Evaluation of melatonin on the precocious puberty: a pilot study.

OBJECTIVE: To evaluate the effect of 6-sulphatoxymelatonin on the sleep quality of girls with precocious puberty. STUDY DESIGN: Ninety-nine girls were divided into three groups: GI, precocious puberty; GII, normal prepubescent; GIII, normal puberty. Questionnaires containing demographic and clinical data were applied. Blood was collected for hormonal evaluation for 6-sulphatoxymelatonin. The modified Rush Sleep Diary was used. RESULTS: The levels of 6-sulphatoxymelatonin were highest in the group without pubertal development (75.23 ± 10.84 ng/ml), second highest in the group with normal puberty (45.66 ± 3.87 ng/ml, p < 0.001) and lowest in the group with true precocious puberty (37.04 ± 5.47 ng/ml). The amount of day sleep was greater in the group without pubertal development compared to other groups. CONCLUSION: Despite the sleep data, melatonin may be involved in the precocious puberty process.

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 Freund's 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.

Altered sleep patterns and physiologic characteristics in spontaneous dwarf rats.

Spontaneous dwarf rats are a useful experimental model for studying various biologic events associated with pituitary dwarfism. Dwarf rats occurred serendipitously in our colony of Wistar rats during experimental breeding. This study aimed to describe the sleep pattern and physiologic characteristics of these rats compared with normal-sized adult rats. Because growth hormone can attenuate the upregulation of ceruloplasmin expression caused by acute inflammation, we also assessed the basal levels of serum ceruloplasmin in these animals. At 90 d of age, body weight and length were significantly lower in dwarf rats relative to normal rats. Dwarves had lower concentrations of serum testosterone and growth hormone, but progesterone was unchanged. Corticosterone levels did not differ between groups. During the light period, the percentage of sleep time recorded and duration of slow-wave sleep did not differ between groups. However, compared with controls, dwarf rats had marked fragmentation of sleep and less paradoxical sleep. During the dark phase, sleep patterns in dwarf rats were within the normal range. Immunoblotting data showed that the levels of ceruloplasmin in serum were lower in dwarf rats. Our findings provide insight into pathologic processes related to growth hormone deficiency.

Influence of chronic cocaine treatment and sleep deprivation on sexual behavior and neurogenesis of the male rat.

The present study investigated the influence of chronic cocaine treatment on genital reflexes associated with paradoxical sleep deprivation (PSD), and possible alterations in hippocampus neurogenesis of the male rat. At 21 days of age, the rats were distributed into two groups and injected with saline or cocaine (7 mg/kg, three times a week for 12 weeks). At age 90 days, they were submitted to a four-day period of PSD (PSD groups) or maintained in home-cages (control groups), challenged with saline or cocaine administration, and placed in observation cages to assess genital reflexes. Two additional groups were used to quantify neurogenesis. PSD rats treated chronically with cocaine and challenged with saline did not differ from their respective control groups. The association of PSD with cocaine potentiated penile erection (PE) when compared to PSD-saline (saline challenged) rats, and these effects were similar to those observed in long-term cocaine treated rats. The bromodeoxyuridine (BrdU) assay indicated a reduction in BrdU-positive cells in the adult hippocampus after chronic cocaine treatment. These findings show that long-term cocaine treatment from brain development through adulthood had a marked effect on sexual responses and neuronal proliferation.

Repeated electroconvulsive shock induces changes in high-affinity [3H]-ouabain binding to rat striatal membranes.

Repeated electroconvulsive shock is an effective treatment for affective disorders. Striatum, hippocampus and brainstem are involved in affective disorders. Sodium-potassium/ATPase is of paramount importance for the proper functioning of the brain and its involvement in the affective disorders has been claimed for a long time. Sodium-potassium/ATPase has an extracellular regulatory binding site to which cardiotonic glycosides, such as ouabain, bind to, thus regulating the activity of the enzyme. Endogenous "ouabain-like" substances exist in the brain and their actions on the sodium-potassium/ATPase resemble ouabain biological properties. The aim of this work was to determine if electroconvulsive shock (ECS) would induce changes in the high-affinity binding of ouabain to the sodium-potassium/ATPase from rat brain regions. Adult, male Wistar rats received one (ECSx1 group) or seven electroshocks (ECSx7 group) delivered daily through ear-clips electrodes. Control rats received the same manipulations; however, no current was delivered through the electrodes (SHAMx1 and SHAMx7 groups). All groups were sacrificed 24 h after the last ECS session. The B (max) and K (D) of high-affinity [(3)H]-ouabain binding were determined in crude membrane preparations from the striatum, hippocampus and brainstem. The results obtained showed a statistically significant increase in the affinity of [(3)H]-ouabain (lower K (D)) to striatal membranes in those rats receiving seven ECS. In the striatum there was no change in the K (D) after one ECS; as well as there was no change in the B (max) after a single or seven ECS. High-affinity [(3)H]-ouabain binding to hippocampus and brainstem did not reveal any significant differences either in K (D) or B (max) after one or seven ECS. The increased affinity of ouabain to the striatal sodium-potassium/ATPase induced by repeated ECS suggests an increased interaction in vivo of the endogenous "ouabain-like" substances with the enzyme and the involvement of the extracellular regulatory allosteric ouabain binding site in the striatal sodium-potassium/ATPase in the effects of electroconvulsive shock.

Rapid eye movement sleep deprivation induces changes in the high-affinity binding of [3H]-ouabain to the rat cortical membranes.

Rapid eye movement sleep (REMS) suppresses seizures. On the other hand, REMS deprivation (REMSD) increases brain susceptibility to seizures. Sodium-potassium/ATPase is involved in the control of brain excitability. Ouabain, a cardiotonic glycoside, binds to a regulatory extracellular allosteric site in the sodium-potassium/ATPase inhibiting/stimulating its activity depending on its concentration. Endogenous ouabain-like substances exist in the brain; therefore, changes in the ouabain binding site may be involved in the increased brain excitability induced by REMSD. Adult, Wistar male rats were deprived of REMS for 96 hours by the flower-pot method (REMSD). A stress control group was kept in the same environment on a larger platform (LP). A third group of rats was kept in the same room in their home-cages (CONTROL). After REMSD all rats were sacrificed by decapitation and their cerebral cortex dissected. High-affinity [3H]-ouabain binding was carried out in cortical crude membrane preparation using 8 concentrations of [3H]-ouabain (1-24 nM). The results show a statistically significant increase of KD in the REMSD rats compared to both CONTROL and LP groups. There were no statistically significant differences in the Bmax among the experimental groups. There was also no change either in cortical activity of K+ stimulated p-nitrophenylphosphatase, the dephosphorylation reaction of phosphorylated sodium-potassium/ATPase or in Mg2+-stimulated p-nitrophenylphosphatase. An increase in the KD of [3H]-ouabain binding to the sodium-potassium/ATPase in REMSD rats indicates a lower affinity to the endogenous inhibitors/stimulators of the enzyme. Therefore, this decreased affinity of the endogenous ouabain-like substances may be involved in the increased excitability induced by REMSD.

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.

Age-related effects on genital reflexes induced by paradoxical sleep deprivation and cocaine in rats.

Although sexual function often decreases with age, a recent study demonstrated that paradoxical sleep deprivation (PSD) was effective in inducing penile erection (PE) in 60% of 22-month-old PSD rats after acute cocaine injection, whereas this behavior was absent in non-PSD control rats. The present study sought to compare alterations in genital reflexes (PE and ejaculation-EJ) induced by PSD followed by acute cocaine or saline at different points in the life span of male rats. Rats of different ages (3, 6, 10, 12, 18, 22 and 28 months), were given a single injection of either saline or cocaine (7 mg/kg, i.p.) after a 4-day period of PSD, and then evaluated for genital reflexes. Results indicated that genital reflexes in PSD rats given saline become less frequent with age and disappear after the age of 18 months. However, cocaine potentiated and prolonged these behaviors until the age of 22 months. Although a number of factors are involved in such a complex phenomenon as PE, we suggest that the previously documented dopamine receptor supersensitivity induced by PSD may be an important contributor to the potentiation by cocaine of genital reflexes after sleep deprivation.

The effect of apomorphine on genital reflexes in male rats deprived of paradoxical sleep.

Drugs that stimulate dopamine (DA) systems can stimulate sexual arousal in male rats and humans, and previous work has shown that cocaine enhances genital reflexes [penile erection (PE) and ejaculation (EJ)] in rats deprived of paradoxical sleep (PS). The present study sought to expand the latter finding by assessing the effects of DA receptor agonist apomorphine in sleep-deprived rats. Apomorphine in doses ranging from 10 to 240 microg/kg was administered intraperitoneally to rats that had been deprived of sleep for 4 days and to normal controls, and the incidence of PEs and EJs was measured for 60 min. Sleep deprivation alone induced PE and this effect was potentiated by apomorphine, with maximal effects occurring with the 120 microg/kg dose; results for this dose group differed from those of PSD groups treated with 0, 10, 20, 40, 80, and 240 microg/kg of apomorphine. Sleep deprivation alone also induced spontaneous EJ, but this response was not potentiated by apomorphine in the dose range tested. We suggest that the potentiating effects of apomorphine on PE are likely due to PSD-induced DA receptor supersensitivity.

Facilitation of ejaculation after methamphetamine administration in paradoxical sleep deprived rats.

This study investigated the effects of methamphetamine (MA) on genital reflexes in paradoxical sleep deprived (PSD) rats. Different doses of MA (0, 4, 16 and 64 mg/kg) were acutely given after PSD or the equivalent time to control animals. We observed enhancement of spontaneous ejaculation in PSD rats with larger doses of MA, the highest of which induced ejaculation in 100% of the PSD rats. This was significantly higher than the 30% in the control. Although testosterone exerts motivational effects on male sexual behavior, our data shows that testosterone levels were lower after the PSD period in saline and in the 64 mg/kg MA groups, which present ejaculation at different rates (20% and 100%, respectively). Progesterone levels were significantly higher in PSD-saline in relation to control group and in the 16 and 64 mg/kg of MA groups compared to the other doses. Since PSD induces dopaminergic alterations and dopamine (DA) has a key role in male sexual behavior, plasma DA was also measured. The DA concentration was enhanced in all PSD groups compared with their control group. The mechanism that activates steroid hormones may represent an important physiological effect through which neurotransmitters can affect behavioral events. These data show that MA facilitates ejaculation in PSD rats, however, further studies need to be carried out in order to clarify the hormonal-neurochemical mechanisms involved.

Influence of paradoxical sleep deprivation and cocaine on development of spontaneous penile reflexes in rats of different ages.

Recent studies have established that paradoxical sleep deprivation (PSD) and cocaine administration induce genital reflexes (penile erection and ejaculation) in adult and old rats. To determine whether the same effects would induce spontaneous genital reflexes in rats of different ages (30-90 days old), we administered with cocaine (7 mg/kg) or saline to rats after a 4-day period of PSD, or at the equivalent time-point in control animals, and penile erection and ejaculation were then evaluated. In PSD rats administered cocaine, erection was observed from 30 days old to 90 days old, when both genital reflexes reached a peak. Animals submitted to PSD and saline injection showed erection from 60 to 90 days old. None of the control (saline and cocaine) groups of any age displayed these behaviors. The effects of PSD on steroid hormone levels showed that, although testosterone levels increased with age, PSD caused a marked decrease in testosterone at all ages evaluated. Progesterone and corticosterone levels were higher in PSD groups than in the respective control groups. These findings suggest that the interaction of PSD and cocaine probably enhances dopaminergic transmission in the brain and may accelerate the development of genital reflexes in male rats.

Cocaine-induced genital reflexes during paradoxical sleep deprivation and recovery.

Paradoxical sleep deprivation (PSD) for 96 h together with cocaine administration elicits genital reflexes (penile erection [PE] and ejaculation [EJ]) in rats. Our objective was to examine genital reflexes after periods of 24, 48, 72, 96, 120, and 144 h of PSD and during a 4-day recovery period in acute cocaine-administered rats. After 24 h of PSD followed by cocaine administration, animals started to display PE and EJ, peaking in the 96th h of PSD, whereas PE and EJ were absent in control animals. The effects of more than 96 h of PSD decrease genital reflexes as observed after 120 and 144 h. Genital reflexes were present in the recovery periods but diminished gradually during the period evaluated. Even short periods of PSD probably cause supersensitivity of dopamine (DA) receptors and exacerbate the effects of cocaine on dopaminergic pathways to induce frequent PE and EJ.

Does paradoxical sleep deprivation and cocaine induce penile erection and ejaculation in old rats?

A recent study has established that paradoxical sleep deprivation (PSD) and cocaine administration elicit genital reflexes (penile erection and ejaculation) in young rats. To discover whether the same effects occurred in old animals submitted to PSD, we administered cocaine (15 mg/kg) to young (3-month) and old (22-month) male rats after a 4-day period of PSD or at the equivalent time-point in control animals. We then evaluated erections and ejaculations. Sixty per cent of the old-PSD group displayed erection, although ejaculation was not observed. Genital reflexes were absent in young and old control groups. We found that PSD reduced testosterone and increased progesterone levels in both young and old PSD groups. In conclusion, our results suggest that although genital reflexes usually decrease with age, testosterone levels alone cannot account for these changes. The interaction of PSD and cocaine probably enhances dopamine transmission in the brain and may elicit penile erection in old rats.

Efeitos de tratamentos antidepressivos crônicos na densidade e afinidade dos sítios de ligação da [3H]-ouabaína na Na+ /K+ - ATPase de membranas corticais de ratos / Effects chronic antidepressant treatment in density and affinity of the sitios of binding [3H]-ouabaina in the Na+/K+ - ATPase in rat barin membrane

Foi a partir da observação dos efeitos farmacológicos de drogas, tais como a reserpina, a imipramina e a iproniazida sobre o humor, que modelos mais bioquímicas para a etiologia da depressão começaram a ser sugeridos. Baseado nos efeitos bioquímicas destas drogas, hipóteses sobre a desregulação de neurotransmissores, como a noradrenalina e a serotonina, foram relacionadas com os transtornos de humor. Entre as alterações observadas em pacientes, a atividade da enzima Na+/K+- ATPase encontrase diminuída em eritrócitos tanto na depressão quanto na mania. Esta enzima tem a função de manter as diferenças de concentrações dos íons Na+ e K+ entre os compartimentos intra/extracelular. Nas células excitáveis sua função é manter e restabelecer o potencial de repouso após uma despolarização, possibilitando desta forma a passagem de outros potenciais de ação. O funcionamento da enzima, possivelmente, é regulado por neurotransmissores, tais como noradrenalina, a serotonina e a dopamina que estão envolvidas com as alterações da atividade desta enzima. O envolvimento da Na+/K+-ATPase com a neurotransmissão e a excitabilidade neuronal, torna o estudo de seu funcionamento importante para a busca da etiologia dos transtornos de humor. Avaliamos, através deste trabalho, o efeito de tratamentos antidepressivos na densidade e afinidade dos sítios de ligação da [3H]-ouabaína na Na+/K+-ATPase de membranas corticais de ratos. A privação de sono paradoxal, procedimento utilizado por ter um efeito antidepressivo, aumentou a densidade dos sítios de ligação da [3H]ouabaína e diminuiu a afinidade destes sítios somente quando o grupo controle de estresse não foi considerado na análise. O eletrochoque convulsivante diário diminuiu o número de sítios de ligação da [3H]ouabaína somente após 7 eletrochoques e, manteve esta alteração até 72 horas após o ultimo eletrochoque. Cinco eletrochoques aumentou a afinidade dos sítios de ligação da [3 H]-ouabaína, mas retomando a valores iguais aos do controle após 72 horas do sétimo eletrochoque. A administração de imipramina uma vez ao dia durante um período de 14 dias não modificou os parâmetros avaliados neste estudo. Estes dados demonstram que diferentes tratamentos antidepressivos afetam diferentemente a enzima Na+/K+-ATPase nos parâmetros densidade e afinidade dos sítios de ligação da [3 H]-ouabaína na Na+/K+-ATPase. Portanto, os dados obtidos não permitem sugerir que alterações na Na+/K+ -ATPase estejam envolvidos na ...(au)