Scopolamine during the paradoxical sleep window impairs radial arm maze learning in rats

It has been proposed that there are paradoxical sleep windows (PSW) during which REM sleep is required for effective learning. Thus, rats deprived of REM sleep during 0-4 (but not 5-8) h after training show impaired learning of a radial maze task. As cholinergic (ACh) systems are active during REM sleep and may be involved in learning, this experiment investigated the effects on learning of pharmacological manipulation of the cholinergic system during the period identified as the PSW. Sprague-Dawley rats were randomly assigned to groups that were physically deprived of REM for 4 h either immediately after training or beginning 4 h after training or treated with the ACh receptor antagonist scopolamine (0-0.4 mg/kg at 0 and 2 h after training or 0.006 mg/kg at 4 and 6 h after training) on each of 9 days of radial maze training. Post-training REM deprivation (0-4 h but not 5-8 h after training) and scopolamine dose-dependently impaired learning. Results suggest that REM sleep and intact ACh neurotransmission are required during the PSW for rats to learn the radial maze task.     

The effect of venlafaxine on behaviour, body weight and striatal monoamine levels on sleep-deprived female rats

Partial sleep deprivation is clinically associated with fatigue, depressive symptoms and reduced memory. Previously, it has been demonstrated that venlafaxine, an atypical antidepressant, increases the levels of noradrenaline and serotonin in rat hippocampus. The aim of this study was to evaluate the effects of venlafaxine on depression, anxiety, locomotor activity and memory in a model of REM sleep (REMs) deprivation in rats. We have also studied the influence of venlafaxine on monoamine levels in the striatum. Six groups of animals (N=20 each) were treated with saline or venlafaxine (1 or 10 mg/kg) during 10 days, submitted or not to REMs deprivation and studied with the forced swimming test of Porsolt (STP), plus-maze, passive avoidance and open-field tests right after sleep deprivation. Animals were also studied for passive avoidance 24 h later (rebound period). Brain samples for monoamine measurements were collected either immediately after REMs deprivation or after 24 h. Both REMs deprivation and venlafaxine showed an antidepressant effect. An anxiolytic effect was also observed after REMs deprivation. Previous treatment with venlafaxine blocked the antidepressant and anxiolytic effects of REMs deprivation. REMs deprivation alone and treatment with venlafaxine 10 mg/kg increased locomotor activity, and this effect was inhibited by venlafaxine in REMs deprived rats. Both venlafaxine treatment and REMs deprivation induced weight loss. Venlafaxine treatment, but not REMs deprivation, induced an increase in striatal dopamine (DA) levels. The combination of REMs deprivation and venlafaxine treatment was associated with an increase in serotonin turnover 24 h after rebound sleep. In this study, venlafaxine treatment hindered most behavioral effects of REMs deprivation and was associated with an interference on dopamine and serotonin systems in the striatum.     

Effect of chronic cocaine treatment on D2 receptors regulating the release of dopamine and acetylcholine in the nucleus accumbens and striatum.

The inhibition of electrically stimulated [3H]DA and [14C]ACh release by a submaximal concentration of quinpirole was measured 1 week after pretreating rats for 9 days with cocaine (15 mg/kg IP, twice per day). Although this pretreatment significantly enhanced behavioral response to a challenge injection of cocaine when compared with rats pretreated with saline only, no significant differences were apparent in the degree of inhibition of electrically evoked [3H]DA or [14C]ACh release by quinpirole in either the nucleus accumbens or striatum. In addition, the potentiation of electrically evoked [3H]DA release and corresponding inhibition of [14C]ACh release by 10 microM cocaine, measured in striatal slices only, was not significantly different between the two treatment groups. These results suggest that the enhanced behavioral response resulting from chronic cocaine treatment (behavioral sensitization) is not caused by a subsensitivity of D2 terminal autoreceptors or by a supersensitivity of postsynaptic D2 receptors on cholinergic neurons.     

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.     

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.     

Evidence for multiple dopamine receptors involved in the modulation of acetylcholine release in the striatum

The involvement of heterogeneous dopamine (DA) receptors in the regulation of striatal cholinergic neurotransmission was investigated by measuring the release of acetylcholine (ACh) from isolated striatum of the rat. The DA agonists apomorphine (3.7 X 10(-7)-7.4 X 10(-4) mol/l) and piribedil (3.3 X 10(-6)-9.9 X 10(-5) mol/l) exerted a biphasic action: in low concentrations they enhanced, while in high concentrations they inhibited, the ouabain-induced release of ACh. The enhancement of ACh release elicited by low concentrations of DA agonists was reversed by a noncataleptogenic dose of pimozide. 6-hydroxydopamine (6-OHDA) pretreatment also prevented the stimulatory action of apomorphine or piribedil on ACh release. In 6-OHDA pretreated striatum, apomorphine caused a biphasic inhibition of ACh release in a concentration dependent manner. DPI (3,4-dihydroxyphenylamino/-2-imidazoline, 2.5 X 10(-5)-2.5 X 10(-4) mol/l) increased the release of ACh in a monophasic manner and did not induce inhibition of transmitter output in 6-OHDA pretreated striatum. Pretreatment of rats with increasing doses of haloperidol or pimozide (0.037-15 mg/kg) exerted a biphasic action on striatal ACh release; low doses decreased and high doses enhanced the transmitter output and the elevation was accompanied by the appearance of catalepsy. From these experiments it is concluded that multiple DA receptors are involved in the regulation of striatal cholinergic neurotransmission. Among these, the presynaptic DA autoreceptors located on nigrostriatal nerve endings are the most sensitive to both agonists and antagonists. DA receptors located on cholinergic interneurons of the striatum, which are postsynaptic in relation to nigrostriatal neurons, possess high and low affinity to apomorphine. Stimulation of DA autoreceptors enhances, while that of postsynaptic DA receptors leads to inhibition of ACh release.     

Protein synthesis in rat brain during sleep

The in vivo response to REM (rapid eye movement) sleep deprivation in rats was evaluated in terms of protein synthesis. Rapid eye movement sleep deprivation was induced by the water tank technique. Five experimental groups were used: normal controls; REM deprived; stressed controls; REM deprived and then allowed recuperative sleep; stressed and then allowed recuperative sleep.A general but non-significant decrease in protein synthesis was observed in the cerebral, cerebellar and brain stem fractions of the REM-deprived group compared to the stressed controls.The REM-deprived and then recuperated group exhibited an increased protein synthesis in the cerebellum but decreased protein in the cerebral and brain stem fractions, compared to the stressed controls.These observations suggest that non-specific stimulation (e.g. stress, emotional and environmental) influences brain metabolism as expressed in protein synthesis, during sleep. Furthermore, REM sleep appears to have a permissive role in the response to this stimulation.     

Reactivity to amphetamine in perinatally undernourished rats: behavioral and neurochemical correlates

Adult rats deprived at perinatal age and then rehabilitated on balanced chow were treated with a multiple amphetamine (AMPH) schedule (2 mg/kg/48 hr) and submitted, on days of injections, to an open-field test. Throughout 11 sessions, deprived rats showed a progressive increase of locomotor activity as compared with controls. Stereotyped activity evaluated during the AMPH treatment did not differ between control and deprived animals. No differences were detected in basal values of the dopaminergic function measured in naive control and deprived animals. By the end of the multiple AMPH treatment, a reduction of striatal DA and DOPAC levels together with a lower apparent DA turnover rate was detected in deprived animals. Besides, DA receptor binding was significantly increased in striatum from deprived rats as compared with controls. These results demonstrate that a repeated AMPH treatment, that was unable to alter the normal behavior of control rats, produced in early undernourished animals a progressive sensitization to AMPH effects, in addition to significant changes in the striatal dopaminergic function.     

莫达非尼对72h快速眼动睡眠剥夺大鼠海马基质金属蛋白酶9和认知功能的影响

目的研究莫达非尼对72 h快速眼动(REM)睡眠剥夺大鼠海马基质金属蛋白酶9(MMP-9)和认知功能的影响。方法将成年雄性SD大鼠随机分为五组(n=6):正常对照组(CC)、环境对照+空间训练组(TC)、空间训练+REM睡眠剥夺组(SD)、SD+莫达非尼200 mg·kg^(-1)·d(-1)·d^(-1)×3 d组(MD)、SD+安慰剂对照组(CMC)。大鼠的空间训练采用Y型迷宫。用改良多平台睡眠剥夺法建立REM睡眠剥夺模型。应用免疫印迹方法测定MMP-9的蛋白质水平。RT-PCR检测MMP-9 mRNA的相对含量。结果TC组比CC组错误反应次数(EN)显著减少(P<0.05),SD组比TC组EN显著增多(P<0.01),CMC组与SD组无显著差别(P>0.05),MD组比CMC组EN显著减少(P<0.01)。TC组比CC组MMP-9蛋白含量显著增高(P<0.01);经72 h睡眠剥夺后,SD组比TC组MMP-9蛋白含量显著增高(P<0.01),而与CMC组比较无显著差异(P>0.05);给予莫达非尼72 h后,MD组比CMC组MMP-9蛋白含量显著降低(P<0.01)。经RT-PCR检测MMP-9 mRNA表达的结果在上述各组中与免疫印迹检测的结果相一致。结论莫达非尼显著提高72 h REM睡眠剥夺大鼠认知功能,可能与其调节MMP-9 mRNA表达有关。     

Chronic treatment with diisopropylfluorophosphate increases dopamine turnover in the striatum of the rat

Following the administration of a single dose of diisopropylfluorophosphate (DFP) there is a rise of acetylcholine (ACh) in the rat striatum and frontal cortex. With chronic treatment, striatal ACh content returns to normal, but frontal cortex ACh remains elevated. In striatum but not frontal cortex, there is a rise of dopamine (DA) content and turnover after chronic DFP treatment. We speculate that DA content and turnover are increased after chronic DFP because the nigrostriatal neuronal feedback loop and local feedback loops are activated to compensate for increased cholinergic tone.     

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     

Administration of GM1 ganglioside restores the dopamine content in striatum after chronic treatment with MPTP

The dopamine (DA) content of the mouse striatum thirty days after treatment with MPTP is significantly reduced. GM1 ganglioside administration during the thirty day period results in a partial restoration of the striatal DA content.     

Alterations in striatal acetylcholine,acetylcholine esterase and dopamine after methadone replacement in morphine-dependent rats

Chronic treatment of rats with morphine was found to produced a significant increase in endogenous ACh and DA as well as a decrease in AChE activity of rat striatum. Narcotic withdrawal for 48 hr resulted in a reversal of morphine-induced changes in striatal ACh levels and AChE activity whereas the enhanced striatal DA remained unaltered. Methadone replacement failed to affect the changes in striatal ACh and AChE activity but abolished the increases in striatal DA seen in morphine-withdrawn rats. Our results suggest that ‘morphine addiction’ in rats may involve alterations in the cholinergic and dopaminergic mechanisms of the striatum and that methadone replacement influences primarily the changes in the dopaminergic system produced by chronic morphine and its subsequent withdrawal.     

Chronic lithium prevents REM sleep deprivation-induced increased responsiveness to apomorphine

REM sleep deprivation of rats induces an increased responsiveness to dopaminergic agonists. Chronic lithium (Li) has been reported to prevent the development of dopamine receptor supersensitivity induced by other agents. The effects of chronic dietary Li administration (producing a mean serum level of 0.96 mequiv. litre-1) and 96 h REM sleep deprivation were studied. Chronic Li completely blocked the increased stereotypy, and partially prevented the aggressive behaviour induced, respectively, by 0.6 and 5 mg kg-1 of apomorphine in REM sleep deprived rats compared with the appropriate control groups. This study constitutes the first attempt to evaluate chronic lithium effects on rats undergoing REM sleep deprivation, chosen as another method of inducing alteration of dopaminergic sensitivity.     

Rapid eye movement sleep deprivation-induced down-regulation of beta-adrenergic receptors in the rat brainstem and hippocampus

Rapid eye movement (REM) sleep deprivation induces a cortical down-regulation of beta-adrenergic receptors. Down-regulation of cortical beta-adrenergic receptors is consistently observed after a number of different chronic antidepressant treatments (drugs and electroconvulsive shock). REM sleep deprivation has an antidepressant effect in humans, and in rats, it decreases immobility in the behavioral despair test, an effect also produced by antidepressant treatments. To verify whether REM sleep deprivation also affects hippocampal beta-adrenergic receptors, we carried out the binding of [3H]-dihydroalprenolol ([3H]-DHA) to hippocampal membranes from rats deprived of REM sleep for 96 h. We also determined the binding of [3H]-DHA to brainstem membranes, a brain region where noradrenergic nuclei are located. Rats were deprived of REM sleep using a water tank with multiple small platforms. [3H-DHA] saturation conditions (concentrations ranging from 0.15 to 6 nM) were obtained in a crude hippocampus and brainstem membrane preparation. Nonspecific binding was determined using DL-propranolol in hippocampus homogenates. In the brainstem homogenates, nonspecific binding was determined in the presence of DL-propranolol or L-isoproterenol. The results obtained showed statistically significant down-regulation of beta-adrenergic receptors in both the hippocampus and the brainstem after REM sleep deprivation. In the hippocampus, there was also a significant decrease in the dissociation constant (KD). In the brainstem, a significant decrease in KD was observed when DL-propranolol was used to determine nonspecific binding. The down-regulation of beta-adrenergic receptors in the hippocampus and brainstem suggests the involvement of these brain areas in the antidepressant effect of REM sleep deprivation.     

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.     

REM sleep deprivation (REMSD) antagonizes naloxone-precipitated withdrawal in acute morphine-dependent rats

In rats allowed undisturbed sleep (control and stress) the administration of naloxone (10 mg/kg, s.c.) to morphine (7.5 mg/kg, s.c. 90 min prior) pretreated animals precipitated a jumping behaviour. REM sleep deprivation (REMSD 96 h, prior) significantly decreased the frequency of the naloxone-precipitated jumping behaviour compared with control and stressed animals. In second animal model for morphine withdrawal, naloxone (10 mg/kg, s.c.) provoked myoclonic twitch activity (MTA) in rats previously exposed to morphine (7.5 mg/kg, s.c., 90 min prior). The intensity of naloxone-induced MTA in REM sleep deprived rats was significantly lower compared to stressed animals, but it is not different from the control group. It is suggested that REMSD interferes with a neural mechanism involved in the development of acute dependence. Results are discussed in light of a possible functional insufficiency of a mu-opioid system during REMSD.     

The flower pot technique of Rapid Eye Movement (REM) sleep deprivation

This technique of REM sleep deprivation may make data interpretation difficult because it can lack selectivity, and because controls may suppress some REM sleep. To correct these difficulties, EEG recordings were made of rats placed in 4 situations for 96 hours: (1) baseline, (2) on 6.5 cm, or (3) 12.5 cm inverted flowerpots surrounded by water, (4) swimming in 10 cm water for 1 hr per 24 hr. Rats on the 6.5 cm pots had 57% as much REM sleep as baseline with no change in non-REM sleep. Rats on 12.5 cm pots initially had 55% as much REM sleep baseline, but by the fourth day increased to baseline levels. The swimming rats had no reduction in REM or non-REM sleep at any time, and thus seem to be a better control. The smaller the platform relative to the size of the rat, the greater the reduction in REM sleep - but at one point, non-REM sleep is decreased. The combination used here depresses REM sleep by about one half but does not reduce non-REM sleep.     

Development of supersensitivity of apomorphine-induced increases in acetylcholine levels and stereotype after chronic fluphenazine treatment

Dopamine agonists administered systemically produce an increase in striatal levels of acetylcholine (ACh). Possible development of postsynaptic dopamine receptor supersensitivity after neuroleptic treatment was studied by measurement of apomorphine (APO)-induced increase in ACh levels in the striatum and olfactory tubercle. Apomorphine-induced Stereotypic behaviour was also measured. Rats received a single subcutaneous injection of either sesame seed oil vehicle or fluphenazine (FLU) decanoate (10mg kg^?1), a long-acting neuroleptic preparation. After 14 days, rats received APO intraperitoneally, in various doses (0.03–1.0 mg kg^?1). Fifteen minutes later, brain tissue was rapidly fixed by microwave irradiation, dissected, and ACh levels determined by means of gas chromatography. Acetylcholine levels were 75nmol g^?1 in olfactory tubercle and 70 nmol g^?1 in striatum. Apomorphine treatment resulted in dose-dependent increases of ACh level in both regions. Apomorphine-induced increases were greater in rats pretreated with FLU than in controls. Using 0.1 mg kg^?1 APO, the higher striatal ACh-elevating effect found 14 days after FLU treatment was also present 21 days, but not 27 days after FLU treatment. At 21 days after subcutaneous injection, 0.25 mg kg^?1 APO induced significantly greater Stereotypic behaviour in FLU-treated rats than in controls. Thus. FLU treatment led to an apparent temporary supersensitivity of APO-induced increases in ACh levels and stereotypic behaviour.     

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.