The cortical topography of local sleep

In a recent series of experiments, we demonstrated that a visuomotor adaptation task, 12 hours of left arm immobilization, and rapid transcranial magnetic stimulation (rTMS) during waking can each induce local changes in the topography of electroencephalographic (EEG) slow wave activity (SWA) during subsequent non-rapid eye movement (NREM) sleep. However, the poor spatial resolution of EEG and the difficulty of relating scalp potentials to the activity of the underlying cortex limited the interpretation of these results. In order to better understand local cortical regulation of sleep, we used source modeling to show that plastic changes in specific cortical areas during waking produce correlated changes in SWA during sleep in those same areas. We found that implicit learning of a visuomotor adaptation task induced an increase in SWA in right premotor and sensorimotor cortices when compared to a motor control. These same areas have previously been shown to be selectively involved in the performance of this task. We also found that arm immobilization resulted in a decrease in SWA in sensorimotor cortex. Inducing cortical potentiation with repetitive transcranial magnetic stimulation (rTMS) caused an increase in SWA in the targeted area and a decrease in SWA in the contralateral cortex. Finally, we report the first evidence that these modulations in SWA may be related to the dynamics of individual slow waves. We conclude that there is a local, plasticity dependent component to sleep regulation and confirm previous inferences made from the scalp data.     

Sleep homeostasis: a role for adenosine in humans?

Sleep is not the mere absence of wakefulness, but an active state which is finely regulated. The homeostatic facet of sleep–wake regulation is keeping track of changes in ‘sleep propensity’ (or ‘sleep need’), which increases during wakefulness and decreases during sleep. Increased sleep propensity following extended prior wakefulness (sleep deprivation) is counteracted by prolonged sleep duration, but also by enhanced non-rapid-eye-movement (nonREM) sleep intensity as measured by electroencephalographic (EEG) slow-wave activity (SWA, power within 1–4 Hz). This highly reliable regulatory feature of nonREM sleep may be the most important aspect of sleep in relation to its function. The neurochemical mechanisms underlying nonREM sleep homeostasis are poorly understood. Here we provide compelling and convergent evidence that adenosinergic neurotransmission plays a role in nonREM sleep homeostasis in humans. Specifically, a functional polymorphism in the adenosine metabolizing enzyme, adenosine deaminase, contributes to the high inter-individual variability in deep slow-wave sleep duration and intensity. Moreover, the adenosine receptor antagonist, caffeine, potently attenuates the EEG markers of nonREM sleep homeostasis during sleep, as well as during wakefulness. Finally, adenosinergic mechanisms modulate individual vulnerability to the detrimental effects of sleep deprivation on neurobehavioral performance, and EEG indices of disturbed sleep after caffeine consumption. While these convergent findings strongly support an important contribution of adenosine and adenosine receptors to nonREM sleep homeostasis, further research is needed to elucidate the underlying mechanisms that mediate the actions of adenosine on sleep and the sleep EEG.     

The competitive NMDA receptor antagonist CPPene stimulates NREM sleep and eating in rats.

Systemic administration of noncompetitive NMDA receptor antagonists, such as MK-801, produces a period of intoxication followed by non- rapid eye movement (NREM) sleep with greatly elevated delta EEG activity. We have hypothesized that the delayed NREM delta EEG increase is a homeostatic response to the immediate elevated limbic metabolism that these drugs produce. Here we test this hypothesis by examining the sleep and EEG effects of CPPene, a competitive NMDA antagonist that does not elevate limbic metabolism. We recorded EEG in seven rats following mid-dark period systemic injections of saline and three doses of CPPene. CPPene did not produce the delayed NREM delta increase. Instead, CPPene increased eating time and dose dependently increased NREM sleep duration shortly after injection. These differences in sleep EEG response to a competitive versus the noncompetitive NMDA antagonists are consistent with the possibility that the increased NREM delta following noncompetitive antagonists is a homeostatic response to increased limbic metabolism.     

Homeostatic Sleep Pressure is the Primary Factor for Activation of Cortical nNOS/NK1 Neurons

Cortical interneurons, immunoreactive for neuronal nitric oxide synthase (nNOS) and the receptor NK1, express the functional activity marker Fos selectively during sleep. NREM sleep ‘pressure'' is hypothesized to accumulate during waking and to dissipate during sleep. We reported previously that the proportion of Fos⁺ cortical nNOS/NK1 neurons is correlated with established electrophysiological markers of sleep pressure. As these markers covary with the amount of NREM sleep, it remained unclear whether cortical nNOS/NK1 neurons are activated to the same degree throughout NREM sleep or whether the extent of their activation is related to the sleep pressure that accrued during the prior waking period. To distinguish between these possibilities, we used hypnotic medications to control the amount of NREM sleep in rats while we varied prior wake duration and the resultant sleep pressure. Drug administration was preceded by 6 h of sleep deprivation (SD) (‘high sleep pressure'') or undisturbed conditions (‘low sleep pressure''). We find that the proportion of Fos⁺ cortical nNOS/NK1 neurons was minimal when sleep pressure was low, irrespective of the amount of time spent in NREM sleep. In contrast, a large proportion of cortical nNOS/NK1 neurons was Fos⁺ when an equivalent amount of sleep was preceded by SD. We conclude that, although sleep is necessary for cortical nNOS/NK1 neuron activation, the proportion of cells activated is dependent upon prior wake duration.     

The GABAA receptor agonist THIP alters the EEG in waking and sleep of mice

THIP is a GABA(A) agonist with hypnotic properties consisting in reducing sleep latency and prolonging and consolidating sleep. THIP has been reported to increase EEG slow-wave activity (SWA; EEG power in the 0.75-4 Hz band) in non-REM (NREM) sleep in both rats and humans. We investigated the effects of THIP on sleep in C57BL/6 mice. EEG recordings were performed after 2, 4 and 6 mg/kg THIP and saline control. The results were compared with analyses of recordings obtained after 6 h of sleep deprivation (SD) in the same strain of mice. The two higher doses of THIP induced an abnormal EEG pattern both in waking and NREM sleep. The EEG was characterized by sporadic asymmetric high-voltage potentials recurring at a low-frequency (<1 Hz) on the background of a low-amplitude EEG pattern. In contrast, after SD the typical regular synchronous high amplitude delta waves predominated. THIP at 4 and 6 mg/kg led to a prominent enhancement of spectral power in the low-frequency range of the waking and sleep EEG which was much higher than the increase attained after 6 h SD. This effect was particularly prominent in the waking EEG. In NREM sleep the increase of spectral power after THIP reflected the frequency of recurrence of the high-voltage potentials, and was restricted to a narrower frequency band than after SD. The EEG changes after 2mg/kg differed little from saline control. Sleep latency was not affected by the two lower doses of THIP, and was prolonged after 6 mg/kg. REM sleep was suppressed after the two higher doses. In contrast to previous results reported in other species, THIP did not have a hypnotic action in mice. The changes induced by THIP in the waking and sleep EEG differed from those caused by enhanced physiological sleep pressure encountered after SD. Considering the abnormal EEG pattern and the similarity of the spectral changes in the sleep and waking EEG, THIP does not seem to exert a specific effect on mechanisms involved in sleep regulation.     

Zebrafish as a Tool in the Study of Sleep and Memory-related Disorders

Sleep is an evolutionarily conserved phenomenon, being an important biological necessity for the learning process and memory consolidation. The brain displays two types of electrical activity during sleep: slow-wave activity or Non-Rapid Eye Movement (NREM) sleep, and desynchronized brain wave activity or Rapid Eye Movement (REM) sleep. There are many theories regarding “Why we need to sleep?”; one of them is the synaptic homeostasis. This theory suggests the role of sleep in the restoration of synaptic homeostasis, which is destabilized by synaptic strengthening triggered by learning during waking and by synaptogenesis during development. Sleep diminishes the plasticity load on neurons and other cells to normalize synaptic strength whereas it reestablishes neuronal selectivity and the ability to learn, leading to the consolidation and integration of memories. The use of zebrafish as a tool to assess sleep and its disorders is growing, although sleep in this animal is not yet divided, for example, into REM and NREM states. However, zebrafish are known to have a regulated daytime circadian rhythm, and their sleep state is characterized by periods of inactivity accompanied by an increase in arousal threshold, preference for resting place, and the “rebound sleep effect” phenomenon, which causes an increased slow-wave activity after a forced waking period. In addition, drugs known to modulate sleep, such as melatonin, nootropics, and nicotine have been tested in zebrafish. In this review, we discuss the use of zebrafish as a model to investigate sleep mechanisms and their regulation, demonstrating this species as a promising model for sleep research.     

H3 agonist immepip markedly reduces cortical histamine release, but only weakly promotes sleep in the rat.

Presynaptic H3 receptors exert negative control on brain histamine synthesis and release and may thereby play a key role in the control of the sleep/wake cycle. This suggests that pharmacological stimulation by H3 receptor agonists may potentially decrease wakefulness and induce sleep. This study reports the effect of a potent and selective H3 agonist, immepip, on EEG assessed sleep/wake phases in Sprague-Dawley rats at doses that significantly modulate brain histamine release. Immepip injected intraperitoneally (i.p.) at 5 or 10 mg kg(-1) induced a sustained decrease in cortical histamine efflux as measured by in vivo microdialysis. In a separate experiment, rats were prepared for EEG/EMG recording and evaluated during the dark phase of their light/dark cycle. The results showed that the same i.p. doses of 5 and 10 mg kg(-1) of immepip was devoid of any significant impact on the sleep/wake phases (active awake, drowsiness and slow wave sleep), except for a slight, albeit significant, decrease in sleep onset latency. These results reveal that a marked H3 receptor agonist-mediated reduction in cortical histamine release is not corroborated by a significant sleep promoting effect and therefore question the hypnotic potential of H3 agonists.     

Going local: insights from EEG and stereo-EEG studies of the human sleep-wake cycle

In the present paper, we reviewed a large body of evidence, mainly from quantitative EEG studies of our laboratory, supporting the notion that sleep is a local and use-dependent process. Quantitative analyses of sleep EEG recorded from multiple cortical derivations clearly indicate that every sleep phenomenon, from sleep onset to the awakening, is strictly local in nature. Sleep onset first occurs in frontal areas, and a frontal predominance of low-frequency power persists in the first part of the night, when the homeostatic processes mainly occur, and then it vanishes. Upon awakening, we showed an asynchronous EEG activation of different cortical areas, the more anterior ones being the first to wake up. During extended periods of wakefulness, the increase of sleepiness-related low-EEG frequencies is again evident over the frontal derivations. Similarly, experimental manipulations of sleep length by total sleep deprivation, partial sleep curtailment or even selective slow-wave sleep deprivation lead to a slow-wave activity rebound localized especially on the anterior derivations. Thus, frontal areas are crucially involved in sleep homeostasis. According to the local use-dependent theory, this would derive from a higher sleep need of the frontal cortex, which in turn is due to its higher levels of activity during wakefulness. The fact that different brain regions can simultaneously exhibit different sleep intensities indicates that sleep is not a spatially global and uniform state, as hypothesized in the theory. We have also reviewed recent evidence of localized effects of learning and plasticity on EEG sleep measures. These studies provide crucial support to a key concept in the theory, the one claiming that local sleep characteristics should be use-dependent. Finally, we have reported data corroborating the notion that sleep is not necessarily present simultaneously in the entire brain. Our stereo-EEG recordings clearly indicate that sleep and wakefulness can co-exist in different areas, suggesting that vigilance states are not necessarily temporally discrete states. We conclude that understanding local variations in sleep propensity and depth, especially as a result of brain plasticity, may provide in the near future insightful hints into the fundamental functions of sleep.     

Central AMPK contributes to sleep homeostasis in mice

AMP-activated protein kinase (AMPK) is an energy-sensing molecular signal involved in glucose and lipid metabolism. The known interaction of sleep with energy metabolism led us to investigate the role of central AMPK in sleep homeostasis. Sleep deprivation (SD) for 6 h increased p-AMPK protein in the hypothalamus and also increased the mRNA level of Ca²⁺/calmodulin (CaM)-dependent protein kinase kinase β (CaMKK2), an activator of AMPK, and carnitine palmitoyltransferase 1 (CPT1), a downstream signaling factor of AMPK. Central injection of compound C (CC), an inhibitor of AMPK, suppressed EEG delta power during NREM sleep, while 5-aminoimidazole-4-carboxamide riboside (AICAR), an activator of AMPK, enhanced EEG delta power. The treatment of both CC and AICAR attenuated rebound responses of delta power in NREM sleep after SD. These results indicate that central AMPK is involved in the regulation of sleep depth and sleep homeostasis.     

Flunitrazepam (Ro 5-4200) and sleep cycle in insomniac patients

The action of flunitrazepam (Ro 5-4200), a benzodiazepine derivative, was assessed on the sleep cycle of insomniac patients by means of all-night reeordings. Baseline placebo nights were compared with the drug (2–8 mg p.o.) and with the placebo post-drug nights.Flunitrazepam induced a shift to faster frequencies of the EEG and a disappearance of sleep stages 3 and 4 while stage 2 was increased. In 10 out of 12 studied insomniacs the compound was effective in inducing and maintaining sleep (decrease in NREM sleep latency, wake time and number of wakes) throughout the drug administration period. Both NREM and REM sleep were increased, the latter most likely in relation to a blockade of processes precluding NREM emergence.The hypnotic action of flunitrazepam was still present during the first withdrawal night, pointing out to a carry over effect.Supported by a grant from Hoffman-La Roche.     

The brain H3-receptor as a novel therapeutic target for vigilance and sleep-wake disorders

Brain histaminergic neurons play a prominent role in arousal and maintenance of wakefulness (W). H(3)-receptors control the activity of histaminergic neurons through presynaptic autoinhibition. The role of H(3)-receptor antagonists/inverse agonists (H(3)R-antagonists) in the potential therapy of vigilance deficiency and sleep-wake disorders were studied by assessing their effects on the mouse cortical EEG and sleep-wake cycle in comparison to modafinil and classical psychostimulants. The H(3)R-antagonists, thioperamide and ciproxifan increased W and cortical EEG fast rhythms and, like modafinil, but unlike amphetamine and caffeine, their waking effects were not accompanied by sleep rebound. Conversely, imetit (H(3)R-agonist) enhanced slow wave sleep and dose-dependently attenuated ciproxifan-induced W, indicating that the effects of both ligands involve H(3)-receptor mechanisms. Additional studies using knockout (KO) mice confirmed the essential role of H(3)-receptors and histamine-mediated transmission in the wake properties of H(3)R-antagonists. Thus ciproxifan produced no increase in W in either histidine-decarboxylase (HDC, histamine-synthesizing enzyme) or H(1)- or H(3)-receptor KO-mice whereas its waking effects persisted in H(2)-receptor KO-mice. These data validate the hypothesis that H(3)R-antagonists, through disinhibition of H(3)-autoreceptors, enhancing synaptic histamine that in turn activates postsynaptic H(1)-receptors promoting W. Interestingly amphetamine and modafinil, despite their potent arousal effects, appear unlikely to depend on histaminergic mechanism as their effects still occurred in HDC KO-mice. The present study thus distinguishes two classes of wake-improving agents: the first acting through non-histaminergic mechanisms and the second acting via histamine and supports brain H(3)-receptors as potentially novel therapeutic targets for vigilance and sleep-wake disorders.     

Effects of olanzapine, risperidone and haloperidol on sleep after a single oral morning dose in healthy volunteers

Objectives To compare the effects of typical and atypical antipsychotic drugs on sleep activity and subjective sleep quality. Design Randomised, double-blind, placebo-controlled, four-period cross-over, clinical trial was used to evaluate the effects of active treatments on objective and subjective sleep variables. Setting Sleep laboratory evaluation. Participants Twenty healthy young volunteers, both sexes. Interventions Single oral morning administrations of olanzapine 5 mg, risperidone 1 mg, haloperidol 3 mg and placebo. Measurements and results Five polysomnographic nights were evaluated: one control night and one after each intervention. Significant increase in total sleep time, sleep efficiency, slow wave sleep (SWS) and rapid eye movement (REM) sleep with decreases in wake time were observed after olanzapine. Decreases in wake time, REM sleep and stage shifts together with increases in stage 2 were obtained after risperidone. Haloperidol showed only a tendency to increase sleep efficiency and stage 2 and to decrease wake time. Olanzapine showed decreases in power density in frequencies higher than 10 Hz during all sleep stages and in frequencies lower than 5 Hz range in SWS; decreases in the dynamics of spindle frequency activity (SFA) in the second and fourth non-rapid eye movement (NREM) episodes were also obtained. Risperidone presented increases in the 3.6–10.8 Hz frequency range in NREM sleep stages and in stage 2. Haloperidol also showed increases in NREM sleep stages and in stage 2, but these were in frequencies higher than 10 Hz, with increases in the dynamics of SFA in the first NREM episode. Only a significant improvement in subjective sleep quality was observed after olanzapine. Conclusions Antipsychotics showed different sleep changes as their neurochemical profiles were distinct. These changes were observed even when the drug was administered 15 h before going to bed.     

Serotonin-2 receptors and human sleep: effect of a selective antagonist on EEG power spectra.

To investigate the effect on the sleep EEG, a 1-mg oral dose of SR 46349B, a novel 5-HT2 antagonist, was administered three hours before bedtime. The drug enhanced slow wave sleep (SWS) and reduced stage 2 without affecting subjective sleep quality. In nonREM sleep (NREMS) EEG slow-wave activity (SWA; power within 0.75-4.5 Hz) was increased and spindle frequency activity (SFA; power within 12.25-15 Hz) was decreased. The relative NREMS power spectrum showed a bimodal pattern with the main peak at 1.5 Hz and a secondary peak at 6 Hz. A regional analysis based on bipolar derivations along the antero-posterior axis revealed significant 'treatment' x 'derivation' interactions within the 9-16 Hz range. In enhancing SWA and attenuating SFA, the 5-HT2 receptor antagonist mimicked the effect of sleep deprivation, whereas the pattern of the NREMS spectrum differed.     

Effects of seganserin, a 5-HT2 antagonist, and temazepam on human sleep stages and EEG power spectra

The effects of seganserin, a specific 5HT2 antagonist, on human sleep were assessed in two experiments and compared to the effects of temazepam and sleep deprivation. During daytime recovery sleep after sleep deprivation, seganserin did not significantly enhance visually scored slow wave sleep (SWS, stages 3 + 4) or the EEG power density in the delta frequencies. Under these conditions temazepam reduced the power density in the delta and theta frequencies. During nighttime sleep after a nap in the evening, seganserin caused an increase in SWS, a reduction in intermittent wakefulness, and an enhancement of the power density in the delta and theta frequencies during non-rapid eye movement (NREM) sleep. Temazepam induced a reduction in the power density in the delta and theta frequencies. It is concluded that the 5HT2 antagonist, seganserin, can induce SWS. However, since the spectral results showed that the changes in the sleep EEG were not identical to those induced by sleep deprivation it seems premature to conclude that 5HT2 receptors are primarily involved in NREM sleep regulation.     

The GABAA agonist THIP produces slow wave sleep and reduces spindling activity in NREM sleep in humans

Recent studies in the rat demonstrated that systemic administration of muscimol and THIP, both selective GABA_A receptor agonists, elevates slow wave activity in the EEG during non-rapid eye movement (NREM) sleep. In this placebo-controlled study, we assessed the influence of an oral dose of 20 mg THIP on nocturnal sleep in young healthy humans. Compared to placebo, THIP increased slow wave sleep by about 25 min. Spectral analysis of the EEG within NREM sleep revealed significant elevations in the lower frequencies (<8 Hz) and reductions in the spindle frequency range (≈10–16 Hz). In accordance with previous findings in the rat, these data imply that GABA_A agonists promote deep NREM sleep, without suppressing REM sleep. These effects are opposite to those induced by agonistic modulators of GABA_A receptors such as benzodiazepines and are at variance with established mechanisms according to which GABA_A agonists and modulatory agonists would have similar effects. The sleep response to GABA_A agonists is highly similar to that evoked by sustained wakefulness, suggesting that GABA_A receptors may be implicated in the homeostatic regulation of sleep. Received: 17 September 1996/Final version: 5 November 1996     

GABA transporter-1 inhibitor NO-711 alters the EEG power spectra and enhances non-rapid eye movement sleep during the active phase in mice

GABA transporter subtype 1 (GAT1) constructs high affinity reuptake sites for GABA in the CNS and regulates GABAergic transmission. Compounds that inhibit GAT1 are targets often used for the treatment of epilepsy; however sedation has been reported as a side effect of these agents, indicating potential sedative and/or hypnotic uses for these compounds. In the current study, we observed the sleep behaviors of mice treated with NO-711, a selective GAT1 inhibitor, in order to elucidate the role of GAT1 in sleep–wake regulation during the active phase. The data revealed that NO-711 at a high dose of 10 mg/kg caused a marked enhancement of EEG activity in the frequency ranges of 3–25 Hz during wakefulness as well as rapid eye movement (REM) sleep. During the non-REM (NREM) sleep, NO-711 (10 mg/kg) elevated EEG activity in the frequency ranges of 1.5–6.75 Hz. Similar changes were found in mice treated with a low dose of 3 mg/kg. NO-711 administered i.p. at a dose of 1, 3 or 10 mg/kg significantly shortened the sleep latency of NREM sleep, increased the amount of NREM sleep and the number of NREM sleep episodes. NO-711 did not affect the sleep latency and the amount of REM sleep. NO-711 dose-dependently increased c-Fos expression in sleep-promoting nucleus of the ventrolateral preoptic area and median preoptic area. However, c-Fos expression was decreased in the wake-promoting nuclei, tuberomammillary nucleus and lateral hypothalamus. These results indicate that NO-711 can increase NREM sleep in mice.     

The impact of age on the hypnotic effects of eszopiclone and zolpidem in the guinea pig

Rational  Eszopiclone and zolpidem are hypnotics that differentially affect sleep and waking states in adult animals. Therefore, it was of interest to compare their effects on the states of sleep and wakefulness in aged animals. Objectives  Our objective was to determine the responses to eszopiclone and zolpidem vis-à-vis sleep and waking states in aged guinea pigs and to compare them with the effects of these hypnotics in adult animals. Methods  Aged guinea pigs were prepared to monitor sleep and waking states and to perform a frequency analysis of the EEG. Eszopiclone and zolpidem were administered intraperitoneally (1, 3, and 10 mg/kg). Results  Eszopiclone produced a more rapid and greater increase in NREM sleep as well as longer duration episodes of NREM sleep compared with zolpidem. There was also a significant increase in the latency to REM sleep with eszopiclone, but not with zolpidem. EEG power during NREM sleep increased in the delta band and decreased in the theta band following eszopiclone administration, whereas zolpidem had no effect on any of the frequency bands analyzed. Conclusions  In aged as well as adult guinea pigs, eszopiclone is a more effective hypnotic insofar as it produces a shorter latency to NREM sleep, a greater amount of NREM sleep and EEG delta waves. Differences in the effects produced by eszopiclone and zolpidem as a function of the aging process likely reflect the fact that they bind to different subunits of the GABA_A receptors, which are differentially reactive to the aging process. This work was supported by Sepracor, Inc., Marlborough, MA, USA.     

Reassessing morphine effects in cats: II. Protracted effects on sleep-wakefulness and the EEG

Adult cats were implanted with standard electrodes to record EEG, EOG, and EMG. After 15 days, morphine sulphate or saline placebo was given IP at 0.5, 1.0, 2.0, 3.0 mg/kg, at least 15 days apart. Cats were continuously recorded for 72 hr postinjection. Wakefulness, drowsiness, NREM and REM sleep percentages were scored from polygraphic features and statistically analysed. There was a dose-dependent suppression of NREM and REM sleep for at least 6 hours postmorphine, with a progressive sleep recovery thereafter. During the insomnia period there was an EEG/behavioral dissociation where bursts of high-voltage waves were seen over a background of desynchrony; meanwhile the animal was first aroused although quiet and later showed stereotypic behavior. There was a prolonged NREM sleep rebound which started later at the higher doses. A significant, relatively brief REM sleep rebound was seen only at the lowest dose. The latency for NREM and REM sleep onset was also dose-dependent. Possible brain sites of morphine actions and similarities with effects in other species are discussed.     

Asymmetrical Synaptic Cooperation between Cortical and Thalamic Inputs to the Amygdale

Fear conditioning, a form of associative learning is thought to involve the induction of an associative long-term potentiation of cortical and thalamic inputs to the lateral amygdala. Here, we show that stimulation of the thalamic input can reinforce a transient form of plasticity (E-LTP) induced by weak stimulation of the cortical inputs. This synaptic cooperation occurs within a time window of 30 min, suggesting that synaptic integration at amygdala synapses can occur within large time windows. Interestingly, we found that synaptic cooperation is not symmetrical. Reinforcement of a thalamic E-LTP by subsequent cortical stimulation is only observed within a shorter time window. We found that activation of endocannabinoid CB1 receptors is involved in the time restriction of thalamic and cortical synaptic cooperation in an activity-dependent manner. Our results support the hypothesis that synaptic cooperation can underlie associative learning and that synaptic tagging and capture is a general mechanism in synaptic plasticity.     

The selective group mGlu2/3 receptor agonist LY379268 suppresses REM sleep and fast EEG in the rat

Studies of ionotropic receptors indicate that glutamate (Glu) neurotransmission plays a role in sleep. Here, we show for the first time that metabotropic 2/3 Glu (mGlu2/3) receptors play an active or permissive role in the control of REM sleep. The potent, selective, and systemically active mGlu2/3 receptor agonist LY379268 was administered systemically in doses of 1.0 and 0.25 mg/kg sc. The drug produced a dose-dependent suppression of rapid eye movement (REM) sleep and fast (10-50 Hz) EEG in non-rapid eye movement (NREM) sleep. The 1.0-mg/kg effect on REM sleep was remarkably powerful: REM sleep was totally suppressed in the 6-h postinjection and reduced by 80% in the next 6 h. NREM duration was unchanged during the REM suppression in spite of the strong and unusual depression of EEG power in fast NREM frequencies. These sleep and EEG effects were unaccompanied by motor or behavioral abnormalities. We hypothesize that the REM and the fast EEG suppression were both caused by a depression of brain arousal levels by LY379268. If correct, depressing arousal by reducing excitatory neurotransmission with an mGlu2/3 receptor agonist produces electrophysiological effects that differ drastically from those produced by depressing arousal by enhancing neural inhibition with GABAergic drugs. This different approach to modifying the excitation/inhibition balance in the brain might yield novel therapeutic actions.