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, IP) 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. Received: 27 December 1995/Final version: 17 December 1996     

Dopamine metabolism and receptor sensitivity in rat brain after REM sleep deprivation

Different dopaminergic mechanisms that could explain behavioral supersensitivity to amphetamine or apomorphine in REM-deprived rats were examined. Four days of REM sleep deprivation induced a highly significant elevation in striatal DOPAC relative to normal controls, but not to stress controls. DOPAC levels in frontal cortex were not affected in any of the groups. Post synaptic D₂ receptor number (B_max) and affinity (K_d) were unchanged in both terminal regions. Similarly, no changes in pre-synaptic receptor sensitivity (apomorphine-induced inhibition of tyrosine hydroxylase) occurred in striatum. A stress control group exhibited no changes in any of the biochemical measures in comparison with either the REM deprived group or unstressed controls. Thus, the enhanced response to dopamine agonists reported previously is not due to altered dopamine receptor sensitivity. Alternative hypotheses to explain enhanced responses to direct and indirect acting dopamine agonists are discussed.     

Effect of REM sleep deprivation on rat brain acetylcholinesterase

Acetylcholinesterase activity was compared in control, rapid eye movement sleep-deprived and recovered rat brain. The activity was estimated in the whole brain, cerebrum, brain stem and cerebellum. Flower pot technique was used for continuing deprivation for two, four and eight days. The results showed that the enzyme activity increased significantly in the deprived rat brain and it returned to control/normal level on recovery. The enzyme activity increased first in the brain stem, while the activity in the cerebellum showed no significant change. Control experiments suggest that the increase was primarily caused by the deprivation. The finding fits well with existing knowledge and would possibly help in explaining earlier observations.     

REM sleep deprivation and food intake

The effect of REM-sleep deprivation (REM-SD) on diet preference was studied in rats. REM-SD for a period of 72 hrs produced an increase in day, night and 24 hrs (day plus night) intakes of Carbohydrate Rich diet (CRD) and Total diet (TD). Body weight (BWt) was also increased. The maximum increase in the above parameters were recorded on the 2nd day of REM-SD. During recovery period the intakes of TD fully recovered, but the BWt and consumption of CRD remained high. Intakes of Balanced diet (BD) remained significantly on the lower side when compared to the pre REM-SD mean values. During REM-SD, the rats preferred CRD than BD. The body temperature did not show any change. The increase in TD intake and BWt could be the result of an increase in insulin level and the change appears to be mediated by the activation of hypothalamic feeding centre.     

Brain norepinephrine and serotonin levels following REM sleep deprivation in the rat

Rats deprived of rapid eye movement (REM) sleep and stress controls showed no change in endogenous levels of norepinephrine and serotonin in the cerebral hemispheres, diencephalon, and brain stem. Following pargyline, the REM sleep deprived and stress control groups showed equally elevated norepinephrine and serotonin levels. These results suggest that enhanced biogenic amine synthesis following REM sleep deprivation is due to non specific stress rather than to loss of REM sleep per se.     

How REM sleep deprivation and amantadine affects male rat sexual behavior

There are conflicting findings about the sexual effects of REM sleep deprivation (REMd). Otherwise, several studies show a dopaminergic hypersensitivity after REMd. The effect of REMd and amantadine (AMA) was studied for standard measures and temporal patterning in the first experiment, in four groups: normal with vehicle, normal with AMA (5.0 and 10 mg/kg), REMd with vehicle and REMd with AMA (5.0 and 10.0 mg/kg). REMd reduced mount latency (ML), intromission latency (IL) and mount number (MN) and increased copulatory efficiency (CE) and hit rate factor. REMd also reduced the mount bout number (MBN) and increased the sexual interaction (mount bout time, MBT) among male and female during copula. AMA stimulates initiation and hit rate factors and accelerates the temporal patterning of sexual behavior, evoking fewer and quicker mount bouts. In the experiments with combination of REMd and AMA administration, AMA did not increase behavior effects evoked by REM deprivation, probably due to a top or a bottom effect, depending on the measures considered. A second experiment studied the effects of AMA (1.25 to 5.0 mg/kg) and REMd on the sexual reflexes of nonimmobilized male rats. REMd enhanced the AMA effects upon the seminal emission reflex, but inhibited the penile erection reflex elicited by 1.25 mg/kg of AMA. Curiously, our results showed that REMd, like AMA, a dopaminergic agonist, causes similar effects of sexual behavior in the male rat, particularly those related to arousal mechanism and hit rate factor. The results are discussed and the effects of REMd probably involve dopaminergic hypersensitivity and increased sexual motivational response.     

莫达非尼对REM睡眠剥夺后大鼠认知功能及突触可塑性的影响*

目的：探讨新型中枢性兴奋剂莫达非尼对不同程度快速动眼（REM）睡眠剥夺与睡眠恢复后大鼠认知功能和大鼠海马突触可塑性的影响。方法：成年雄性SD大鼠随机分为莫达非尼组与对照组,每组分5个不同的REM睡眠剥夺和恢复时间点（SD1d,SD3d,SD5d,SD5d/RS6h,SD5d/RS12h）,采用改良多平台水环境REM睡眠剥夺法进行REM睡眠剥夺,利用Y迷宫测定大鼠学习记忆能力,运用蛋白质免疫印记（Western Blot）技术对大鼠海马突触素（SynapsinⅠ）蛋白作选择性半定量分析,免疫组织化学和电镜观察的方法分析大鼠海马CA3区SynapsinⅠ的表达,观察突触可塑性变化。结果：莫达非尼组的错误反应次数（EN）在REM睡眠剥夺后小于对照组,差异有统计学意义（P〈0.05）,睡眠恢复后两组EN比较,差异无统计学意义（P〉0.05）,总反应时间（TRT）两组比较,差异也无统计学意义（P〉0.05）。Western Blot结果显示SD1d,SD3d,SD5d/RS6h和SD5d/RS12h时莫达非尼组Syn- apsinⅠ表达比对照组增多（P〈0.05）,SD5d时两组SynapsinⅠ表达无显著差异（P〉0.05）,免疫组化结果与其一致;电镜下观察SD1d时莫达非尼组的突触联系、突触前膜囊泡数量均较对照组增加。结论：REM睡眠剥夺会引起大鼠认知功能下降,大鼠海马CA3区SynapsinⅠ表达降低,而莫达非尼可以抑制睡眠剥夺后SynapsinⅠ的表达减少,诱导大鼠海马突触可塑性变化,可改善REM睡眠剥夺后的认知行为。     

Effects of REM sleep deprivation on central alpha 1- and beta-adrenoceptors in rat brain

In the present experiment the effects of 'rapid-eye-movement' sleep deprivation (REMd) on cortical alpha 1- and beta-adrenoceptor binding sites in the rat brain were investigated. REMd was induced for 72 hr in two different ways: by the platform and the pendulum technique. In addition, three control groups were run. Determination of alpha 1- and beta-adrenoceptor sites in the cortex was done by 3H-prazosin and 3H-dihydroalprenolol binding studies, respectively. Both REM sleep deprived groups showed a small but significant decrease in the number of beta-adrenoceptor sites along with a small increase in affinity. On the other hand, alpha 1-adrenoceptor binding and affinity were not changed. These results agree with the effects of tricyclic antidepressant drug treatment. Common effects of REMd and tricyclic drugs are discussed in terms of modulation of tonic arousal processes.     

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.     

REM sleep deprivation induces a decrease in norepinephrine-stimulated 3H-cyclic AMP accumulation in slices from rat brain

Beta adrenergic sites in rat brain are reduced after repeated treatment with antidepressant drugs, with REM sleep deprivation (REMSd) having the same effect. This paper reports the effects of REMSd in the production of 3H-cyclic AMP in frontal cortical slices by NE challenge. Data presented in this paper report a marked decrease in 3H-cyclic AMP synthesis after REMSd, which is in accordance with previous results showing adrenergic receptor down-regulation following REMSd. Results are discussed in view of possible interaction with dopaminergic systems and depression management.     

The effects of REM sleep deprivation on striatal dopamine receptor sites

3H-Spiroperidol binding to dopamine receptor sites of rat striatal tissue was studied following 24, 48, 72 and 96 hr of rapid eye movement sleep deprivation (REM dep.). The density of dopamine receptor binding sites (Bmax) was decreased after 48, 72, and 96 hr of REM dep. The apparent dissociation constant (KD) decreased after 96 hr, indicating an increase in apparent affinities. The control experimental animals also presented a time-dependent decrease of Bmax and KD as compared to unhandled controls. These results suggest that dopaminergic mechanisms may indeed be involved in the effects of REM sleep deprivation and/or stress.     

Clozapine decreases neuropeptide Y-like immunoreactivity and neuropeptide Y mRNA levels in rat nucleus accumbens.

The aim of this study was to evaluate the effect of acute, subchronic (14 days) and chronic (28 days) intraperitoneal (i.p.) administration of clozapine (10 or 25 mg/kg) on neuropeptide Y (NPY) system activity in the nucleus accumbens of the rat. NPY-like immunoreactivity (NPY-LI) decreased 24 h after subchronic clozapine while NPY mRNA after both acute and subchronic clozapine treatment. NPY-LI levels were also reduced 8 days after cessation of chronic lower-dose treatment. Subchronic (14 days) administration of the 5-HT2A antagonist ketanserin (1 mg/kg i.p.) or the dopamine D2/D3 antagonist (+/-) sulpiride (100 mg/kg i.p.) reduced NPY-LI levels, whereas the dopamine D1-like antagonist SCH 23390 (0.5 mg/kg i.p.), dopamine D4 antagonist L-745,870 (1 mg/kg per os), and alpha1-adrenergic antagonist prazosin (0.2 mg/kg i.p.) had no effect. There were no significant differences between the ketanserin-induced decrease in NPY-LI levels and the effects of the following two-drug combinations: ketanserin and SCH 23390, ketanserin and L-745,870, and ketanserin and prazosin. The study has shown that clozapine reduces NPY system activity in the rat nucleus accumbens. It seems that the action of clozapine is partly mediated by blockade of 5-HT2A and D2/D3 dopaminergic receptors.     

Does REM sleep deprivation induce subsensitivity of presynaptic dopamine or postsynaptic acetylcholine receptors in the rat brain?

Yawning behavior was used to evaluate the sensitivity of presynaptic dopamine receptors and postsynaptic acetylcholine receptors of normal and REM sleep-deprived (REMSD) rats. The results show a lowering of the dose-response curve obtained with apomorphine and pilocarpine, as well as a shift to the right in the curve obtained with physostigmine. These results suggest that REMSD induces subsensitization of presynaptic dopamine receptors and/or postsynaptic acetylcholine receptors with different characteristics related to the mechanism of action of the cholinomimetic agent employed.     

REM sleep deprivation decreases apomorphine-induced stimulation of locomotor activity but not stereotyped behavior in mice.

1. Effects of rapid eye movement (REM) sleep deprivation on central dopaminergic system were investigated by testing the behavioral responses to apomorphine and brain dopamine metabolism in mice. 2. REM sleep deprivation for 48 hr significantly suppressed apomorphine.HCl (3.0 and 6.0 mg/kg, i.p.)-stimulated spontaneous locomotor activity without affecting the intensity of stereotyped behavior. 3. Neither the latency of nociceptive response in a hot-plate test nor the duration of pentobarbital-induced sleep was changed by REM sleep deprivation. 4. Dopamine turnover in the striatum and the nucleus accumbens of REM sleep-deprived mice was significantly higher than that of control animals. 5. These results suggest that REM sleep deprivation may decrease the function of postsynaptic dopamine receptor in the mesolimbic but not nigrostriatal dopaminergic system.     

REM sleep deprivation decreases the antinociceptive property of enkephalinase-inhibition, morphine and cold-water-swim

Rats treated with phosphoramidon (an enkephalinase-inhibitor 250 micrograms, i.c.v.), morphine (20 micrograms i.c.v.) or subjected to cold-water-swim (CWS, animals forced to swim in water at 5 degrees C for 5 min) showed consistent analgesia. The antinociceptive effect of phosphoramidon, morphine and CWS was antagonised by REM sleep deprivation (REMSD). It is suggested that normal duration of REM sleep is of importance for the anti-nociceptive activity of endogenous and exogenous opiates.     

Increased REM sleep after intra-dorsal raphe nucleus injection of flesinoxan or 8-OHDPAT: prevention with WAY 100635.

The effects of 8-OHDPAT and flesinoxan, two selective 5-HT(1A) receptor agonists, and of WAY 100635, a selective 5-HT(1A) receptor antagonist, on spontaneous sleep were studied in adult rats implanted for chronic sleep recordings. The serotonergic ligands were microinjected directly into the dorsal raphe nucleus (DRN). Direct administration of flesinoxan (25.0-50.0 ng) into the DRN induced a significant increment of REM sleep (REMS) during the second and third 2 h of recording. Microinjection of 8-OHDPAT (50.0 ng) induced similar effects on REMS during the second 2 h of recording. On the other hand, intra-DRN injection of WAY 100635 (12.5-50.0 ng) significantly reduced REMS during the second 2 h recording period. REM sleep values had also decreased significantly during the first 2 h of recording after the 50 ng dose. Pretreatment with WAY 100635 (25.0 or 50.0 ng) prevented the increase of REMS induced by flesinoxan (25.0 ng) during the second two recording hours. Our findings support the proposal that activation of somatodendritic 5-HT(1A) receptors in the DRN increases REMS, whereas their blockade induces the opposite effect.     

REM sleep deprivation changes behavioral response to catecholaminergic and serotonergic receptor activation in rats

The effects of REM sleep deprivation (REMD) on apomorphine-induced aggressiveness and quipazine-induced head twitches in rats were determined. Forty-eight hr of REMD increased apomorphine-induced aggressiveness, and reduced (immediately after completing of REMD) or increased (96 hr after completing of REMD) quipazine-induced head twitches. Results are discussed in terms of similarity to pharmacological effects of other antidepressive treatments.