Biomedical subjects

Rita Jakus

Publications and source records attributed to Rita Jakus.

8 recordsLinked to original sources

PubMed2005

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.

Acoustic Stimulation↗

PubMed2004

Increased wakefulness, motor activity and decreased theta activity after blockade of the 5-HT2B receptor by the subtype-selective antagonist SB-215505.

Serotonin-2 receptor antagonists, like ritanserin, greatly enhance deep slow wave sleep (SWS-2) and low-frequency EEG power in humans and rodents. 5-HT(2A) and 5-HT(2C) receptors may be involved in these effects, but the role of the 5-HT(2B) receptor is still unclear. To investigate the role of the 5-HT(2B) receptor in regulation of the sleep-wake cycle, the subtype-selective antagonist SB-215505 (0.1, 0.3 and 1.0 mg kg(-1) i.p.) was administered to Sprague-Dawley rats at light onset (beginning of passive phase). EEG, EMG and motor activity were recorded during the subsequent 8 h. SB-215505 dose-dependently increased wakefulness (W) at the expense of the intermediate stage of sleep, paradoxical sleep (PS) and SWS-2 in the first hour. Parallel to increased W, significantly increased motor activity was found. Spectral analysis of the EEG in W showed a dose-dependent decrease in power density in the 3-8 Hz frequency range (maximum effect at 6 Hz). In light slow wave sleep and SWS-2, the drug reduced low-frequency (<8 Hz) EEG power, suggesting decreased sleep intensity after SB-215505 treatment. In PS, the drug dose-dependently decreased EEG power solely in the theta (6-9 Hz) band, primarily affecting the peak power value (7 Hz). The well-known SWS-2 enhancing effect of 5-HT(2) receptor antagonists is mediated by 5-HT(2A) and/or 5-HT(2C) receptors. In contrast, blockade of 5-HT(2B) receptors increases motor activity and W along with decreased theta activity during W and PS. Activation of 5-HT(2B) receptors may contribute to initiation of sleep and to theta generation during W and PS under physiological conditions.

Animals↗

PubMed2004

Effect of two noncompetitive AMPA receptor antagonists GYKI 52466 and GYKI 53405 on vigilance, behavior and spike-wave discharges in a genetic rat model of absence epilepsy.

The present study was conducted to investigate the effects of two noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists, GYKI 52466 and GYKI 53405 (the racemate of talampanel) on the generation of spike-wave discharges (SWD) parallel with the vigilance and behavioral changes in the genetic absence epilepsy model of WAG/Rij rats. Intraperitoneal (i.p.) administration of GYKI 52466 (1-[4-aminophenyl]-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine; 3, 10 and 30 mg/kg, i.p.), the prototypic compound of the 2,3-benzodiazepine family, caused a fast dose-dependent increase in the number and cumulative duration of SWD. These changes were accompanied by dose-dependent increase in duration of light slow wave sleep (SWS1) and passive awake, vigilance states associated with the presence of SWD. In addition a short, transient behavioral activation occurred that was followed by strong ataxia and immobility, decrease of active wakefulness and increase in deep slow wave sleep. GYKI 53405 (7-acetyl-5-(4-aminophenyl)-8-methyl-8,9-dihydro-7H-1,3-dioxolo[4,5-b][2,3]benzodiazepine, the racemate of talampanel, 16 mg/kg, i.p.) failed to affect any measure of SWD and vigilance. When used as a pretreatment, GYKI 52466 (10 mg/kg) slightly attenuated SWD-promoting effects of the 5-HT1A receptor agonist 8-OH-DPAT, it decreased cumulative duration and average time of paroxysms. In conclusion, AMPA receptors play moderate role in regulation of epileptic activity, and some of these effects are connected to their effects on vigilance in this model.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

PubMed2004

Effects of a single dose of 3,4-methylenedioxymethamphetamine on circadian patterns, motor activity and sleep in drug-naive rats and rats previously exposed to MDMA.

RATIONALE: Despite the well documented neurochemical actions of 3,4-methylenedioxymethamphetamine (MDMA), acute effects in rats previously exposed to the drug have not been extensively explored. OBJECTIVE: To examine motor activity and vigilance effects of MDMA in drug-naive rats and in rats exposed to the drug 3 weeks earlier. METHODS: MDMA (15 mg/kg, i.p.) was administered to Dark Agouti rats. Motor activity, wakefulness, light slow wave sleep (SWS-1), deep slow wave sleep (SWS-2) and paradoxical sleep (PS), sleep and PS latencies were measured. Acrophases and amplitudes of the 24 h cycles were calculated by cosinor analysis. In parallel groups, local cerebral glucose utilization (lCMRglu) and (3H)-paroxetine binding were measured in motor areas of the brain. RESULTS: In drug-naive rats MDMA caused marked increases in motor activity and wakefulness for at least 5-6 h. Circadian patterns of motor activity and sleep/vigilance parameters were altered up to 5 days after treatment. Despite most parameters tending to return to normal, there were still significant effects of MDMA on motor activity, wakefulness, and SWS-2 28 days later. Acute MDMA administration caused significant increases in lCMRglu, but after 3 weeks lCMRglu was decreased in the same brain areas. No significant change in [3H]paroxetine binding was observed in motor areas, although significant reductions were seen elsewhere (neocortex -81%). In rats exposed to MDMA 3 weeks earlier, most acute effects induced by MDMA administration were similar to those in drug-naive rats, but shorter duration of the acute effects were found in motor activity and vigilance. CONCLUSIONS: Our findings provide evidence that MDMA use can lead to long-term changes in regulation of circadian rhythms, motor activity and sleep generation.

Animals↗

PubMed2004

Selective 5-HT1A and 5-HT7 antagonists decrease epileptic activity in the WAG/Rij rat model of absence epilepsy.

Recent studies have provided evidence that activation of 5-HT1A receptors increases epileptic activity in the WAG/Rij rat model of absence epilepsy, and additional data have suggested the involvement of 5-HT7 receptors as well. Therefore, we have tested the effects of the selective 5-HT1A receptor antagonist WAY-100635 and the selective 5-HT7 receptor antagonist SB-258719 on spontaneous epileptic activity. In general, both compounds reduced epileptic activity compared to vehicle. Significant decreases were found in the number of paroxysms and the cumulative and average duration of spike-wave discharges (SWDs), although the time courses of these effects induced by the two compounds were clearly different. These results provide evidence that activation of 5-HT1A and 5-HT7 receptors plays a significant role in regulating SWD activity in this animal model of absence epilepsy.

Animals↗

PubMed2003

Despite the general correlation of the serotonin transporter gene regulatory region polymorphism (5-HTTLPR) and platelet serotonin concentration, lower platelet serotonin concentration in migraine patients is independent of the 5-HTTLPR variants.

Platelet serotonin (5-HT) concentrations in a headache-free period during the mid-follicular phase and the serotonin transporter gene regulatory region polymorphism (5-HTTLPR) were measured in female migraine patients without aura (n = 64) and healthy controls (n = 42). High-pressure liquid chromatography (HPLC) was used to determine the platelet 5-HT concentration and genetic polymorphism was determined by polymerase chain reaction. Significantly lower platelet 5-HT concentrations were found in migraine patients compared to controls. Concerning the 5-HTTLPR polymorphism, the S/S genotype was associated with a significantly higher platelet 5-HT concentration (P = 0.027) in the whole study population. This association between the 5-HTTLPR genotypes and platelet 5-HT concentrations was independent of the diagnosis. In addition, the platelet 5-HT concentration was lower in migraineurs in all genotypes (S/S, S/L, L/L). In conclusion, 5-HTTLPR variants may have an effect on the platelet 5-HT concentrations, but the lower 5-HT concentrations in migraine patients seem to be determined by other factors.

Adult↗

PubMed2003

5-HT2C receptors inhibit and 5-HT1A receptors activate the generation of spike-wave discharges in a genetic rat model of absence epilepsy.

The present study was conducted to investigate the role of 5-HT(2C) and 5-HT(1A) receptors in the generation of spike-wave discharges (SWD) in the genetic absence epilepsy model Wistar Albino Glaxo rats from Rijswijk, Netherlands (WAG/Rij rats). We have determined the effects of the 5-HT(2C) receptor preferring agonist m-chlorophenyl-piperazine (m-CPP), the selective 5-HT(2C) receptor antagonist SB-242084, the selective 5-HT(1A) receptor antagonist WAY-100635, two selective serotonin re-uptake inhibitors (SSRI, fluoxetine and citalopram) and their combinations in this model. The 5-HT(2C) agonist m-CPP caused marked, dose-dependent decreases in the cumulative duration and number of SWD administered either intraperitoneally (0.9 and 2.5 mg/kg) or intracerebroventricularly (0.05 and 0.1 mg/kg). Treatment with SB-242084 (0.2 mg/kg, ip) alone failed to cause any significant change in SWD compared to vehicle. Pretreatment with SB-242084 (0.2 mg/kg, ip) eliminated the effects of m-CPP on SWD. Fluoxetine (5.0 mg/kg, ip) alone caused moderate increase in SWD. After pretreatment with SB-242084, the effect of fluoxetine was significantly enhanced. The combination of SB-242084 and citalopram (2.5 mg/kg, ip) caused a similar effect, namely an increase in SWD. In contrast, pretreatment with WAY-100635 significantly attenuated the effect of fluoxetine. In conclusion, these results indicate that the increase in endogenous 5-HT produces a dual effect on SWD; the inhibition of epileptiform activity is mediated by 5-HT(2C), the activation by 5-HT(1A) receptors.

Action Potentials↗

PubMed2002

Acute and long-term effects of the 5-HT2 receptor antagonist ritanserin on EEG power spectra, motor activity, and sleep: changes at the light-dark phase shift.

Parallel effects of a single injection of the 5-HT(2) receptor antagonist ritanserin on EEG power spectra, sleep and motor activity were measured for a 20-h period in freely moving Sprague-Dawley rats. Ritanserin (0.3 mg/kg, i.p.), administered at light onset (passive phase), caused an immediate transient increase in the EEG power density in the low frequency range (0.25-6 Hz, mainly delta activity) and a depression in the high frequency range (27-30 Hz) accompanied by a decrease in vigilance and light slow wave sleep (SWS-1), intermediate stage of sleep and increase in deep slow wave sleep (SWS-2) compared to control treatment. All these effects were over 8 h after the injection. Twelve hours after the injection, at dark onset (active phase), there was a marked increase in vigilance and motor activity and decrease in SWS-1 and spindle frequency activity in the control animals, but all these changes were diminished by ritanserin treatment. These effects resulted in a significant relative increase in the intermediate band (peak: 12-15 Hz) of the EEG power spectra and thus, a relative increase in thalamo-cortical synchronization caused by ritanserin at dark onset. Because ritanserin is a selective 5-HT(2) receptor antagonist, we conclude that under physiological conditions serotonin increases EEG desynchronization and produces an increase in vigilance level and motor activity by tonic activation of 5-HT(2) receptors. This regulatory mechanism plays an important role in the waking process, and the appearances of its effects in the light and dark phase are markedly different.

Animals↗