Search PubMed⌕ Search

Biomedical subjects

M Radulovacki

Publications and source records attributed to M Radulovacki.

At least 55 records · Page 3Linked to original sources
PubMed1985

Prenatal exposure to diazepam results in enduring reductions in brain receptors and deep slow wave sleep.

After prenatal exposure to diazepam (Valium), mature rats at 4 months of age displayed slow wave sleep (SWS) electroencephalographic patterns indicating impaired synchronization and SWS mechanisms. These animals spent a much greater portion of their SWS in the lighter SWS I, as compared to the control group which showed a predominance of the deeper SWS II. At one year of age, the diazepam-exposed rats had much fewer diazepam-specific binding sites in the thalamus than the vehicle-exposed controls. These results provide first evidence for a physiological role for benzodiazepine receptors by showing that prenatal exposure to diazepam has an enduring and detrimental effect on their ontogenesis and sleep mechanisms.

Animals↗
PubMed1985

A comparison of the dose response effects of pyrimidine ribonucleosides and adenosine on sleep in rats.

The dose-response effects of intracerebroventricular (ICV) infusion of the pyrimidine ribonucleosides cytidine and uridine and the purine ribonucleoside adenosine on sleep and wakefulness (W) in rats were examined and compared. All three drugs were administered at doses of 1,10, and 100 nmol in volumes of 5 microliter, with control animals receiving equivolumetric infusions of 0.9% saline. Treatment with 1 nmol cytidine significantly increased W and decreased both deep slow wave sleep (S2) and total sleep (TS) during both the 3-6 and 0-6 h recording periods. In addition, this dose of cytidine significantly increased light slow wave sleep (S1) during the first 3 h of recording. The 10 nmol dose of cytidine increased W and decreased TS during the 0-6 h recording. ICV administration of uridine produced no significant changes in sleep and W at any dose during any of the recording periods examined. In contrast, adenosine exhibited significant hypnotic effects at all doses examined. All three doses of adenosine significantly reduced W and increased TS during both the 0-3 and 0-6 h recording periods. The 1 and 100 nmol doses of adenosine also significantly increased S2 during both the 0-3 and 0-6 h periods. In addition, the 100 nmol dose of adenosine significantly decreased W and increased both S2 and TS during the second 3 h of recording. Both the 1 and 100 nmol doses of adenosine also significantly reduced the latencies to the onset of rapid eye movement (REM) sleep.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1985

Lack of effect of 1-methylisoguanosine on sleep in rats.

The dose-response effects of intracerebroventricular (i.c.v.) administration of 1-methylisoguanosine (MIG) on sleep in rats were examined. Not even the largest dose (100 nmol/rat) of 1-methylisoguanosine produced significant hypnotic effects, whereas doses of 10 and 100 nmol/rat suppressed rapid eye movement sleep in rats. The only statistically significant effect of 1-methylisoguanosine on sleep latencies was an increase in the latency of S2 after intracerebroventricular administration of 100 nmol/rat of the drug. These effects of 1-methylisoguanosine on sleep were unlike those of both adenosine and the benzodiazepines, suggesting that, contrary to earlier speculations, 1-methylisoguanosine does not interact with central adenosine or benzodiazepine receptors.

Adenosine↗
PubMed1984

Diazepam and midazolam increase light slow-wave sleep (SWS1) and decrease wakefulness in rats.

Rats implanted with electrodes for polygraphic recordings were injected with diazepam (5 mg/kg, i.p.) or midazolam (10 mg/kg, i.p.) and recorded for 6 h during the 8 h of darkness of a 16 h light/8 h dark cycle. The results show that administration of diazepam reduced SWS1 latency by 92%, and increased SWS1 and total sleep by 255% and 59%, respectively, in comparison to control. Administration of midazolam increased SWS1 by 158% and total sleep by 57% when compared to control. These findings correlate well with the effects of benzodiazepines on sleep stage 2 in humans and indicate that benzodiazepine hypnotics increase only the behaviorally lighter stage of SWS in rats as well as in human subjects.

Animals↗
PubMed1984

Circadian variation of [3H]N6-(L-phenylisopropyl)adenosine binding in rat brain.

Since considerable recent experimental evidence suggests a role for the purine nucleoside adenosine in the regulation of mammalian sleep, circadian variations of adenosine receptor binding were examined in whole rat brain using [3H]N6-(L-phenylisopropyl)adenosine ([3H]L-PIA). These results demonstrate a significant circadian variation in the number of [3H]L-PIA binding sites (Bmax) with a maximum 3 h after the beginning of the dark phase of a 12 h light/12 h dark cycle, and a minimum 8 h later (P less than 0.025). The dissociation constant (Kd) of [3H]L-PIA at adenosine receptors did not exhibit any statistically significant circadian variation. These data indicate a daily rhythm in the number of adenosine receptors without a change in Kd and may support the hypothesized involvement of adenosine in the regulation of sleep in rats.

Adenosine↗
PubMed1984

[3H]N6-(L-Phenylisopropyl) adenosine binding in brains from young and old rats.

The binding of [3H]N6-(L-Phenylisopropyl) adenosine (L-PIA) to membrane preparations of whole brains from normal male Sprague-Dawley rats 12 and 84 weeks of age, respectively, was examined. Two populations of binding sites, probably corresponding to A1 and A2 adenosine receptors, were detected in both young and old rats. No statistically significant differences between young and old rats were detected but both the numbers of binding sites (Bmax) and dissociation constants (KD) for both high and low affinity binding sites were greater in 84 week old rats. These results were compared to earlier studies of adenosine receptors and related to previously reported changes in sleep with aging in rats.

Adenosine↗
PubMed1984

Adenosine analogs and sleep in rats.

The effects of N6-L-(phenylisopropyl)adenosine, cyclohexyladenosine and adenosine-5'-N-ethylcarboxamide on sleep were examined in rats. These effects consist of 1) increased slow-wave sleep2 from 6.6 to 45.7%, in all doses used for cyclohexyladenosine and adenosine-5'-N-ethylcarboxamide and for 0.1 and 0.3 mumol/kg of N6-L-(phenylisopropyl)adenosine and 2) increased values for rapid-eye-movement-sleep, amounting to 56.2 and 51.6% for 0.1 mumol/kg of cyclohexyl-adenosine and 0.3 mumol/kg of N6-L-(phenylisopropyl)adenosine, respectively. Slow-wave sleep1 decreased but values for wakefulness and total sleep were unchanged for 0.03, 0.1 and 0.3-mumol/kg doses of the drugs. Only 0.9-mumol/kg dose of cyclohexyladenosine and N6-L-(phenylisopropyl)adenosine increased wakefulness and decreased total sleep, whereas the same dose of adenosine-5'-N-ethylcarboxamide increased total sleep during the 0- to 3-hr time interval. All three agents reduced rapid-eye-movement sleep at the 0.9-mumol/kg dose. The results indicate that the effect on sleep of all three adenosine analogs was obtained with nanomolar doses of the drugs and that it diminished or disappeared when the drug dose reached micromolar range (0.9 mumol/kg). It appears, therefore, that activation of A1 rather than A2 receptors contributed to the sleep effects of the drugs because adenosine and adenosine analogs activate A1 receptors in nanomolar quantities whereas activation of A2 receptors requires micromolar concentration of these compounds.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1983

Hypnotic effects of deoxycorformycin in rats.

Rats implanted with EEG and EMG electrodes were treated with deoxycoformycin (0.5 or 2.0 mg/kg, i.p.), and polygraphically recorded for 6 h. Deoxycoformycin is a potent inhibitor of adenosine deaminase and would be expected to elevate the levels of adenosine in the central nervous system. The 0.5 mg/kg dose of the drug increased REM sleep and reduced REM sleep latency while the dose of 2.0 mg/kg increased deep slow-wave sleep (S2). These results appear to be consistent with those reported previously for the adenosine analog, N6-(L-phenylisopropyl)-adenosine (L-PIA) and indicate a hypnotic role for adenosine.

Adenosine Deaminase Inhibitors↗
PubMed1983

The effects of adenosine and 2'-deoxycoformycin on sleep and wakefulness in rats.

The effects of adenosine (12.5 nmol/rat, i.c.v.) and 2'-deoxycoformycin (2.0 mumol/kg, i.p.) on sleep and wakefulness were examined in rats. Adenosine significantly decreased wakefulness and increased both deep slow-wave sleep and total sleep. 2'-Deoxycoformycin, a potent inhibitor of adenosine deaminase, was administered at a dose which did not produce significant sedative and hypnotic effects, when given alone (although a 4-fold greater dose of this drug has been shown to be hypnogenic in rats) in order to examine the possible potentiation of exogenously administered adenosine. No such potentiation was observed, since treatment with both drugs produced effects qualitatively similar, although not statistically significant, to those of adenosine alone. These data clearly indicate that adenosine is a hypnogenic substance in rats and suggest that these effects may involve adenosinergic receptor-mediated modulation of the activity of central adenylate cyclase.

Adenosine↗
PubMed1983

Neither REM sleep deprivation nor rebound influences 3H-diazepam binding n rat brain.

Rats were placed on either small (subjected to REM sleep deprivation) or large circular platforms (stress controls) surrounded by water for 96 hours. Six animals from each group were either decapitated immediately following 96 hours or placed in cages and decapitated 6 hours later. Benzodiazepine receptor binding in rat brain cortices and brain stems was assessed using 3H-diazepam as the ligand. Scatchard analysis of these data showed that neither REM sleep deprivation nor REM sleep rebound affected the kinetics of 3H-diazepam binding (Bmax or apparent KD) in vitro.

Animals↗
PubMed1983

Human tryptamine metabolism decreases during night sleep.

Fourteen healthy male volunteers took part in a study which aimed to determine whether utilization of tryptamine changes in relation to sleep and wakefulness. For this purpose urine samples were collected every 4 hr and urinary tryptamine and indoleacetic acid (IAA) were determined by fluorometric and spectrophotometric methods. Urinary concentration of IAA progressively increased during the day and fell during the night when subjects were asleep but not when subjects were awake. This evidence indicates that behavioral state rather than circadian variation determines the level of urinary IAA. Tryptamine (T) concentration also progressively increased during the day and continued to increase during the night. The mean log10 (IAA/T) ratio indicates that tryptamine metabolism decreases during the night when subjects are asleep. Therefore, human sleep may be associated with diminished activity of peripheral tryptamine.

Adult↗
PubMed1983

Sleep suppressant action of fenfluramine in rats. II. Evidence against the involvement of presynaptic serotonergic mechanism.

The present study investigated the involvement of presynaptic serotonergic mechanisms in the sleep suppressant action of fenfluramine, an indirect serotonin (5-HT) receptor agonist. Rats implanted with cerebrocortical and dorsal neck muscle electrodes were pretreated with either fluoxetine, an inhibitor of 5-HT uptake, or p-chlorophenylalanine (PCPA), an inhibitor of 5-HT synthesis. Animals were continuously monitored by the EEG for 12 hr after an i.p. injection of 5 mg/kg of dl-fenfluramine hydrochloride. Pretreatment with fluoxetine failed to antagonize the fenfluramine-induced suppression of slow-wave sleep and rapid-eye-movement sleep. However, chemical analyses showed that fluoxetine pretreatment completely prevented the depletion of brain 5-HT produced by fenfluramine, suggesting that fenfluramine did not gain entry into serotonergic neurons. Depletion of brain 5-HT by PCPA also failed to antagonize the sleep suppression caused by fenfluramine as well as that observed after administration of quipazine, a direct 5-HT receptor stimulant. Because administration of fenfluramine to PCPA-pretreated rats produced no additional depletion of 5-HT, it appears that 5-HT was no longer available for release by fenfluramine in these animals. Furthermore, neither pretreatment with fluoxetine nor PCPA antagonized the head-shaking induced by fenfluramine, a behavior associated with activation of central 5-HT receptors. These data indicate that the suppression of sleep produced by fenfluramine is not mediated through release of 5-HT as brain 5-HT concentrations were not related to the behavioral effects of the drug. The sleep suppressant action of fenfluramine may therefore result from a direct action of the drug on postsynaptic 5-HT receptors.

Animals↗
PubMed1983

Sleep suppressant action of fenfluramine in rats. I. Relation to postsynaptic serotonergic stimulation.

The effects of fenfluramine, an indirect serotonin (5-HT) receptor agonist, on sleep and brain indole- and catecholamines were examined in rats. Animals implanted with cerebrocortical and dorsal neck muscle electrodes were continuously monitored by the EEG for 12 hr after i.p. injections of dl-fenfluramine hydrochloride (1, 5 and 10 mg/kg). Fenfluramine produced a dose-dependent suppression of both slow-wave sleep (SWS) and rapid-eye-movement sleep (REMS). Accompanying these effects was a dose-dependent increase in head-shaking, a behavior associated with activation of central 5-HT receptors. The incidence of head-shaking was inversely related to SWS and REMS time. At doses which significantly suppressed sleep (5 and 10 mg/kg), fenfluramine lowered whole brain 5-HT and 5-hydroxyindoleacetic acid concentrations without affecting brain catecholamines. Pretreatment with metergoline (2.5 and 5.0 mg/kg i.p.), a 5-HT receptor antagonist, 1 hr before the administration of fenfluramine (5 mg/kg) blocked the fenfluramine-induced suppression of SWS in a dose-dependent manner and prevented head-shaking behavior, but failed to prevent the suppression of REMS. In contrast, pretreatment with alpha-flupenthixol (0.2 mg/kg i.p.), a dopamine receptor antagonist, had no effect on the suppression of sleep and the stimulation of head-shaking behavior produced by fenfluramine. These data suggest that the suppression of SWS but not of REMS by fenfluramine is mediated by activation of the serotonergic system. The increase in serotonergic activity produced by fenfluramine may result from the drug-induced release of 5-HT with subsequent stimulation of postsynaptic 5-HT receptors. These findings are consistent with our hypothesis that pharmacological stimulation of 5-HT receptors suppresses sleep in the rat.

Animals↗
PubMed1982

Effects of REM sleep deprivation and desipramine on beta-adrenergic binding sites in rat brain.

Rats were subjected to REM sleep deprivation by the flower pot method for 7 days. Another group of rats received either desipramine (10 mg/kg, i.p.), a tricyclic antidepressant, or saline (i.p.) once daily for 7 days. beta-Adrenergic receptor sensitivity in rat brain cortices was assessed by determining the maximum number of [3H]dihydroalprenolol binding sites by Scatchard analysis. Administration of desipramine caused a 26% reduction in beta-adrenergic receptor density (P less than 0.01) while REM sleep deprivation reduced beta-adrenergic receptor density by 13%, which was not statistically significant.

Animals↗
PubMed1982

Methysergide blocks the sleep suppressant action of quipazine in rats.

The aim of the present study was to examine the effect of methysergide, a 5-hydroxytryptamine (5-HT) receptor antagonist, on the sleep suppression produced by the 5-HT receptor agonist, quipazine. Treatment with methysergide maleate (5 mg/kg, IP) 15 min before the administration of quipazine blocked quipazine-induced suppression of flow-wave sleep (SWS), but failed to prevent the decrease in rapid-eye-movement sleep (REMS) produced by quipazine. Treatment with methysergide also prevented the head-shaking behavior induced by quipazine, a phenomenon associated with increased activity of the central serotonergic system. Furthermore, it was shown that administration of methysergide alone (1 or 5 mg/kg, IP) had little effect on sleep or head-shaking behavior. The present data provide pharmacological evidence that the suppression of SWS but not REMS by quipazine may be a result of stimulation of 5-HT receptors.

Animals↗
PubMed1982

alpha-Flupenthixol increases slow-wave in rats: effect of dopamine receptor blockade.

alpha-Flupenthixol (0.2 mg/kg, i.p.), a dopamine receptor blocker, significantly increased slow-wave sleep and decreased wakefulness in rats when administered either at the onset of a 12-hr light period or a 12-hr dark period. The same dose of the drug strongly antagonized the dopamine-mediated stereotype produced by an injection of apomorphine (1 mg/kg, i.p.) for at least 9-hr, indicating that dopamine receptors were blocked throughout most of the recording session. The results suggest a relationship between the blockade of dopamine receptors and the increase of slow-wave sleep time.

Animals↗
PubMed1982

L-Tryptophan's effects on brain chemistry and sleep in cats and rats: a review.

In this review I shall discuss published and unpublished work from my laboratory dealing with L-tryptophan's effects on brain monoamines and sleep in cats and rats. From our work it appears that normal animals may not be suitable subjects for testing sleep-inducing effect of tryptophan since their slow-wave sleep (SWS) latency is relatively short. In polyphasic sleepers like cats, we did not observe tryptophan's hypnotic effect with any dosage used (10, 30 or 135 mg/kg). However, we found small, but statistically significant, sleep-inducing effect of tryptophan (30 mg/kg, IP) in normal rats. We have tried, therefore, to create insomniac cats with long sleep latencies by using methysergide, a serotonin receptor blocker. The results show that in insomniac cats hypnotic effect of tryptophan, a precursor to brain serotonin, was observed. It involved not only reduction of sleep latencies but also an increase in SWS. It seems likely that tryptophan's partial reversal of methysergide's effect in cats occurred via a dual mechanism of serotonergic activation and catecholaminergic deactivation, while its sleep-inducing effect in normal rats may have been due to the attenuation of the activity of brain catecholamines.

Animals↗