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Matrix metalloproteinase-9 activity increased by two different types of epileptic seizures that do not induce neuronal death: A possible role in homeostatic synaptic plasticity

Matrix metalloproteases (MMPs) degrade or modify extracellular matrix or membrane-bound proteins in the brain. MMP-2 and MMP-9 are activated by treatments that result in a sustained neuronal depolarization and are thought to contribute to neuronal death and structural remodeling. At the synapse, MMP actions on extracellular proteins contribute to changes in synaptic efficacy during learning paradigms. They are also activated during epileptic seizures, and MMP-9 has been associated with the establishment of aberrant synaptic connections after neuronal death induced by kainate treatment. It remains unclear whether MMPs are activated by epileptic activities that do not induce cell death. Here we examine this point in two animal models of epilepsy that do not involve extensive cell damage. We detected an elevation of MMP-9 enzymatic activity in cortical regions of secondary generalization after focal seizures induced by 4-aminopyridine (4-AP) application in rats. Pro-MMP-9 levels were also higher in Wistar Glaxo Rijswijk (WAG/Rij) rats, a genetic model of generalized absence epilepsy, than they were in Sprague-Dawley rats, and this elevation was correlated with diurnally occurring spike-wave-discharges in WAG/Rij rats. The increased enzymatic activity of MMP-9 in these two different epilepsy models is associated with synchronized neuronal activity that does not induce widespread cell death. In these epilepsy models MMP-9 induction may therefore be associated with functions such as homeostatic synaptic plasticity rather than neuronal death.

Effects of sleep deprivation on extracellular serotonin in hippocampus and frontal cortex of the rat.

Sleep deprivation improves the mood of depressed patients, but the exact mechanism behind this effect is unclear. An enhancement of serotonergic neurotransmission has been suggested. In this study, we used in vivo microdialysis to monitor extracellular serotonin in the hippocampus and the frontal cortex of rats during an 8 h sleep deprivation period. These brain regions were selected since both have been implicated in depression. The behavioral state of the animal was continuously monitored by polygraphic recordings during the experiment. Sleep deprivation produced a gradual decline in extracellular serotonin levels, both in the hippocampus and in the frontal cortex. In order to investigate whether the reduction in serotonin was due to other factors than sleep deprivation, i.e. time of day effect, another experiment was performed. Here animals were allowed to sleep during most of the recording period. This experiment showed the expected changes in extracellular serotonin levels: consistently higher levels in the awake, non-sleep deprived animals compared to during sleep, but no time of day effect. The reduction in extracellular serotonin during sleep deprivation may suggest that serotonin does not play a major role in the mood-elevating effect of sleep deprivation. However, since 5-HT levels are strongly behavioral state dependent, by eliminating sleep, there may be a net increase in serotonergic neurotransmission during the sleep deprivation period.

Rapid eye movement (REM) sleep homeostatic regulatory processes in the rat: Changes in the sleep–wake stages and electroencephalographic power spectra

The aim of this study was to elucidate physiological processes that are involved in the homeostatic regulation of REM sleep. Adult rats were chronically instrumented with sleep-wake recording electrodes. Following post-surgical recovery, rats were habituated extensively for freely moving polygraphic recording conditions. On the first experimental recording day (baseline day, BLD), polygraphic signs of undisturbed sleep-wake activities were recorded for 4 h (between 11:00 AM and 3:00 PM). During the second experimental recording day (REM sleep deprivation day, RDD), rats were selectively deprived of REM sleep for the first 2 h and then allowed to have normal sleep-wake for the following 2 h. The results demonstrated that during the first 2 h, compared to BLD, RDD recordings exhibited 87.80% less time in REM sleep and 16% more time in non-REM (NREM) sleep. The total percentages of wakefulness remained comparable between the BLD and RDD. During the RDD, the mean number of REM sleep episodes was much higher than in the BLD, indicating increased REM sleep drive. Electroencephalographic (EEG) power spectral analysis revealed that selective REM sleep deprivation increased delta power but decreased theta power during the residual REM sleep. During the last 2 h, after REM sleep deprivation, rats spent 51% more time in REM sleep compared to the BLD. Also during this period, the number of REM sleep episodes with the shortest (5-30 s) and longest (>120 s) duration increased during the RDD. These findings suggest that the REM sleep homeostatic process involves increased delta- and decreased theta-frequency wave activities in the cortical EEG.

Sleep and waking following microdialysis perfusion of the selective 5-HT1A receptor antagonist p-MPPI into the dorsal raphe nucleus in the freely moving rat

The aim of this study was to examine the involvement of the dorsal raphe nucleus (DRN) presynaptic serotonergic 5-HT1A autoreceptors on sleep and waking parameters, in particular rapid eye movement (REM) sleep. In a previous study, the systemic administration of the selective 5-HT1A receptor antagonist p-MPPI reduced REM sleep in a dose-dependent manner suggesting a blockade of the 5-HT1A autoreceptors. In the present study, a blockade by microdialysis perfusion of 10 microM and 100 microM of p-MPPI for 7 h into the DRN in freely behaving rats influenced vigilance state only to a small extent. The administration of 10 microM of p-MPPI induced a reduction of total REM sleep mainly due to a suppression of REM sleep during the third 2 h period of the recording of sleep and waking. Perfusion of 100 microM of p-MPPI decreased total transition type sleep (TRANS) but the effect on REM sleep did not reach significance. There was no change in waking or slow wave sleep (SWS) following any of the doses. The data suggest that 5-HT1A receptor-mediated mechanisms in the DRN may be only moderately important in the serotonergic modulation of REM sleep.

Citalopram: differential sleep/wake and EEG power spectrum effects after single dose and chronic administration.

The sleep/wake effects of the selective serotonin re-uptake inhibitor citalopram were studied in both a single-dose study with three dose levels (0.5, 2.0 and 5.0 mg/kg), and a 5-week chronic administration study (15 mg/kg/24 h). Single doses of citalopram resulted in a dose-dependent inhibition of rapid eye movement (REM) sleep. After chronic citalopram treatment there was a sustained REM sleep inhibition. Single doses of citalopram resulted in only minor changes in non-REM (NREM) sleep as well as in NREM EEG power spectral density. Chronic administration resulted in a major shift from SWS-2 to SWS-1. The observed corresponding changes in EEG power density were regional. A 30 to 40 percent reduction of power density in the 0.5-15 Hz range in the fronto-parietal EEG derivation was seen for the whole 8-h registration period. In the fronto-frontal EEG derivation only minor changes were seen. A decreasing trend in NREM sleep power density between 0.5 and 7 Hz, usually seen during the course of the light period, was not observed in the chronic condition, but was seen in control and single-dose condition, suggesting altered diurnal distribution of slow wave activity in the chronic condition. The data indicate that acute and chronic administration of citalopram shows clear differences in sleep effect, which may be caused by alteration of serotonergic transmission, and may be related to the antidepressant effect.

Sleep and EEG power spectrum effects of the 5-HT1A antagonist NAN-190 alone and in combination with citalopram

The sleep and waking and EEG power spectrum effects of the putative 5-HT1A antagonist NAN-190 (0.5 mg/kg, i.p.) were studied alone and in co-administration with the selective serotonin re-uptake inhibitor citalopram (5.0 mg/kg, i.p.) in the rat. Citalopram, as in a prior dose-response study, reduced REM sleep. In addition, a slight increase in NREM sleep was observed. Citalopram reduced NREM fronto-parietal (FP) EEG power density in the 5-20 Hz range. When administered alone, NAN-190 suppressed REM sleep in the first 2 h, and reduced SWS-2 in the first 4 after administration. NAN-190 also suppressed selectively NREM sleep slow-wave activity in both fronto-frontal (FF) and FP EEG power spectrum. When administered in combination with citalopram, an attenuation of the power density reduction in the 7-15 Hz range in the FF EEG of citalopram alone, was observed. However, the EEG power spectral density and REM sleep suppressive effects of NAN-190 were both augmented. The results are compatible with the notion that serotonin is involved in the modulation of the slow wave activity in the EEG during NREM sleep. The results are cordant with other data suggesting that postsynaptic 5-HT1A stimulation might increase slow wave activity in the NREM EEG, and that serotonergic stimulation of other receptor subtypes (possibly 5-HT2) may decrease slow wave activity in the NREM EEG.

Sleep/waking effects following intrathecal administration of the 5-HT1A agonist 8-OH-DPAT alone and in combination with the putative 5-HT1A antagonist NAN-190 in rats

Sleep, waking, and EEG power spectra were investigated in rats after intrathecal (IT) administration of a 5-HT(1A) agonist and a 5-HT(1A) antagonist. Total slow wave sleep (TSWS) was increased and waking was decreased over the 8-h recording period after the 5-HT(1A) agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (38 nmol). Within TSWS, SWS1 was unchanged while SWS-2 tended to be increased. The 5-HT(1A) antagonist 1-[2-Methoxyphenyl)-4-(4-(2-phthalimido)-butyl]piperazine hydrobromide (NAN-190) did not change any sleep/waking stages. Combined treatment with 8-OH-DPAT and NAN-190 increased variance. Following the combination, sleep and waking were not significantly different from control. SWS-2 tended to be reduced compared to the effect of 8-OH-DPAT alone. There were no systematic changes in neither waking nor TSWS fronto-frontal or fronto-parietal EEG power spectrum after any of the treatments, indicating that sleep quality was not changed. The results confirm earlier data suggesting that in the spinal cord, stimulation of 5-HT(1A) receptors have a dampening effect on transmission of sensory information, leading to deactivation and thereby increased sleep tendency. The reason why the 8-OH-DPAT effect was not clearly antagonized by the putative 5-HT1A antagonist NAN-190, may be due to the generally weak antagonistic and also partial agonistic effect of NAN-190 as reported in the literature.

Sleep effects following intrathecal administration of the 5-HT1A agonist 8-OH-DPAT and the NMDA antagonist AP-5 in rats

The modulating effect of an intrathecally (i.t.) administered 5-HT1A agonist and an NMDA antagonist on sleep, waking and EEG power spectra was investigated in rats. The 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (38 nmol) increased total slow wave sleep (TSWS) and decreased waking over the 8 h recording period. The TSWS increase was mostly due to an increase in SWS1. Sleep latency to SWS1 was also reduced. The NMDA antagonist dl-2-amino 5-phosphonovaleric acid (AP-5) (31.5 nmol) reduced waking. SWS1 was increased, but TSWS was not changed. An increase in REM sleep was seen during the last part of the recording. Combined treatment with 8-OH-DPAT and AP-5 reduced waking and increased TSWS. No change in REM sleep was seen. There were no systematic changes in either waking, TSWS or REM fronto-frontal or fronto-parietal EEG power spectrum after any of the treatments. The results suggest that in the spinal cord stimulation of 5-HT1A receptors have a dampening effect on transmission of sensory information, leading to deactivation and thereby increased possibilities for sleep induction. Blockade of the NMDA receptors may also lead to a small dampening of sensory transmission with similar consequences.

Safety in pediatric imaging: an update

Many assumptions are made when imaging children. In particular a judgement is made regarding how safe or unsafe each imaging modality is, using relatively arbitrary definitions and distinctions, due to the lack of robust scientific data. Here, the latest evidence is reviewed, particularly regarding the medical exposure to ionizing radiation (X-rays and CT) and MRI in childhood. The best evidence currently available suggests a small but convincing risk of cumulative low-dose ionizing radiation in children. Given our predictions for the children imaged today, it seems reasonable to pursue non-ionizing-based techniques wherever possible, although there is emerging evidence that MRI and ultrasound may have hitherto unknown effects. As our knowledge base expands, we must continually review our practice in light of the latest scientific data.

Lesion of descending 5-HT pathways increases zimeldine-induced waking in rats

Sleep, waking, and EEG power spectra were investigated in rats with spinal 5,6-dihydroxytryptamine (5,6-DHT) lesions, following 20 mg/kg zimeldine or vehicle IP injections. 5,6-DHT selectively lesioned the descending serotonergic pathways. Lesion alone did not change sleep and waking stages compared to baseline, except for a reduction in REM sleep. Consistent with earlier findings, zimeldine in nonlesioned rats increased waking the first 2 h of recording. Zimeldine treatment in lesioned rats gave a significant additional 50% increase in waking the first 2 h and a corresponding decrease in total slow wave sleep, suggesting a potentiation of these effects. Zimeldine gave no significant changes in waking EEG power spectral density. Lesion gave a tendency to reduction between 4.0 and 15.5 Hz compared with baseline, and between 10.0 and 16.5 compared to the independent control group. In both comparisons, the combined treatment strengthened this effect, again suggesting a potentiating effect of lesion. In sleep, zimeldine reduced power over the whole spectrum (0.5-20.0 Hz), less in the lower frequencies than in the higher frequencies.