [³H]-SCH23390, [³H]-raclopride and [³H]-WIN35,428 to D1 and D2 dopaminergic receptors and dopamine transporter sites throughout the brain, respectively. Sleep deprivation induced a significant decrease in plasma PRL secretion (2.58 ± 0.95 ng/mL) compared with the control group (25.25 ± 9.18 ng/mL). The binding to D1 and D2 binding sites was not significantly affected by sleep deprivation; however, dopamine transporter binding was significantly increased in subdivisions of the caudate-putamen - posterior (16.52 ± 0.5 vs 14.44 ± 0.6), dorsolateral (18.84 ± 0.7 vs 15.97 ± 0.7) and ventrolateral (24.99 ± 0.5 vs 22.54 ± 0.7 µCi/g), in the sleep-deprived mice when compared to the control group. These results suggest that PRL is not the main mechanism involved in the earlier onset of the disease observed in sleep-deprived NZB/NZWF1 mice and the reduction of PRL concentrations after sleep deprivation may be mediated by modifications in the dopamine transporter sites of the caudate-putamen.

Prostaglandin involvement in hyperthermia induced by sleep deprivation: a pharmacological and autoradiographic study.

AIMS: Hyperthermia is a characteristic functional effect of sleep deprivation (SD). We hypothesize here that prostaglandin E2 (PGE2) could be involved in hyperthermia induced by sleep deprivation. MAIN METHODS: To address this issue we examined the effects of a selective cyclo-oxygenase-2 inhibitor (COX-2) agent on hyperthermia induced by SD in rats. We also investigated binding to PGE2 receptors in hypothalamic brain areas of sleep-deprived rats using in vitro autoradiography. Male Wistar rats were deprived of sleep for 96 h using the platform technique. Sleep deprived and control groups received saline or Celecoxib (20, 30 and 40 mg/kg; p.o.) daily during the SD period. Colonic temperature was measured daily. KEY FINDINGS: Results indicated that core temperature of sleep-deprived rats that receiving saline increased from the first to the fourth day of SD compared to baseline and to the respective control group. However, the hyperthermia induced by SD was not blocked by COX-2 inhibitor at any dose. [(3)H]PGE2 binding did not differ significantly among the groups in any of a number of hypothalamic areas examined. SIGNIFICANCE: Although SD rats showed no response to the COX-2 inhibitor and no alterations in [(3)H]PGE2 binding, the possibility remains that other prostaglandin system and/or receptor subtypes may be altered by SD.

Paradoxical sleep deprivation increases plasma endothelin levels

The endothelins (ET-1, 2 and 3) constitute a family of 21 amino acid peptides with potent biological activities. ET-1 is one of the most potent endogenous vasoconstrictors so far identified and its increased concentration in plasma appears to be closely related to the pathogenesis of arterial hypertension as well as to obstructive sleep apnea (OSA). OSA patients exhibit repetitive episodes of apnea and hypopnea that result in hypoxia and consecutive arousals. These patients are chronically sleep deprived, which may aggravate the hypertensive features, since literature data show that sleep deprivation results in hypertension both in humans and in animals. Based on the reported relationship between ET-1, hypertension and sleep deprivation consequences, the purpose of the present study was to determine plasma ET concentrations in paradoxical sleep-deprived animals. Male Wistar rats, 3 to 4 months old (N = 10 per group), were deprived of sleep for 24 and 96 h by the platform technique and plasma ET-1/2 was measured by radioimmunoassay. Analysis of plasma revealed that 96 h of sleep deprivation induced a significant increase in ET-1/2 release (6.58 fmol/ml) compared to control (5.07 fmol/ml). These data show that sleep deprivation altered plasma ET-1/2 concentrations, suggesting that such an increase may participate in the genesis of arterial hypertension and cardiorespiratory changes observed after sleep deprivation

Paradoxical sleep deprivation increases plasma endothelin levels.

The endothelins (ET-1, 2 and 3) constitute a family of 21 amino acid peptides with potent biological activities. ET-1 is one of the most potent endogenous vasoconstrictors so far identified and its increased concentration in plasma appears to be closely related to the pathogenesis of arterial hypertension as well as to obstructive sleep apnea (OSA). OSA patients exhibit repetitive episodes of apnea and hypopnea that result in hypoxia and consecutive arousals. These patients are chronically sleep deprived, which may aggravate the hypertensive features, since literature data show that sleep deprivation results in hypertension both in humans and in animals. Based on the reported relationship between ET-1, hypertension and sleep deprivation consequences, the purpose of the present study was to determine plasma ET concentrations in paradoxical sleep-deprived animals. Male Wistar rats, 3 to 4 months old (N = 10 per group), were deprived of sleep for 24 and 96 h by the platform technique and plasma ET-(1/2) was measured by radioimmunoassay. Analysis of plasma revealed that 96 h of sleep deprivation induced a significant increase in ET-(1/2) release (6.58 fmol/ml) compared to control (5.07 fmol/ml). These data show that sleep deprivation altered plasma ET-(1/2) concentrations, suggesting that such an increase may participate in the genesis of arterial hypertension and cardiorespiratory changes observed after sleep deprivation.

Differential effects of acute cold and footshock on the sleep of rats.

Several studies have shown that 1 h of immobilisation stress during the rat's active period results in rebound of paradoxical (PS) and slow wave sleep (SWS). Since the effects of stress on behaviour and physiological parameters vary according to the stimulus, the present study sought to examine the activation of the hypothalamic-pituitary-adrenal (HPA) axis and the sleep pattern of rats submitted to 1 h of footshock, immobilisation or cold, or 18 h of PS deprivation (PSD). Stress sessions began between 0900 and 0930 h. Immediately after the end of the stress session, or at the corresponding time for controls, animals were blood sampled for determination of ACTH and corticosterone (CORT) plasma levels. In Experiment 2, animals were implanted with electrodes for basal and post-stress polysomnographic recording (6 h long). The results showed that all stressors produced an activation of the HPA axis; however, footshock induced the largest ACTH levels, whereas cold resulted in the highest CORT levels. In regard to the sleep data, immobilisation and PSD led to a rebound of SWS (+16.87% and +9.37%, respectively) and PS (+42.45% and +55.25%, respectively). Immobilisation, however, induced an increased number of PS episodes, whereas PSD resulted in longer PS episodes. Cold stress produced an exclusive rebound of SWS (+14.23%) and footshock promoted sustained alertness during the animal's resting period (+47.18%). These results indicate that different stimuli altered the sleep pattern in a distinct manner; and these alterations might be related to the state of the HPA axis activation.

The effects of acute cocaine administration in paradoxical sleep-deprived rats.

Recent studies demonstrate the action of cocaine on reward pathways, which are activated by pleasant stimuli. Cocaine's mechanism of action involves the blockade of dopamine and norepinephrine reuptake by the presynaptic terminal. Paradoxical sleep (PS) deprivation is known to induce several behavioural alterations most of which suggest the occurrence of supersensitivity of D2 and a subsensitivity of ß1and ß2receptors.The present study sought to examine the effects of PS deprivation on the actions of cocaine on the erection and ejaculation behaviours in rats. Four different doses of cocaine (3.5, 7.0, 15.0 and 30.0 mg/kg) were acutely administered to Wistar male rats, at the end of a 4-day period of PS deprivation or at the equivalent time-point to control animals. Moreover, 15 mg/kg of cocaine were administered in animals submitted to immobilization, footshock and forced swimming. The data were analysed by the Chi-square test, and revealed that only PS-deprived animals exhibited penile erections and ejaculation behaviours, which were absent in control animals. PS deprivation increases the sexual behaviour of male rats, probably due to its action on dopaminergic systems. However, further studies need to be carried out in order to clarify the mechanisms involved between PS deprivation and cocaine.