Serotonin and sleep-wakefulness.
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Animals↗
Biomedical subjects
A Wauquier
Publications and source records attributed to A Wauquier.
Melatonin modulates the sensitivity of 5-hydroxytryptamine-2 receptor-mediated sleep-wakefulness regulation in the rat.
The interaction between melatonin and two 5-hydroxytryptamine (5-HT2) compounds was studied on sleep patterns in rats. Administration of the 5-HT2 receptor antagonist ritanserin (0.63 mg/kg, i.p.) resulted in a significant increase of deep slow wave sleep (SWS2) and a decrease of paradoxical sleep (PS). The 5-HT2 receptor agonist DOM (1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane) (0.63 mg/kg, i.p.) produced a significant reduction of both SWS2 and PS. Melatonin (1 mg/kg, i.p.) alone did not alter sleep but counteracted the sleep effects induced by ritanserin as well as DOM. It is proposed that melatonin modulates the sensitivity of 5-HT2 receptor-mediated sleep response probably by an indirect route.
Animals↗
Selective vulnerability of synaptic transmission in hippocampus to ex-vivo ischemia: effects of extracellular ionic substitution in the postischemic period.
After 10-60 min of normothermic complete ischemia, hippocampal slices were prepared and allowed to recover for 60 min. The presence or absence of an evoked transsynaptic response was measured in CA1, CA3, and dentate gyrus. A selective vulnerability of the field excitatory postsynaptic potential to ischemia was found (CA1 greater than CA3 greater than dentate gyrus). Recovery of synaptic transmission in CA1 and CA3 was significantly improved by decreasing extracellular Ca2+ and increasing Mg2+ after ischemia. Addition of an N-methyl-D-aspartate antagonist further improved functional recovery. Postischemic reduction in extracellular Cl- increased recovery in CA1 and CA3, whilst reduction in Na+ was deleterious.
Animals↗
Functional role of 5-HT2 receptors in the regulation of sleep and wakefulness in the rat.
Recently developed agents specifically acting on different 5-hydroxytryptamine (5-HT) receptor populations were used to analyze the functional role of 5-HT2 receptor subtypes in the sleep-wakefulness cycle of the rat. The 5-HT2 receptor antagonist ritanserin injected intraperitoneally (IP) (0.04-2.5 mg/kg) induced an increase in deep slow wave sleep (SWS2) duration at the expense of wakefulness (W), light slow wave sleep (SWS1) and paradoxical sleep (PS). The stimulation of 5-HT2 receptors by 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) produced a dose-related increase in W and a dose-dependent decrease in both SWS2 and PS. Pretreatment with ritanserin (0.16-2.5 mg/kg) or with cinanserin (2.5-5 mg/kg), another 5-HT2 receptor antagonist, dose-dependently reversed the W enhancement and the SWS2 deficit produced by DOM, but not the PS deficit. Sleep-wakefulness alterations (increase in W and SWS1 combined with a suppression of SWS2 and PS) observed after IP injection of two putative 5-HT1 receptor agonists, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) (2.5 mg/kg) and 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (RU 24969) (0.63 mg/kg), were not modified by ritanserin pretreatment (0.16-2.5 mg/kg). These results further support the hypothesis that the serotonergic system plays an active role in the regulation of the sleep-wakefulness cycle in the rat and that 5-HT2 receptors are involved in this action. In addition, it is suggested that 5-HT1 receptor subtypes are unlikely to interact with 5-HT2 receptors in the sleep-wakefulness modulation mediated through 5-HT2 receptors.
DOM 2,5-Dimethoxy-4-Methylamphetamine↗
Differential effects of the new antipsychotic risperidone on sleep and wakefulness in the rat.
The effects of risperidone, a new antipsychotic with potent 5-hydroxytryptamine2 (5-HT2) and dopamine-D2 (DA-D2) antagonistic properties, were studied on sleep-wakefulness patterns in rats. Administration of low doses (0.01-0.16 mg/kg i.p.) resulted in a significant increase of deep slow wave sleep (SWS2) and a decrease of wakefulness (W) and light slow wave sleep (SWS1). High doses (0.63-2.5 mg/kg) produced opposite effects. Paradoxical sleep (PS) was significantly reduced over the dose range tested. The increase of SWS2 after low doses of risperidone could be related to a predominant and potent 5-HT2 receptor blocking activity.
Animals↗
Long-term neurological assessment of the post-resuscitative effects of flunarizine, verapamil and nimodipine in a new model of global complete ischaemia.
In anesthetized rats, global complete ischaemia lasting for 9 min was induced by controlled hydraulic compression of the chest. A neurological score, based on cranial and spinal reflexes, postural tone, gait, movement and limb placement, was determined at 2 hr and 1, 2, 3, 7, 14, 21 and 28 days after resuscitation. Three doses of three calcium antagonists, flunarizine, verapamil and nimodipine and their respective solvents, were given intravenously during the resuscitation. The total neurological score was significantly better than solvent with 0.16 and 0.63 mg/kg of flunarizine and 0.04 and 0.16 mg/kg of verapamil; it was significantly better with solvent (10% ethanol) than with 0.04 and 0.16 mg/kg of nimodipine. The deficiency in tactile placing reactions of the hindpaws was the most resistant to therapy. This non-invasive model of global ischaemia in rats seems useful for the evaluation of drugs, since it requires minimal anesthesia and allows assessment of neurological recovery over an extended period of time.
Anesthesia↗
The light-dark cycle modulates the effects of ritanserin on sleep-wakefulness patterns in the rat.
The 5-HT2 receptor antagonist ritanserin (0.63 mg/kg IP) produced differential effects on sleep-wakefulness patterns in rats when administered during the light or dark period: an increase in the duration of deep slow wave sleep at the expense of light slow wave sleep, paradoxical sleep and wakefulness when injected during the light period, and no major sleep alteration when given at dark onset. Since circadian variations in serotonin receptor density might modulate the sleep response, we examined the effects of ritanserin on sleep in rats exposed to continuous light for 10 days, and whether 5-HT2 receptors were affected in separate groups of rats exposed to similar conditions. No significant changes in the KD- and Bmax -values of various receptors were found. However, ritanserin produced greater effects in continuous light conditions than when given during the light period in the 12-hr light-dark condition. This suggests a possible role of 5-HT2 receptors in the organization of sleep when the environmental photoperiod is disturbed.
Animals↗
Photochemical stroke model: flunarizine prevents sensorimotor deficits after neocortical infarcts in rats.
We produced unilateral photochemical infarcts in the hindlimb sensorimotor neocortex of 186 rats by intravenous injection of the fluorescein derivative rose bengal and focal illumination of the intact skull surface. Infarcted rats showed specific, long-lasting deficits in tactile and proprioceptive placing reactions of the contralateral limbs, mostly the hindlimb. Placing deficits were most prominent during transition to immobility and/or when independent limb movements were required. Administration of flunarizine, a Class IV calcium antagonist, 30 minutes after infarction resulted in marked sparing of sensorimotor function in 30 rats. In contrast to 20 vehicle-treated rats, which remained deficient for at least 21 days, 15 (75%) of the rats treated with 1.25 mg/kg i.v. flunarizine showed normal placing on Day 1 after infarction, whereas the remaining five (25%) recovered within 5 days. Oral treatment of 10 rats with 40 mg/kg flunarizine was also effective. Neocortical infarct volume and thalamic gliosis, assessed 21 days after infarction, did not differ between 30 flunarizine- and 30 vehicle-treated rats. However, when 4-hour-old infarcts were measured in 16 rats, posttreatment with intravenous flunarizine reduced infarct size by 31%. In combination with appropriate behavioral analyses, photochemical thrombosis may constitute a relevant stroke model, in which flunarizine preserved behavioral function during a critical period, corresponding to the spread of ischemic damage.
Animals↗
Evidence for a role of the N-methyl-D-aspartate (NMDA) receptor in cortical spreading depression in the rat.
The neurotransmitter glutamate activates the N-methyl-D-aspartate (NMDA), quisqualate and kainate receptors. It has been proposed, but also disputed, that local release of glutamate would play a pivotal role in cortical spreading depression (SD). We tested this hypothesis by investigating the influence of NMDA antagonists on SD, using the non-competitive NMDA antagonists ketamine, phencyclidine (PCP) and MK-801 and the competitive NMDA antagonist DL-2-amino-7-phosphonoheptanoate (2-APH), injected intraperitoneally in rats anesthetized with alfentanil. SD was elicited by cathodal DC-stimulation of the frontal cortex. SD propagation was followed using two ion-sensitive microelectrodes placed in the parietal and occipital cortex. The NMDA antagonists increased SD threshold, decreased the propagation velocity and decreased the duration of the accompanying extracellular DC, K+ and Ca2+ changes at the following doses: 40 mg/kg ketamine, 10 mg/kg PCP, 0.63 mg/kg MK-801, 10 and 40 mg/kg 2-APH. With each NMDA antagonist failure of SD propagation between both microelectrodes could be observed. SD elicitation (or propagation) was inhibited completely with 80 mg/kg ketamine, 3.1 mg/kg MK-801 and 160 mg/kg 2-APH. These NMDA antagonists have also anticonvulsant properties. None of these effects on SD were observed with high doses of other anticonvulsants such as 80 mg/kg phenytoin or 40 mg/kg diazepam. These experiments indicate that endogenous release of excitatory amino acids and their action on the NMDA receptor play an important role in the initiation, propagation and duration of SD.
2-Amino-5-phosphonovalerate↗
Effects of ritanserin on sleep disturbances of dysthymic patients.
Ritanserin, a selective and potent serotonin-2 antagonist, is effective in the treatment of a variety of syndromes related to anxiety and depression, including dysthymic disorder. In animals and healthy volunteers, ritanserin specifically increases slow-wave sleep and the hypothesis arises that this effect on sleep may contribute to its therapeutic properties. Therefore, we studied the effects of ritanserin on sleep in a group of dysthymic patients (DSM-III). Polygraphic recording as well as subjective evaluations of the quality of sleep were performed before and at the end of a 4-week period of double-blind medication with either ritanserin (10 mg o.d. in the morning) or placebo. At baseline, patients showed at fragmented and superficial sleep, with low amounts of slow wave sleep. Ritanserin significantly increased Slow Wave Sleep and changed the frequency and distribution of some stage transitions during the night. No other sleep parameters were modified by ritanserin treatment.
Adult↗
Relationships between quantitative EEG measures and pharmacodynamics of alfentanil in dogs.
Intravenous alfentanil was administered as a constant 1 h infusion to 6 dogs. Before, during and up to 3 h after infusion, the effects of 3 doses (0.001, 0.004 and 0.016 mg/kg/min) on 6 quantitative EEG measures (zero-crossing frequency, root mean square (rms) amplitude, spectral edge, relative delta, alpha and beta power) were assessed in relation to plasma concentrations of alfentanil. All EEG measures, except zero-crossing frequency and rms amplitude, showed statistically significant dose-dependent changes in peak effect and duration. In addition, times-to-peak effect and return-to-baseline were sensitive to dose. The EEG effects of the low dose were smaller than those of the middle and high doses, whose peak effects did not statistically differ; but the high dose produced more persistent effects, which outlasted the infusion period for a longer time. Alfentanil-induced changes in rms amplitude and relative delta power showed the widest dynamic ranges. Measurable EEG changes occurred at low plasma concentrations, but EEG responses saturated at the middle dose. Significant correlations between plasma concentration and EEG effect were obtained for only the subperiod ranging from onset of infusion to peak EEG effect, indicating very short concentration-effect equilibration delays. On the other hand, clockwise concentration-effect loops were suggestive of acute tolerance: EEG responses peaked before peak plasma levels and they returned to baseline at dose-dependently higher plasma concentrations of alfentanil.
Alfentanil↗
Episodic barrel rotations induced by intrastriatal injection of quinolinic acid in rats. Inhibition by anticonvulsants.
Unilateral intrastriatal injection of quinolinic acid (2,3 pyridine dicarboxylate; QUIN) in the rat produces episodic barrel rotations and tonic-clonic forepaw movements, lasting for several hours. We investigated whether intraperitoneal posttreatment with anticonvulsants could abolish this phenomenon when it is already fully developed, and whether their potency ratio was similar in models of epilepsy. All 8 tested antiepileptics, namely carbamazepine, clonazepam, diazepam, diphenylhydantoin, ethosuximide, flunarizine, phenobarbital and sodium valproate decreased this behaviour in a dose-dependent way. Six other drugs with anticonvulsant properties were also effective: DL-2-amino-7-phosphonoheptanoic acid, desipramine, etomidate, ketamine, meprobamate and sabeluzole. The ED50-values for halving the frequency of the episodes of barrel rotation correlated well with published ED50-values for inhibition of tonic hindpaw extension in the maximal metrazol seizure test (rs = .95, p less than 0.001) and with the ED50-values for halving the duration of the forepaw clonus in the rat-kindling model (rs = .93, p less than 0.001). This quinolinic acid test allows visualization of the onset of action of anticonvulsants, with each animal as its own control. In order to assess whether this test is also sensitive to drugs influencing the symptoms of Huntington's disease, the effect of the dopamine antagonists haloperidol and pimozide, the acetylcholinesterase inhibitor physostigmine and the anticholinergics atropine and dexetimide were investigated as well. The experiments suggested that the barrel rotations and clonic forepaw movements, only 3-6 hours after intrastriatal injection of QUIN respond to anticonvulsants, but are not specifically sensitive to drugs used in the symptomatic treatment of Huntington's disease.
Animals↗
Spreading depression and central nervous system pharmacology.
Spreading depression is a reversible response of brain tissue to a local insult. It has been postulated to be the physiological substrate for the aura phase of classic migraine. The properties and mechanisms of spreading depression were studied in the parietal neocortex of the alfentanil-anesthesized rat, by using a cup electrode that provided close control of the electrical stimulus while allowing specific ion (K+) and potential recordings to be made directly beneath the cathode, the region of origin of the stimulus-induced spreading depression. Cathodal stimulation caused the extracellular K+ concentration to rise, and spreading depressions were observed when this concentration exceeded 8-12 mM in the upper 100-200 microns of cortex. In some experiments extracellular [K+] continued to increase for 5-10 sec after termination of the stimulus, without detectable after-discharge in the potential record, before subsiding. While spreading depression could easily be induced by pressure on the cortex, local damage incidental to opening the dura rarely induced spreading depression. This suggests that a local (1-mm2) neurovascular injury is not likely to induce spreading depression--at least in normal cortex--and so is probably not the source of the spreading depression postulated to generate the aura of classic migraine. Mechanisms of spreading depression, and drugs that influence spreading depression, are reviewed, and possible uses of spreading depression in the pharmacology of the central nervous system are considered.
Animals↗
Effects of temperature and temperature gradients on ion-sensitive microelectrodes.
Ion-sensitive microelectrodes are widely used in studies of mammalian tissues. Often the tissue is maintained at 37 degrees C, some 10-15 degrees C above room temperature. The temperature difference between the room and the preparation was found to be capable of altering the measured ion potential by as much as 10 mV. The change depended on 3 factors: the temperature dependence of the Nernst slope, the temperature dependence of the interference factor, and the thermoelectric potential induced by the temperature difference between the two ends of the ion-exchanger column. Certain combinations of these changes can cancel each other, resulting in spurious but apparently temperature-insensitive readings. The first two factors can produce errors when the temperature of calibration differs from the temperature of the tissue being measured. Serious errors in measurements of ion concentration can also occur, due to all 3 factors, if a temperature gradient exists across the ion exchanger column; this situation can easily occur when recording from exposed mammalian tissues. The use of a short ion-exchanger column will reduce but not eliminate effects due to a temperature gradient.
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Brain ischemia as a target for Ca2+ entry blockers.
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Animals↗
Effects of lithium on dopamine behavioural supersensitivity induced by rapid eye movement sleep deprivation.
The effects of lithium on the potentiation of d-amphetamine-induced hyperlocomotion were evaluated in rapid eye movement (REM) sleep deprived rats. Under control conditions, pretreatment with lithium during 7 days did not modify the hyperlocomotion produced by d-amphetamine. REM sleep deprivation induced a pronounced potentiation of the locomotor response to d-amphetamine. In a stress control group this potentiation also occurred, but to a lesser degree than in the REM sleep deprived group. Lithium pretreatment prevented the increased response to d-amphetamine in both REM sleep deprived and stress control animals. The effects of lithium in REM sleep deprived rats are in accordance with reports that lithium is able to prevent the development of dopamine receptor supersensitivity. However, it cannot be excluded that in both REM sleep deprived and stress control groups the increased response to d-amphetamine is related to noradrenergic changes and/or noradrenergic-dopaminergic interactions. REM sleep deprivation seems to be an interesting model to study the underlying mechanisms of manic-depressive illness.
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On the possible central effects of calcium antagonists.
The present paper discusses the possible central effects of calcium antagonists on the central nervous system in the light of present knowledge of the role of Ca2+ in physiological and pathophysiological processes.
Animals↗
Effects of phenytoin and flunarizine on the rise in extracellular potassium induced by repetitive stimulation of rat cerebral cortex.
At a critical intensity of repetitive stimulation, [K+]0 in cerebral cortex increases rapidly to a "ceiling" value of 10-12 mM. Phenomena related to this rapid regenerative increase in [K+]0 were investigated using K+-sensitive microelectrodes. The critical intensity required to induce this rise was found to be increased by phenytoin (90 mg/kg preload + 30 mg/kg presurgery) but not by flunarizine (30 mg/kg preload + 10 mg/kg presurgery), when the stimulus (20 Hz, 0.4 ms pulse duration, 5 or 40 s train duration) was applied to a 1 mm2 area of parietal neocortex in alfentanil-anesthesized rats. Flunarizine and phenytoin appear to differ in their mechanisms of anti-epileptic action.
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