Nature of the estrous cycle, incidence of anovulation, chromosome gametopathies and fetal death in female rats with 2,4-dichlorophenoxyacetic acid (2,4-D) before pregnancy

The effect of herbicide--2,4-D, injected before pregnancy begins, on the main parameters of the reproductive function of the female rats has demonstrated that chronic administration in doses 1 mg/kg and 12 mg/kg per day for 2 months results in certain disturbances in the estrus cycle, manifesting as prolongation of the diestrus phase and in changes of estrus and meta-estrus++ duration, as well as in an essential increase in rates of anovulatory cycles. Single administration of the preparation during the preovulatory period (50 mg/kg) produces certain disturbances in the chromosomal complex, manifesting as appearance of numerical chromosomal aberrations. When the administration is acute (10 mg/kg and 50 mg/kg) an essential increase of the embryonal death takes place, in the first case--at the expense of ++pre-implantational, and in the second--both at the expense of pre- and ++post-implantational death. At chronic administration increasing rate of the intrauterine death takes place mainly at the expense of ++post-implantational death of embryos.     

Effects of chloramphenicol and thiamphenicol on sleep of the mouse]

The oral administration of 0.25-2.0 g/kg of chloramphenicol at 9h selectively suppresses paradoxical sleep in mice for a duration of 2-4 hours. A dose of 1 g/kg given at 17h suppresses paradoxical sleep for 7 hours. Slow wave sleep decreased for 2 hours after administration. Thiamphenicol (1 g/kg) has no effect under the same conditions.     

Effects of [des-Tyr-D-Phe3]beta-casomorphin (2-5) on sleep pattern in rats.

The effects of the antidepressant-like acting peptide [des-Tyr-D-Phe3]beta-casomorphin(2-5) (Pro-D-Phe-Pro-Gly, BCH-325) on sleep were studied in rats. The rats received subcutaneous injections of BCH-325 in acute experiments (doses: 4, 20, 100, 500 and 2500 nmol/kg) and in a 10-day chronic experiment (50 nmol/kg/day). Acute administration of 20 and 100 nmol/kg enhanced wakefulness, 500 and 2500 nmol/kg enhanced paradoxical sleep, and 4 nmol/kg had no effect. Chronic administration resulted in an increase of paradoxical sleep during the first 5 days of drug treatment. Thus the sleep effects of BCH-325 differ from those of typical antidepressants and other psychotropic drugs.     

Effect of neurotropic substances on sleep disorders caused by electrical stimulation of the hypothalamus in cats

The total period of sleep decreased as a result of the REM-sleep deficite following rage reaction induced in cats by the electrical stimulation of the hypothalamus. Haloperidol (1, 2, 3 mg/kg), diazepam (0.5, 1 mg/kg), nitrazepam (1, 6 mg/kg), glutetymide (10, 30, 60 mg/kg), pentobarbital (5, 15, 30 mg/kg) failed to eliminate sleep disturbances induced by rage reaction; lithium hydroxybutyrate (100, 150 mg/kg), dimedrol (1.5, 6 mg/kg) and imipramine increased the total sleep time on account of the slow wave phase; sodium hydroxybutyrate (100 mg/kg) normalized the electrophysiological pattern of sleep, decreasing the REM-sleep latency and the number of waking cats, and increasing the total REM-sleep time and the number of REM-sleep episodes.     

On the sleep promoting effects of BR-16A: interaction with GABAergic modulators

Pentobarbitone-induced hypnosis test was used as an animal model to explore the role of BR-16A, a polyherbal formulation in sleep. Pentobarbitone produces quick sleep latency (onset) and prolongation of total sleep time (duration). Sleep latency and total sleep time were used as a parameters for the evaluation. BR-16A potentiated the effect of triazolam (0.1 mg/kg, ip) and alprazolam (0.25 mg/kg, ip). Melatonin (5.0 mg/kg, ip) and zolpidem (0.5 mg/kg, ip) did not produce any significant effect on sleep parameters. However, alprazolam (0.25mg/kg, ip) potentiated the effect of BR-16A (100 mg/ kg, po) in higher dose only. Sleep promoting effect of BR-16A in combination with GABAergic drugs (triazolam and alprazolam,) suggested that these drugs have common mechanism in sleep promoting effect of pentobarbitone and could be used along with other GABAergic hypnotics for the treatment of insomnia. This may reduce the dose of the latter drug(s). BR-16A can be used for the treatment of sleep and sleep-related disorders.     

Effects of progesterone on apneic events during behaviorally defined sleep in male rats

Drug therapy with progesterone has been applied to the patients with sleep apnea syndrome, but its clinical efficacy is equivocal. In the present study, we examined the effects of progesterone (1 and 30 mg/kg, i.p.) on the apneic events during behaviorally defined sleep in male rats at 4, 14 and 26 weeks of age by using a whole body plethysmographic measurement. The number of events of spontaneous apnea (SA) and post-sigh apnea (PSA) increased with aging. The duration of SA or PSA was also prolonged in old rats. A low dose (1 mg/kg) of progesterone significantly decreased the number of both SA and PSA, and this effect increased in an age-dependent manner. However, progesterone had no effect on the duration of SA and PSA. Neither the basal respiratory rate nor the total sleep time was changed. On the other hand, a higher dose (30 mg/kg) of progesterone had no effect on the number of SA and PSA, while it prolonged the duration of PSA. It also prolonged the total sleep time without affecting the basal respiratory rate. Pretreatment with mifepristone (5 mg /kg, i.p.), an antagonist of progesterone receptors, inhibited the effects of the low dose of progesterone, but did not show any antagonistic effect on the high dose-induced changes. These results suggest that the progesterone-mediated mechanisms are involved, at least partly, in respiratory function during sleep and the progesterone therapy is possibly effective within an appropriate dose range for the sleep apnea syndrome.     

A tryptic hydrolysate from bovine milk alphaS1-casein improves sleep in rats subjected to chronic mild stress

The putative effects of a tryptic bovine alphaS1-casein hydrolysate on stress-induced sleep disorders were investigated and their possible link with typical blood stress parameters such as plasma corticosterone concentrations and glycaemia was assessed. Rats were subjected to chronic stress in the form of environmental disturbances, while receiving an oral administration of the alphaS1-casein hydrolysate (CH). Chronic stress significantly reduced sleep duration in control rats during the first 2 days of the stress period, but stress-induced sleep disturbance was prevented in CH-treated rats. Indeed, CH administration allowed the maintenance of slow wave sleep (SWS) duration and even a slight increase in paradoxical sleep (PS) duration in treated rats. Results on plasma corticosterone concentrations and on glycemia values were inconclusive with respect to the implication of the HPA axis in this study. However, the protective effect of the alphaS1-casein hydrolysate on sleep during exposure to our chronic mild stress conditions may be mediated by modulation of the central adrenergic response.     

A biorhythmologic approach to evaluating forced swimming as an experimental model of a "depressive" state

Rhythmical structure of forced swimming was studied on rats. Reserpine (1 mg/kg, 24 h before testing), clonidine (150 mkg/kg) and prolonged repeated striatal stimulation induced behavioural depression with reorganization of swimming rhythm and increase of short cycles (less than 6 s) of immobility. After chronic administration of antidepressants (imipramine, amitriptyline, niamid, 10 mg/kg/day, during 14 days), on the contrary, the number of these cycles diminished, while the number of active swimming cycles increased. Chrono-biological "index of depression" is suggested to express more exactly behavioural depression and specific activity of antidepressants than usual registration of immobility time.     

Analysis of the action of the sleep neuropeptide (DSIP) on sleep organization in cats and rats

After administration of delta-sleep inducing peptide to cats and albino rats the decrease of total duration of paradoxical phase of sleep is more significant than prolongation of slow-wave sleep. Similar disturbances in the behaviour of animals were observed during deprivation of paradoxical sleep. This data strongly suggest that the DSIP influences the most ancient mechanisms of sleep regulation.     

An attempt to influence by drugs recovery sleep after sleep deprivation.

Rats were deprived of sleep by placing them for 36 hours in a slowly moving drum. After this procedure, during recovery sleep, the latency of onset of the first rhombencephalic - paradoxical sleep period decreased and the proportion of telencephalic/rhombencephalic - slow wave sleep reversed (during the first hour of recovery sleep). Repeated administration during the deprivation period of physostigmine (0,5 mg/kg i. p. in 30 min intervals 20-30 times) inducing in waking animals in EEG pattern close to that of rhombencephalic sleep, or atropine (1 mg/kg i. p. in 60 min intervals 10-15 times) evoking an activity resembling telencephalic sleep, did not change the above measures of recovery sleep. Pharmacologically induced sleep-like patterns did not substitute for the sleep the rats were deprived off.     

Effects of clozapine (Leponex) on sleep patterns in the cat.

This study examined the effects of clozapine on sleep-wakefulness profile in cats prepared for chronic recording of sleep. Clozapine in single dose (i.p.) of 5 mg/kg drastically reduced slow-wave sleep (SWS) and paradoxical sleep (PS), while wakefulness and drowsy pattern were increased. These changes lasted approximately 24 h and were followed by sleep recovery. PS had a priority of recovery. Some similarities between clozapine effects on sleep in cat and human were mentioned.     

Dietary selenium supplementation prolongs pentobarbital induced hypnosis

The present studies characterized the influence of dietary selenium (Na2SeO3) on the duration of pentobarbital (PB) induced hypnosis (sleep) in the rat. Rats were fed semipurified diets varying from 0.01 to 2.0 mg Se/kg for up to 4 weeks. Consumption of diets containing 1.0 and 2.0 mg Se/kg significantly prolonged PB induced hypnosis. Hepatic selenium, but not hepatic glutathione peroxidase activity, correlated with the length of PB induced hypnosis. The prolongation of hypnosis caused by diets containing 1.0 mg Se/kg was substantially reduced or eliminated by repeated exposure to PB. Although single exposure to increasing quantities of PB (60-100 mg/kg body weight) led to a progressive increase in sleep duration, the proportional increase caused by supplemental selenium (2.0 vs 0.1 microg Se/g) remained relatively constant (approximately 25%). Increasing maturity was inversely related to the duration of PB induced hypnosis, regardless of dietary selenium provided. Consumption of the 2.0 mg Se/kg diet prolonged PB induced hypnosis to a greater degree in immature than in mature rats (P < 0.05). Consumption of the selenium enriched diet (2 microg Se/g) resulted in an increase in cytochrome 2B, but had no effect on cytochrome 1A compared to controls (0.1 microg Se/g). Pretreatment of rats with P450 enzymes activators (i.e., PB, Aroclor 1254, or 3-methylcholanthrene) shortened the duration of PB induced sleep and masked the effects of dietary selenium. The current studies document that dietary selenium can influence the response to pentobarbital induced hypnosis and likely relates to changes in drug detoxification enzymes.     

GABA metabolism and the formation of a sensorimotor cortex evoked potential in the presence of excess zinc ions

Changes in GABA content, the enzymatic activity of its metabolism and the formation of sensorimotor cortical evoked potential (EP) were studied following long-term ZnCl2 administration. It has been established that a single ZnCl2 injection at a dose of 0.1 and 1 mg/kg was accompanied by an increase in the amplitude of sensorimotor cortical EP, though GABA accumulation in this brain structure was observed. This might account for the prolongation of the period of the potential appearance. Long-term (for 7, 14, 21 days) ZnCl2 administration at a dose of 0.1 mg/kg produced a sharp depression in the potential appearance and an increase in GABA content by 50% with the enhancement of glutamate decarboxylase activity and the attenuation of GABA-transaminase activity.     

Effects of low dose cocaine on REM sleep in the freely moving rat

Cocaine administration can be disruptive to sleep. In compulsive cocaine users, sleep disruption may be a factor contributing to relapse. The effects of cocaine on sleep, particularly those produced by low doses, have not been extensively studied. Low dose cocaine may stimulate brain reward systems that are linked to the liability of abusing of this drug. This study was designed to assess the effects of the acute administration of low to moderate cocaine doses on sleep in the rat. Polygraphic recordings were obtained from freely moving, chronically instrumented rats over a 6-h period after the administration of either cocaine (as a 2.5-10 mg/kg intraperitoneal dose) or saline. Following cocaine administration, time spent by the rats in wakefulness increased and slow wave sleep decreased in a dose-dependent manner, compared to controls. These changes lasted between 1 to 3 h following the cocaine administration. Rapid eye movement (REM) sleep was decreased during a 2- to 3-h period following the injection of 5 and 10 mg/kg doses of cocaine. In contrast, REM sleep increased during the periods 2-4 h after the administration of 2.5 and 5 mg/kg doses of cocaine. These results indicate that sleep can be significantly altered by low doses of cocaine when administered subacutely.     

Methylphenidate exposure induces dopamine neuron loss and activation of microglia in the basal ganglia of mice

Background

Methylphenidate (MPH) is a psychostimulant that exerts its pharmacological effects via preferential blockade of the dopamine transporter (DAT) and the norepinephrine transporter (NET), resulting in increased monoamine levels in the synapse. Clinically, methylphenidate is prescribed for the symptomatic treatment of ADHD and narcolepsy; although lately, there has been an increased incidence of its use in individuals not meeting the criteria for these disorders. MPH has also been misused as a “cognitive enhancer” and as an alternative to other psychostimulants. Here, we investigate whether chronic or acute administration of MPH in mice at either 1 mg/kg or 10 mg/kg, affects cell number and gene expression in the basal ganglia.

Methodology/Principal Findings

Through the use of stereological counting methods, we observed a significant reduction (∼20%) in dopamine neuron numbers in the substantia nigra pars compacta (SNpc) following chronic administration of 10 mg/kg MPH. This dosage of MPH also induced a significant increase in the number of activated microglia in the SNpc. Additionally, exposure to either 1 mg/kg or 10 mg/kg MPH increased the sensitivity of SNpc dopaminergic neurons to the parkinsonian agent 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Unbiased gene screening employing Affymetrix GeneChip® HT MG-430 PM revealed changes in 115 and 54 genes in the substantia nigra (SN) of mice exposed to 1 mg/kg and 10 mg/kg MPH doses, respectively. Decreases in the mRNA levels of gdnf, dat1, vmat2, and th in the substantia nigra (SN) were observed with both acute and chronic dosing of 10 mg/kg MPH. We also found an increase in mRNA levels of the pro-inflammatory genes il-6 and tnf-α in the striatum, although these were seen only at an acute dose of 10 mg/kg and not following chronic dosing.

Conclusion

Collectively, our results suggest that chronic MPH usage in mice at doses spanning the therapeutic range in humans, especially at prolonged higher doses, has long-term neurodegenerative consequences.     

Induction of paradoxical sleep (PS) by infusion of cerebrospinal fluid from PS-deprived rats

In the rat, alpha-Methyldopa (alpha-MD, 50 mg/kg i.p.) induced during 8 hrs. an important reduction of paradoxical sleep (PS) and an increase of light slow waves sleep (SWS1). These effects were reversed by intraventricular infusion of cerebrospinal fluid (CSF) from PS-deprived donor rats, and PS restauration depended directly on the duration of the deprivation in the donor. It is probable that hypnogenic substances accumulate in the CSF during PS-deprivation, and that these factors can by-pass the noradrenergic step in the chain of biochemical events normally leading to the appearance of PS.     

地西泮和戊巴比妥钠对两种小鼠镇静催眠作用强度的观察

目的：观察地西泮和戊巴比妥纳对不同种属小鼠自主活动和睡眠效应的影响,为筛选影响中枢神经系统功能的药物提供可参考的选择动物的依据。方法：分别取昆明种和ICR小鼠各40只,设对照组和地西泮给药组,每组20只,给药组ig地西泮4mg／kg,对照组给生理盐水,连续3天,末次给药后45分钟测定小鼠自主活动。另取两种小鼠各20只,分别ip戊巴比妥钠50mg／kg,观察两种小鼠的睡眠情况,记录潜伏期和睡眠时间。结果：ICR小鼠ig地西泮后,表现明显的镇静作用,自主活动的次数和对照组比较明显减少,P〈0．01;而昆明种小鼠给相同剂量的地西泮,小鼠自主活动的次数减少不明显,P〉0．05。昆明种和ICR小鼠同样ip阈上剂量的戊巴比妥钠,两者在睡眠潜伏期上无明显差异,但在睡眠时间上,则ICR小鼠的睡眠时间明显长于昆明种小鼠,P〈0．01。结论：ICR小鼠对中枢抑制药的反应性更好,适合于这类药物的筛选,尤其对作用相对较弱的中药制剂,可能提高筛选的阳性率。     

Involvement of the intestinal microflora in nitrazepam-induced teratogenicity in rats and its relationship to nitroreduction

A study was undertaken to investigate the relationship between nitroreduction of nitrazepam and its teratogenic effects and the involvement of the intestinal microflora in Sprague-Dawley rats. Incubation of bacterial suspensions from rat cecal contents with nitrazepam resulted in extensive reduction to 7-aminonitrazepam. Rat liver homogenates also reduced nitrazepam but only under anaerobic conditions. Following oral administration of 300 mg/kg nitrazepam to pregnant rats, total excretion of reduced metabolites (7-aminonitrazepam and 7-acetylaminonitrazepam) in urine and feces accounted for approximately 30% of the administered dose. When antibiotics were administered to dams to deplete their intestinal microflora prior to administration to nitrazepam, the total excretion of the reduced metabolites in the urine and feces decreased to 2% of the dose. Nitroreductase activity of cecal contents was almost completely suppressed by antibiotic pretreatment, but the activity of liver homogenates was not significantly altered by the same treatment. The incidence of nitrazepam-induced malformations was markedly decreased by antibiotic pretreatment. These results suggest that the intestinal microflora plays an important role in the reductive metabolism of nitrazepam and that the teratogenicity of nitrazepam may be related to its nitroreduction by the microflora.     

Induction of micronuclei in mouse bone-marrow erythrocytes in association with hypothermia after administration of the sigma receptor ligand E-5842

Oral administration of E-5842, a new sigma1 receptor ligand being developed as an antipsychotic drug, to male mice at single doses of 50, 100, 200 and 400 mg/kg produced marked and sustained decreases in rectal temperature. Both the intensity and the duration of the hypothermic effect increased with dose. Maximum decreases from the mean pre-administration temperature (36.2 degrees C) ranged from 7.5 to 12.9 degrees C for animals receiving 50 and 400 mg/kg doses, respectively. Examination of bone-marrow smears obtained 24, 48 and 72 h after administration revealed a slight but statistically significant (p < 0.05) increase in the frequency of micronucleated polychromatic erythrocytes (MNPCE) at the 48 h sampling for animals receiving the 200 mg/kg dose. These animals showed decreases from pre-administration temperature of approximately 12 degrees C, with recovery being observed 24 h after administration. When the hypothermic effect of E-5842 administration was avoided by housing treated animals under conditions of increased environmental temperature (30 degrees C) for 24 h, MNPCE frequency reverted to vehicle control values. Further, in E-5842-treated animals with an increased MNPCE frequency there was a shift in the distribution of the relative areas of micronuclei in MNPCE towards higher values. In addition, there was a statistically significant increase (p < 0.001) in the number of relatively large micronuclei (micronucleus diameter > or = 1/4 cytoplasm diameter) similar to that produced by administration of the mitotic spindle inhibitor colchicine (1 mg/kg), suggesting disturbance of mitotic apparatus as the possible underlying mechanism. The results suggest that the slight increase in MNPCE frequency observed 48 h after administration of a 200 mg/kg dose of E-5842 is due to a hypothermic effect and not to a direct effect of E-5842 on DNA.     

Effect of intravenously-administered putative and potential antagonists of ethanol on sleep time in ethanol-narcotized mice

Groups of male CD-1 mice (n = 12/group) were injected intraperitoneally (IP) with 5 g ethanol/kg of body weight. After loss of righting reflex, they were given vehicle or one of 2-3 doses of reputed or potential antagonists of ethanol intravenously (IV). Sleep time was measured from loss to return of righting reflex. Mean sleep time (MST) was increased significantly (P less than 0.05) by a large dose of dl-amphetamine (24 mg/kg) and by 4-aminopyridine (1, 5 mg/kg). Significant (P less than 0.01) increases were also produced by small and large doses of aminophylline (25, 100 mg/kg) and by yohimbine (1, 5 mg/kg). MST was not altered significantly by small and medium doses of dl-amphetamine (6, 12 mg/kg), a medium dose of aminophylline (50 mg/kg), or by any doses of naloxone, thyrotropin-releasing hormone, propranolol, physostigmine, doxapram, or Ro 15-4513. When Ro 15-4513 was given IP 15 minutes before ethanol (n = 6/group), onset and duration of narcosis were not altered. None of the compounds tested was an effective IV antidote for deep ethanol narcosis because of drug side effects, toxicity, prolongation of MST, or insufficient shortening of MST.