Sleep and local field potential effect of the D2 receptor agonist bromocriptine during the estrus cycle and postpartum period in female rats.

BACKGROUND: Pituitary lactotrophs are under tonic dopaminergic inhibitory control and bromocriptine treatment blocks prolactin secretion. METHODS: Sleep and local field potential were addressed for 72 h after bromocriptine treatments applied during the different stages of the estrus cycle and for 24 h in the early- and middle postpartum period characterized by spontaneously different dynamics of prolactin release in female rats. RESULTS: Sleep changes showed strong dependency on the estrus cycle phase of the drug application. Strongest increase of wakefulness and reduction of slow wave sleep- and rapid eye movements sleep appeared during diestrus-proestrus and middle postpartum treatments. Stronger sleep-wake effects appeared in the dark phase in case of the estrus cycle treatments, but in the light phase in postpartum treatments. Slow wave sleep and REM sleep loss in case of estrus cycle treatments was not compensated at all and sleep loss seen in the first day post-injection was gained further later. In opposition, slow wave sleep loss in the light phase after bromocriptine injections showed compensation in the postpartum period treatments. Bromocriptine treatments resulted in a depression of local field potential delta power during slow wave sleep while an enhancement in beta and gamma power during wakefulness regardless of the treatment timing. CONCLUSIONS: These results can be explained by the interplay of dopamine D2 receptor agonism, lack of prolactin release and the spontaneous homeostatic sleep drive being altered in the different stages of the estrus cycle and the postpartum period.

Sleep- and sleep deprivation-related changes of vertex auditory evoked potentials during the estrus cycle in female rats.

The estrus cycle in female rodents has been shown to affect a variety of physiological functions. However, little is known about its presumably thorough effect on auditory processing during the sleep-wake cycle and sleep deprivation. Vertex auditory evoked potentials (vAEPs) were evoked by single click tone stimulation and recorded during different stages of the estrus cycle and sleep deprivation performed in metestrus and proestrus in female rats. vAEPs showed a strong sleep-dependency, with the largest amplitudes present during slow wave sleep while the smallest ones during wakefulness. Higher amplitudes and longer latencies were seen in the light phase during all vigilance stages. The largest amplitudes were found during proestrus (light phase) while the shortest latencies were seen during estrus (dark phase) compared to the 2nd day diestrus baseline. High-amplitude responses without latency changes were also seen during metestrus with increased homeostatic sleep drive. More intense and faster processing of auditory information during proestrus and estrus suggesting a more effective perception of relevant environmental cues presumably in preparation for sexual receptivity. A 4-h sleep deprivation resulted in more pronounced sleep recovery in metestrus compared to proestrus without difference in delta power replacement suggesting a better tolerance of sleep deprivation in proestrus. Sleep deprivation decreased neuronal excitability and responsiveness in a similar manner both during metestrus and proestrus, suggesting that the negative consequences of sleep deprivation on auditory processing may have a limited correlation with the estrus cycle stage.

Ketamine affects homeostatic sleep regulation in the absence of the circadian sleep-regulating component in freely moving rats.

Pharmacological effects of ketamine may affect homeostatic sleep regulation via slow wave related mechanisms. In the present study effects of ketamine applied at anesthetic dose (80 mg/kg) were tested on neocortical electric activity for 24 h in freely moving rats. Ketamine effects were compared to changes during control (saline) injections and after 6 h gentle handling sleep deprivation (SD). As circadian factors may mask drug effects, an illumination protocol consisting of short light-dark cycles was applied. Ketamine application induced a short hypnotic stage with characteristic slow cortical rhythm followed by a long-lasting hyperactive waking resulting pharmacological SD. Coherence analysis indicated an increased level of local synchronization in broad local field potential frequency ranges during hyperactive waking but not during natural- or SD-evoked waking. Both slow wave sleep and rapid eye movement sleep were replaced after the termination of the ketamine effect. Our results show that both ketamine-induced hypnotic state and hyperactive waking can induce homeostatic sleep pressure with comparable intensity as 6 h SD, but ketamine-induced waking was different compared to the SD-evoked one. Both types of waking stages were different compared to spontaneous waking but all three types of wakefulness can engage the homeostatic sleep regulating machinery to generate sleep pressure dissipated by subsequent sleep. Current-source density analysis of the slow waves showed that cortical transmembrane currents were stronger during ketamine-induced hypnotic stage compared to both sleep replacement after SD and ketamine application, but intracortical activation patterns showed only quantitative differences. These findings may hold some translational value for human medical ketamine applications aiming the treatment of depression-associated sleep problems, which can be alleviated by the homeostatic sleep effect of the drug without the need for an intact circadian regulation.

Convergent cross-species pro-cognitive effects of RGH-235, a new potent and selective histamine H3 receptor antagonist/inverse agonist.

The histamine H3 receptor is a favourable target for the treatment of cognitive deficits. Here we report the in vitro and in vivo profile of RGH-235, a new potent, selective, and orally active H3 receptor antagonist/inverse agonist developed by Gedeon Richter Plc. Radioligand binding and functional assays were used for in vitro profiling. Procognitive efficacy was investigated in rodent cognitive tests, in models of attention deficit hyperactive disorder (ADHD) and in cognitive tests of high translational value (rat touch screen visual discrimination test, primate fixed-foreperiod visual reaction time task). Results were supported by pharmacokinetic studies, neurotransmitter release, sleep EEG and dipsogenia. RGH-235 displayed high affinity to H3 receptors (Ki = 3.0-9.2 nM, depending on species), without affinity to H1, H2 or H4 receptors and >100 other targets. RGH-235 was an inverse agonist ([35S] GTPγS binding) and antagonist (pERK1/2 ELISA), showing favourable kinetics, inhibition of the imetit-induced dipsogenia and moderate effects on sleep-wake EEG. RGH-235 stimulated neurotransmitter release both in vitro and in vivo. RGH-235 was active in spontaneously hypertensive rats (SHR), generally considered as a model of ADHD, and revealed a robust pro-cognitive profile both in rodent and primate tests (in 0.3-1 mg/kg) and in models of high translational value (e.g. in a rodent touch screen test and in non-human primates). The multiple and convergent procognitive effects of RGH-235 support the view that beneficial cognitive effects can be linked to antagonism/inverse agonism of H3 receptors.

Homeostatic sleep regulation in the absence of the circadian sleep-regulating component: effect of short light-dark cycles on sleep-wake stages and slow waves.

BACKGROUND: Aside from the homeostatic and circadian components, light has itself an important, direct as well as indirect role in sleep regulation. Light exerts indirect sleep effect by modulating the circadian rhythms. Exposure to short light-dark cycle (LD 1:1, 1:1 h light - dark) eliminates the circadian sleep regulatory component but direct sleep effect of light could prevail. The aim of the present study was to examine the interaction between the light and the homeostatic influences regarding sleep regulation in a rat model. METHODS: Spontaneous sleep-wake and homeostatic sleep regulation by sleep deprivation (SD) and analysis of slow waves (SW) were examined in Wistar rats exposed to LD1:1 condition using LD12:12 regime as control. RESULTS: Slow wave sleep (SWS) and REM sleep were both enhanced, while wakefulness (W) was attenuated in LD1:1. SWS recovery after 6-h total SD was more intense in LD1:1 compared to LD12:12 and SWS compensation was augmented in the bright hours. Delta power increment during recovery was caused by the increase of SW number in both cases. More SW was seen during baseline in the second half of the day in LD1:1 and after SD compared to the LD12:12. Increase of SW number was greater in the bright hours compared to the dark ones after SD in LD1:1. Lights ON evoked immediate increase in W and decrease in both SWS and REM sleep during baseline LD1:1 condition, while these changes ceased after SD. Moreover, the initial decrease seen in SWS after lights ON, turned to an increase in the next 6-min bin and this increase was stronger after SD. These alterations were caused by the change of the epoch number in W, but not in case of SWS or REM sleep. Lights OFF did not alter sleep-wake times immediately, except W, which was increased by lights OFF after SD. CONCLUSIONS: Present results show the complex interaction between light and homeostatic sleep regulation in the absence of the circadian component and indicate the decoupling of SW from the homeostatic sleep drive in LD1:1 lighting condition.

Complete sleep and local field potential analysis regarding estrus cycle, pregnancy, postpartum and post-weaning periods and homeostatic sleep regulation in female rats.

Sleep and local field potential (LFP) characteristics were addressed during the reproductive cycle in female rats using long-term (60-70 days) recordings. Changes in homeostatic sleep regulation was tested by sleep deprivation (SDep). The effect of mother-pup separation on sleep was also investigated during the postpartum (PP) period. First half of the pregnancy and early PP period showed increased wakefulness (W) and higher arousal indicated by elevated beta and gamma activity. Slow wave sleep (SWS) recovery was suppressed while REM sleep replacement was complete after SDep in the PP period. Pup separation decreased maternal W during early-, but increased during middle PP while did not affect during late PP. More W, less SWS, higher light phase beta activity but lower gamma activity was seen during the post-weaning estrus cycle compared to the virgin one. Maternal sleep can be governed by the fetuses/pups needs and their presence, which elevate W of mothers. Complete REM sleep- and incomplete SWS replacement after SDep in the PP period may reflect the necessity of maternal REM sleep for the offspring while SWS increase may compete with W essential for maternal care. Maternal experience may cause sleep and LFP changes in the post-weaning estrus cycle.

Region-specific adenosinergic modulation of the slow-cortical rhythm in urethane-anesthetized rats.

Slow cortical rhythm (SCR) is a rhythmic alternation of UP and DOWN states during sleep and anesthesia. SCR-associated slow waves reflect homeostatic sleep functions. Adenosine accumulating during prolonged wakefulness and sleep deprivation (SD) may play a role in the delta power increment during recovery sleep. NREM sleep is a local, use-dependent process of the brain. In the present study, direct effect of adenosine on UP and DOWN states was tested by topical application to frontal, somatosensory and visual cortices, respectively, in urethane-anesthetized rats. Local field potentials (LFPs) were recorded using an electrode array inserted close to the location of adenosine application. Multiple unit activity (MUA) was measured from layer V-VI in close proximity of the recording array. In the frontal and somatosensory cortex, adenosine modulated SCR with slow kinetics on the LFP level while MUA remained mostly unaffected. In the visual cortex, adenosine modulated SCR with fast kinetics. In each region, delta power increment was based on the increased frequency of state transitions as well as increased height of UP-state associated slow waves. These results show that adenosine may directly modulate SCR in a complex and region-specific manner which may be related to the finding that restorative processes may take place with varying duration and intensity during recovery sleep in different cortical regions. Adenosine may play a direct role in the increment of the slow wave power observed during local sleep, furthermore it may shape the region-specific characteristics of the phenomenon.

Sleep deprivation decreases neuronal excitability and responsiveness in rats both in vivo and ex vivo.

Sleep deprivation has severe consequences for higher nervous functions. Its effects on neuronal excitability may be one of the most important factors underlying functional deterioration caused by sleep loss. In the present work, excitability changes were studied using two complementary in vivo and ex vivo models. Auditory evoked potentials were recorded from freely-moving animals in vivo. Amplitude of evoked responses showed a near-continuous decrease during deprivation. Prevention of sleep also reduced synaptic efficacy ex vivo, measured from brain slices derived from rats that underwent sleep deprivation. While seizure susceptibility was not affected significantly by sleep deprivation in these preparations, the pattern of spontaneous seizure activity was altered. If seizures developed, they lasted longer and tended to contain more spikes in slices obtained from sleep-deprived than from control rats. Current-source density analysis revealed that location and sequence of activation of local cortical networks recruited by seizures did not change by sleep deprivation. Moderate differences seen in the amplitude of individual sinks and sources might be explained by smaller net transmembrane currents as a consequence of decreased excitability. These findings contradict the widely accepted conception of synaptic homeostasis suggesting gradual increase of excitability during wakefulness. Our results also indicate that decreased neuronal excitability caused by sleep deprivation is preserved in slices prepared from rats immediately after deprivation. This observation might mean new opportunities to explore the effects of sleep deprivation in ex vivo preparations that allow a wider range of experimental manipulations and more sophisticated methods of analysis than in vivo preparations.

Characteristic changes in the slow cortical waves after a 6-h sleep deprivation in rat.

Sleep deprivation is followed by an increase in EEG delta power during recovery sleep indicating an increased sleep propensity. Delta waves mostly reflect the rhythmic recurring of generalized hyperpolarizations (DOWN state) in cortical neurons causing large, deep-positive waves in the LFP. Enhancement of delta power in recovery sleep can be the consequence of either the more frequent occurrence, or the higher amplitude caused by higher synchrony, or the longer duration of these DOWN states. In the present experiments, we examined these possibilities and found the strongest increase in the incidence of slow deep positive LFP waves (slow waves) following sleep deprivation indicating enhancement of DOWN state inducing and/or weakening of UP state maintaining processes. The strong decrease in multiunit activity during slow waves was preceded by a gradual buildup of activity. The significant correlation between these changes both in control and recovery recordings indicate that excitation might determine the subsequent drop in activity. Increased sensitivity of cortical neurons to excitation might offer an explanation for this observation. Current-source-density analysis indicated in our experiments that the first sources during DOWN states appeared in layer III-IV. Activation was then displaced to layer V. In the motor cortex, both corticocortical and thalamocortical fibers terminate in layer III that provides a strong feedforward excitation to layer V. As propagation of facilitatory signals through cortical layers is downwardly biased, disfacilitation might also follow this pattern. Sleep deprivation caused only quantitative differences in the sink-source patterns, indicating that existing processes were enhanced by sleep deprivation.

Cholinergic modulation of slow cortical rhythm in urethane-anesthetized rats.

Slow cortical rhythm (SCR) is characterized by rhythmic cycling of active (UP) and silent (DOWN) states in cortical cells. In urethane anesthesia, SCR appears as alternation of almost isoelectrical EEG periods and low-frequency, high-amplitude large shifts with superimposed high-frequency activity in the local field potentials (LFPs). Dense cholinergic projection reaches the cortex from the basal forebrain (BF), and acetylcholine (ACh) has been demonstrated to play a crucial role in the regulation of cortical activity. In the present experiments, cholinergic drugs were administered topically to the cortical surface of urethane-anesthetized rats to examine the direct involvement of ACh and the BF cholinergic system in the SCR. SCR was recorded by a 16-pole vertical electrode array from the hindlimb area of the somatosensory cortex. Multiple unit activity (MUA) was recorded from layer V to VI in close proximity of the recording array. Neither a low dose (10 mM solution) of the muscarinic antagonist atropine or the nicotinic agonist nicotine (1 mM solution) had any effect on SCR. In contrast, the higher dose (100 mM solution) of atropine, the cholinergic agonist carbachol (32 mM solution), and the cholinesterase inhibitor physostigmine (13 mM solution) all decreased the number of UP states, delta power (0-3 Hz) and MUA. These results suggest that cholinergic system may influence SCR through muscarinic mechanisms during urethane anesthesia. Cholinergic activation obstructs the mechanisms responsible for local or global synchronization seen during SCR as this rhythm was disrupted or aborted. Muscarinic antagonism can evoke similar changes when high dose of atropine is applied.

Interaction of slow cortical rhythm with somatosensory information processing in urethane-anesthetized rats.

Slow cortical rhythm (SCR) is a rhythmic alteration of active (hypopolarized), and silent (hyperpolarized) epochs in cortical cells. SCR was found to influence sensory information processing in various models, but these studies yielded inconsistent results. We examined sensory processing in anesthetized rats during SCR by recording multiple unit activity (MUA) and evoked field potentials (eFPs). Evoked field potentials as well as spontaneous FP changes around spontaneous activations were analyzed by subsequent current source density (CSD) analysis. MUA responses and eFPs were recorded from the hindlimb area (HL) of the somatosensory cortex (SI) to electrical stimuli of the tibial nerve during active and silent states, respectively. Stimulus-associated MUA above the ongoing background activity did not differ significantly in active vs. silent states. Short-latency (<50 ms) eFP responses consisted of a sequence of deep-negative and deep-positive waves. Parameters of the first negative deflection were similar in both states. Stimulation in the silent state occasionally induced 500-700 ms long spindles in the alpha range (10-16 Hz). Spindles were never observed in responses to active state stimulation. CSD analysis showed moderately different cortical sink-source patterns when the stimulus was applied during active vs. silent state. Sinks first appeared in layer IV, V and VI, corresponding sources were in layer I/II, V and VI. Stronger activation appeared in the infraganular layers in the case of active state. CSD of spontaneous FPs revealed some sequential activation pattern in the cortex when strongest and earlier sink appeared in layer III during active states.

The effect of prefrontal stimulation on the firing of basal forebrain neurons in urethane anesthetized rat.

The basal forebrain (BF) contains a heterogeneous population of cholinergic and non-cholinergic corticopetal neurons and interneurons. Neurons firing at a higher rate during fast cortical EEG activity (f>16Hz) were called F cells, while neurons that increase their firing rate during high-amplitude slow-cortical waves (f<4Hz) were categorized as S-cells. The prefrontal cortex (PFC) projects heavily to the BF, although little is known how it affects the firing of BF units. In this study, we investigated the effect of stimulation of the medial PFC on the firing rate of BF neurons (n=57) that were subsequently labeled by biocytin using juxtacellular filling (n=22). BF units were categorized in relation to tail-pinch induced EEG changes. Electrical stimulation of the medial PFC led to responses in 28 out of 41 F cells and in 8 out of 9 S cells. Within the sample of responsive F cells, 57% showed excitation (n=8) or excitation followed by inhibitory period (n=8). The remaining F cells expressed a short (n=6) or long inhibitory (n=6) response. In contrast, 6 out of the 8 responsive S cells reduced their firing after prefrontal stimulation. Among the F cells, we recovered one cholinergic neuron and one parvalbumin-containing (PV) neuron using juxtacellular filling and subsequent immunocytochemistry. While the PV cell displayed short latency facilitation, the cholinergic cell showed significant inhibition with much longer latency in response to the prefrontal stimulus. This is in agreement with previous anatomical data showing that prefrontal projections directly target mostly non-cholinergic cells, including GABAergic neurons.

Morphological characterization of electrophysiologically and immunohistochemically identified basal forebrain cholinergic and neuropeptide Y-containing neurons.

The basal forebrain (BF) contains cholinergic as well as different types of non-cholinergic corticopetal neurons and interneurons, including neuropeptide Y (NPY) containing cells. BF corticopetal neurons constitute an extrathalamic route to the cortex and their activity is associated with an increase in cortical release of the neurotransmitter acetylcholine, concomitant with low voltage fast cortical EEG activity. It has been shown in previous studies (Duque et al. in J Neurophysiol 84:1627-1635, 2000) that in anesthetized rats BF cholinergic neurons fire mostly during low voltage fast cortical EEG epochs, while increased NPY neuronal firing is accompanied by cortical slow waves. In this paper, electrophysiologically and neurochemically characterized cholinergic and NPY-containing neurons were 3D reconstructed from serial sections and morphometrically analyzed. Cholinergic and NPY-containing neurons, although having roughly the same dendritic surface areas and lengths, were found to differ in dendritic thickness and branching structure. They also have distinct patterns of dendritic endings. The subtle differences in dendritic arborization pattern may have an impact on how synaptic integration takes place in these functionally distinct neuronal populations. Cholinergic neurons exhibited cortically projecting axons and extensive local axon collaterals. Elaborate local axonal arbors confined to the BF also originated from NPY-containing neurons. The presence of local axon collaterals in both cholinergic and NPY neurons indicates that the BF is not a mere conduit for various brainstem inputs to the cortex, but a site where substantial local processing must take place.

Long term effects of sleep deprivation on the mammalian circadian pacemaker.

STUDY OBJECTIVES: In mammals, sleep is controlled by a homeostatic process, which regulates depth of sleep, and by the circadian clock of the suprachiasmatic nucleus (SCN), which regulates 24-h rhythms in timing of sleep. Sleep deprivation is known to cause molecular and physiological changes and results in an alteration in the timing of sleep. It is generally assumed that following sleep deprivation, homeostatic mechanisms overrule the circadian clock, allowing animals to sleep during their active phase. However, recent evidence indicates that sleep states have direct access to the circadian pacemaker of the SCN. We questioned therefore whether sleep deprivation may have long-term effects on the circadian pacemaker, which may explain altered sleep patterns following sleep deprivation. DESIGN: To test this hypothesis, we combined SCN recordings of electrical impulse frequency through stationary implanted electrodes in freely moving rats with electroencephalogram recordings in the same animal before, during, and after a mild 6-h sleep deprivation. MEASUREMENTS AND RESULTS: Following sleep deprivation, SCN neuronal activity was significantly reduced to about 60% of baseline levels. The decrements in SCN activity were most obvious during NREM sleep and REM sleep and lasted for 6-7 hours. CONCLUSIONS: The data show that sleep deprivation influences not only sleep homeostatic mechanisms, but also SCN electrical activity, resulting in a strong reduction in circadian amplitude in the major output signal from the SCN.

Effect of basal forebrain neuropeptide Y administration on sleep and spontaneous behavior in freely moving rats.

Neuropeptide Y (NPY) is present both in local neurons as well as in fibers in the basal forebrain (BF), an area that plays an important role in the regulation of cortical activation. In our previous experiments in anaesthetized rats, significant EEG changes were found after NPY injections to BF. EEG delta power increased while power in theta, alpha, and beta range decreased. The aim of the present experiments was to determine whether NPY infusion to BF can modulate sleep and behavior in freely moving rats. In this study, microinjections were made into the BF. Saline was injected to the control side, while either saline or one of two doses of NPY (0.5 microl, 300-500 pmol) to the treated side. EEG as well as behavioral changes were recorded. Behavioral elements after the NPY injections changed in a characteristic fashion in time and three consecutive phases were defined. In phase I (half hour 2), activated behavioral items (moving, rearing, grooming) appeared frequently. In phase II (half hours 3 and 4) activity decreased, while motionless state increased. Reappearance of activity was seen in phase III (half hours 5 and 6). NPY injections caused sleep-wake changes. The three phases described for behavioral changes were also reflected in the sleep data. During phase I, lower NPY dose increased wakefulness and decreased deep sleep. Reduced behavioral activity seen in phase II was partially reflected in the sleep. In this phase, wakefulness tended to increase in the third half hour, while decreased in the 4th half hour. Deep sleep and total slow wave sleep non-significantly decreased in the third and increased in the 4th half hour. In most cases, wakefulness was elevated again during Phase III, while sleep decreased. Length of single sleep-wake epochs did not change after NPY injections. Our results suggest a role for NPY in the integration of sleep and behavioral stages via the BF.

Effect of cortical spreading depression on basal forebrain neurons.

During natural sleep and anesthesia, rhythmic hypo- and hyperpolarizations alternate in cortical pyramidal cells and are reflected as slow (<1 Hz) cortical rhythm at the level of the electroencephalogram (EEG). Membrane potential changes in pyramidal neurons were initially attributed to the rhythmic fluctuation of the cholinergic input as the basal forebrain (BF) neurons fire in synchrony with cortical waves, but a more recent proposal suggested that the slow rhythm was of cortical origin. In the present experiments, interaction between the cortex and the BF was examined in urethane-anesthetized rats. BF neuronal activity was inhibited by local infusion of lidocaine into the substantia innominata in one group of rats, while in another group, the slow cortical rhythm was blocked by inducing spreading depression (SD) in the cortex. Slow cortical rhythm persisted after unilateral lidocaine injection, but rhythmic firing in BF neurons disappeared following SD induction. These findings support the view that slow cortical rhythm is generated in the cortex and transmitted to the BF through descending fibers. According to anatomical data, these fibers can excite cholinergic cells only indirectly as they terminate on non-cholinergic neurons. Thus, timing of activity changes in BF neurons during the slow cortical rhythm might give some clue regarding their transmitter specificity.

Lateral entorhinal cortex lesions rearrange afferents, glutamate receptors, increase seizure latency and suppress seizure-induced c-fos expression in the hippocampus of adult rat.

The entorhinal cortex (EC) provides the predominant excitatory drive to the hippocampal CA1 and subicular neurones in chronic epilepsy. Here we analysed the effects of one-sided lateral EC (LEC) and temporoammonic (alvear) path lesion on the development and properties of 4-aminopyridine-induced seizures. Electroencephalography (EEG) analysis of freely moving rats identified that the lesion increased the latency of the hippocampal seizure significantly and decreased the number of brief convulsions. Seizure-induced neuronal c-fos expression was reduced in every hippocampal area following LEC lesion. Immunocytochemical analysis 40 days after the ablation of the LEC identified sprouting of cholinergic and calretinin-containing axons into the dentate molecular layer. Region and subunit specific changes in the expression of ionotropic glutamate receptors (iGluRs) were identified. Although the total amount of AMPA receptor subunits remained unchanged, GluR1(flop) displayed a significant decrease in the CA1 region. An increase in NR1 and NR2B N-methyl-d-aspartate (NMDA) receptor subunits and KA-2 kainate receptor subunit was identified in the deafferented layers of the hippocampus. These results further emphasize the importance of the lateral entorhinal area in the spread and regulation of hippocampal seizures and highlight the potential role of the rewiring of afferents and rearrangement of iGluRs in the dentate gyrus in hippocampal convulsive activity.

Despite similar anxiolytic potential, the 5-hydroxytryptamine 2C receptor antagonist SB-242084 [6-chloro-5-methyl-1-[2-(2-methylpyrid-3-yloxy)-pyrid-5-yl carbamoyl] indoline] and chlordiazepoxide produced differential effects on electroencephalogram power spectra.

Serious efforts have been made to develop anxiolytics with improved clinical utility and reduced side effects. 5-Hydroxytryptamine (5-HT)(2C) receptor antagonists are potential anxiolytics; however, their effects on vigilance are not well characterized. To compare the effects of benzodiazepines and subtype-selective 5-HT(2C) receptor antagonists on anxiety, vigilance, and electroencephalogram (EEG) power density, social interaction test and polygraphic recordings were performed in male Sprague-Dawley rats after chlordiazepoxide (CDP; 4.0 mg/kg i.p.) and SB-242084 (6-chloro-5-methyl-1-[2-(2-methylpyrid-3-yloxy)-pyrid-5-yl carbamoyl] indoline) (0.1, 0.3, and 1.0 mg/kg i.p.) treatment. CDP and SB-242084 (0.3 and 1.0 mg/kg) had similar anxiolytic effects. Spectral analysis of EEG in wakefulness (W) and paradoxical sleep (PS) showed an opposite effect on activity (5-9 Hz); it decreased after CDP, whereas it increased after SB-242084 (even at 0.1 mg/kg). In addition, CDP significantly decreased slow-wave activity (0.5-4 Hz) in deep slow-wave sleep (SWS-2) and increased power at frequencies above 12 Hz mainly in W and PS. A markedly increased intermediate stage of sleep was also found after CDP treatment. At the highest dose, SB-242084 increased W and decreased SWS-2. In summary, low but potent anxiolytic doses of the subtype-selective 5-HT(2C) receptor antagonist SB-242084 did not affect vigilance states but caused an increased activity in W, raising the possibility of a cognitive-enhancing effect of the drug. In contrast, acute CDP administration, based on spectral analysis of the EEG, produced a more superficial sleep along with a decreased activity.

Transient alterations in neuronal and behavioral activity following bensultap and fipronil treatment in rats.

In the present multilevel study, neuromodulatory effect of two insecticides, bensultap and fipronil were investigated in rats. Although the new generation of insecticides shows greater affinity to invertebrate as compared to mammalian receptors, toxic effect of these compounds in vertebrates cannot be excluded. The aim of the study was to follow the course of neuronal changes in rats for 1 week after a high-dose insecticide exposure. Alterations in synaptic excitability, in sleep-wake pattern and in behavior were analyzed using conventional in vitro brain slice method, long-lasting EEG recordings, and open-field tests. The two chemicals examined in this study induced only weak and transient effects. Bensultap, acting on nicotinic acetylcholine receptors, caused a transient decrease in neuronal excitability. Sleep and behavioral changes demonstrated a similar time course. Fipronil, on the other hand, increased excitability and its effect lasted slightly longer. All effects were greatest on the first day following 'poisoning', and measured variables usually returned to normal within a week. These results suggest that the studied compounds do have some effects on the mammalian nervous system, but this effect is usually mild and temporary.

EEG effect of basal forebrain neuropeptide Y administration in urethane anaesthetized rats.

Neuropeptide Y (NPY) is present both in local neurons as well as in fibers in the basal forebrain (BF), an area that plays an important role in the regulation of cortical activation. In previous studies, NPY axons were found to innervate corticopetal cholinergic cells in this area. In addition, identified NPY positive neurons have been shown to be silent during cortical activation, but active during slow EEG waves. However, no in vivo studies have shown the effect of local NPY release in the BF on the EEG. In the present experiments, the EEG was examined following NPY injection (0.5 microl, 300-500 pmol) into the BF of urethane-anaesthetized rats. Fronto-parietal EEG was recorded on both sides and relative EEG power was calculated in the delta (0-3 Hz), theta (3-9 Hz), alpha (9-16 Hz) and beta (16-48 Hz) frequency bands. We found a significant increase in relative delta power and a decrease in the power of all higher frequency bands (theta, alpha, beta) after NPY injection. These results suggest that NPY can inhibit cortical activation via the BF.