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5-Hydroxytryptamine (5-HT)2A antagonists are promising therapeutic agents for the treatment of sleep maintenance insomnias, but unlike hypnotics, they have limited effects on sleep initiation. This study evaluated the effects of several 5-HT₂A antagonists (eplivanserin, volinanserin and AVE8488) alone and/or in combination with the short-acting hypnotic, zolpidem, on the rat sleep profile. A repeated-measures design was used in which rats were treated with eplivanserin (3 and 10 mg/kg, i.p. or p.o.), volinanserin (0.3-3 mg/kg, i.p.), AVE8488 (0.1-3 mg/kg, i.p.) and zolpidem (3 and 10 mg/kg, p.o.). In addition, animals received a combination of eplivanserin (3 mg/kg, p.o.) and zolpidem (3 mg/kg, p.o.). Electroencephalogram was analyzed for 6 h after administration. Eplivanserin did not modify wakefulness and non-rapid eye movement sleep (NREMS), while zolpidem (10 mg/kg po) induced a marked increase in NREMS duration. Volinanserin (1 and 3 mg/kg) and AVE8488 (0.3 mg/kg) similarly increased NREMS, while reducing wakefulness. Moreover, the 5-HT₂A antagonists and, to a lesser extent, zolpidem, increased duration of NREMS episodes, while decreasing their frequency. When eplivanserin was co-administered with zolpidem, a synergistic effect was observed as the combination produced an increase in NREMS time and bouts duration. These findings confirm further that 5-HT₂A antagonists promote the maintenance of sleep, and suggest that combining a 5-HT₂A antagonist with a short-acting hypnotic may be a useful strategy for the treatment of insomnia.

The experience of traumatic stress often leads to long-lasting alteration in sleep quality and behavior. The objective of the present experiment was to investigate the short- and long-term effects of acute inescapable stress (i.e. two electric foot-shocks of 1.5 mA; 2 s) on sleep/wakefulness parameters and behavior in Swiss mice using electroencephalographic (EEG) analysis. Baseline EEG recording was performed in the home cage for 6 h prior to the application of the foot-shocks in the presence of an object (i.e. a plastic prism). One, 7, 14 or 21 days later, a second 6 h EEG recording session was performed after mice had been exposed or not to the same object for 5 min in their home cage. Results showed that at day 1, 7, 14 and 21 post-stress, shocked mice displayed sleep fragmentation as shown by an increase in the number of sleep episodes, regardless the presence of the object or not. In animals exposed to the object, the total duration of wakefulness over 6 h was significantly increased at days 7, 14 and 21 post-stress, and rapid eye movement (REM) sleep was significantly decreased at day 14 post-shock. Moreover, in the behavioral experiment, conditioned avoidance to a shock-paired object, which appeared as soon as 24 h after shock application, turned into generalized avoidance towards an unknown object 21 days after stress. These findings demonstrate that an acute inescapable stress exposure may cause long-lasting alterations in sleep patterns and behavior. Such modifications may be reminiscent of the profound changes observed in patients suffering from post-traumatic stress disorder.

The characterization of the first selective orally active and brain-penetrant beta3-adrenoceptor agonist, SR58611A (amibegron), has opened new possibilities for exploring the involvement of this receptor in stress-related disorders. By using a battery of tests measuring a wide range of anxiety-related behaviors in rodents, including the mouse defense test battery, the elevated plus-maze, social interaction, stress-induced hyperthermia, four-plate, and punished drinking tests, we demonstrated for the first time that the stimulation of the beta3 receptor by SR58611A resulted in robust anxiolytic-like effects, with minimal active doses ranging from 0.3 to 10 mg/kg p.o., depending on the procedure. These effects paralleled those obtained with the prototypical benzodiazepine anxiolytic diazepam or chlordiazepoxide. Moreover, when SR58611A was tested in acute or chronic models of depression in rodents, such as the forced-swimming and the chronic mild stress tests, it produced antidepressant-like effects, which were comparable in terms of the magnitude of the effects to those of the antidepressant fluoxetine or imipramine. Supporting these behavioral data, SR58611A modified spontaneous sleep parameters in a manner comparable to that observed with fluoxetine. Importantly, SR58611A was devoid of side effects related to cognition (as shown in the Morris water maze and object recognition tasks), motor activity (in the rotarod), alcohol interaction, or physical dependence. Antagonism studies using pharmacological tools targeting a variety of neurotransmitters involved in anxiety and depression and the use of mice lacking the beta3 adrenoceptor suggested that these effects of SR58611A are mediated by beta3 adrenoceptors. Taken as a whole, these findings indicate that the pharmacological stimulation of beta3 adrenoceptors may represent an innovative approach for the treatment of anxiety and depressive disorders.

Noncompetitive N-methyl-D-aspartate (NMDA) blockers induce schizophrenic-like symptoms in humans, presumably by impairing glutamatergic transmission. Therefore, a compound potentiating this neurotransmission, by increasing extracellular levels of glycine (a requisite co-agonist of glutamate), could possess antipsychotic activity. Blocking the glycine transporter-1 (GlyT1) should, by increasing extracellular glycine levels, potentiate glutamatergic neurotransmission. SSR504734, a selective and reversible inhibitor of human, rat, and mouse GlyT1 (IC50=18, 15, and 38 nM, respectively), blocked reversibly the ex vivo uptake of glycine (mouse cortical homogenates: ID50: 5 mg/kg i.p.), rapidly and for a long duration. In vivo, it increased (minimal efficacious dose (MED): 3 mg/kg i.p.) extracellular levels of glycine in the rat prefrontal cortex (PFC). This resulted in an enhanced glutamatergic neurotransmission, as SSR504734 potentiated NMDA-mediated excitatory postsynaptic currents (EPSCs) in rat hippocampal slices (minimal efficacious concentration (MEC): 0.5 microM) and intrastriatal glycine-induced rotations in mice (MED: 1 mg/kg i.p.). It normalized activity in rat models of hippocampal and PFC hypofunctioning (through activation of presynaptic CB1 receptors): it reversed the decrease in electrically evoked [3H]acetylcholine release in hippocampal slices (MEC: 10 nM) and the reduction of PFC neurons firing (MED: 0.3 mg/kg i.v.). SSR504734 prevented ketamine-induced metabolic activation in mice limbic areas and reversed MK-801-induced hyperactivity and increase in EEG spectral energy in mice and rats, respectively (MED: 10-30 mg/kg i.p.). In schizophrenia models, it normalized a spontaneous prepulse inhibition deficit in DBA/2 mice (MED: 15 mg/kg i.p.), and reversed hypersensitivity to locomotor effects of d-amphetamine and selective attention deficits (MED: 1-3 mg/kg i.p.) in adult rats treated neonatally with phencyclidine. Finally, it increased extracellular dopamine in rat PFC (MED: 10 mg/kg i.p.). The compound showed additional activity in depression/anxiety models, such as the chronic mild stress in mice (10 mg/kg i.p.), ultrasonic distress calls in rat pups separated from their mother (MED: 1 mg/kg s.c.), and the increased latency of paradoxical sleep in rats (MED: 30 mg/kg i.p.). In conclusion, SSR504734 is a potent and selective GlyT1 inhibitor, exhibiting activity in schizophrenia, anxiety and depression models. By targeting one of the primary causes of schizophrenia (hypoglutamatergy), it is expected to be efficacious not only against positive but also negative symptoms, cognitive deficits, and comorbid depression/anxiety states.

The age-constrained pollen data of a sedimentary sequence from the crater Lake Masoko, southern Tanzania (9‡20PS, 33‡45PE, 770 m), display a continuous record of vegetation for the past 4200 years. This record provides evidence that wetter Zambezian woodlands always occupied this area during the late Holocene, reaching a maximum extent between 2800 and 1650 cal yr BP related to increase in summer monsoon intensity. However, three main episodes of decline have been detected, between 3450 and 2800 cal yr BP, between 1650 and 1450 cal yr BP and from 1200 to 500 cal yr BP, for which a climatic interpretation, decrease in the summer monsoon strength, was preferentially advanced. The first is synchronous with lowstand of many tropical African lakes and, so, mainly induced by increased aridity. In contrast, the abrupt change in the pollen record at 1650^1550 cal yr BP is marked by a large extension of grasslands at the expense of arboreal cover, further by an increase in Ricinus communis and an intensification of burning. It could thus indicate local clearance of vegetation by man. However, at the same time, the decline of montane forest suggests the impact of a more regional change. During the last episode, between 1200 and 500 cal yr BP, dry climatic conditions are inferred from a combination of pollen, diatom and magnetic proxies, although the occurrence of Late Iron Age settlements in the region means that local human interference cannot be excluded. This study illustrates the difficulties in deciphering ecological and anthropological changes from pollen data in African tropical regions. A 2003 Elsevier B.V. All rights reserved.

Charcoal analysis from a short core in a small tropical crater lake (Lake Masoko, SW Tanzania) reveals changes in charred-particle deposition and properties, consistent with high climatic variability for the last 4200 years. This is evidenced by automated image analysis of charcoal size distributions, thermal resistant carbon (soot) and black carbon elemental analysis. Charcoal-particle transport in the lake decreases during dry spells, and increases with stronger runoff regime in the catchment area under humid periods and/or during abrupt low-stands of the lake. However, between 1830 and 1560 cal. yr BP, charcoal-distribution variability and an abrupt increase in particulate carbonaceous particles testify to regional emissions from forest fires and atmospheric transport. This event was followed by a prolonged period of material accumulation but regional climatic drying. After 1560 cal. yr BP, large charcoal fragment accumulation and a rise in the length:width ratio of microcharcoal indicate fires closer to the lake and the opening of the local woodland. These new data give evidence of large-scale fire development just prior to a pollen-inferred vegetation change and late Iron Age activity in the area, which probably coincide with an altered fire regime. In fact, charcoal-size distribution and particulate carbon elemental analysis constrain the sources of fossil carbonaceous particles, and provide an accurate proxy of fire and climatic change in southern tropical Africa.

In the central sector of the Main Ethiopian Rift, the Ziway–Shala lake basin system includes four present-day residual lakes, from north to south, lakes Ziway, Langano, Abijata, and Shala. This region of East Africa is under the influence of the Intertropical Convergence Zone seasonal migration. Thus it has been designated as a potential core site by the ERICA Project (`Environmental Research for Intertropical Climate in Africa'). The four lakes have been subjected to strong changes in water level and water salinity at least during the Late Pleistocene. The purpose of this study is to produce a model of basin formation and sediment accumulation for this system of lakes, in order to separate the effects of climatic change from environmental variations induced by local or regional factors such as volcano-tectonic forcings. In addition to an exhaustive synthesis of available data, various investigations have been used to develop this model: 3D remote sensing, high-resolution seismics, coring, and structural, sedimentological, and hydrological field studies. New AMS radiocarbon dating helped to refine the pre-existing stratigraphic framework for this region, and basin age estimations were calculated using mean sediment accumulation rates. The history of the Ziway–Shala lake basin system has been reconstructed from the Late Pliocene–Early Pleistocene period (106 yr), mainly characterized by catastrophic explosive volcanic eruptions. The early-middle Pleistocene–Late Pleistocene period (104–106 yr) was marked by a regional volcano-tectonic paroxysm, resulting in major changes in the morphology of the area, with the formation of the Abijata, Ziway and Shala lake basins. From ∼0.20 Ma, the Ziway–Shala basin history is marked by the eastward migration of volcano-tectonic activity, resulting in the development of the youngest basin of the Ziway–Shala system, the Langano Basin. The joint history of sedimentation in the Ziway, Langano, Abijata, and Shala lake basins started during the early-Late Pleistocene period (101–104 yr) and is characterized from this period up to the present-day by a series of climatically controlled rises and falls of lake level.

5-Hydroxytryptamine (5-HT)2A antagonists are promising therapeutic agents for the treatment of sleep maintenance insomnias, but unlike hypnotics, they have limited effects on sleep initiation. This study evaluated the effects of several 5-HT₂A antagonists (eplivanserin, volinanserin and AVE8488) alone and/or in combination with the short-acting hypnotic, zolpidem, on the rat sleep profile. A repeated-measures design was used in which rats were treated with eplivanserin (3 and 10 mg/kg, i.p. or p.o.), volinanserin (0.3-3 mg/kg, i.p.), AVE8488 (0.1-3 mg/kg, i.p.) and zolpidem (3 and 10 mg/kg, p.o.). In addition, animals received a combination of eplivanserin (3 mg/kg, p.o.) and zolpidem (3 mg/kg, p.o.). Electroencephalogram was analyzed for 6 h after administration. Eplivanserin did not modify wakefulness and non-rapid eye movement sleep (NREMS), while zolpidem (10 mg/kg po) induced a marked increase in NREMS duration. Volinanserin (1 and 3 mg/kg) and AVE8488 (0.3 mg/kg) similarly increased NREMS, while reducing wakefulness. Moreover, the 5-HT₂A antagonists and, to a lesser extent, zolpidem, increased duration of NREMS episodes, while decreasing their frequency. When eplivanserin was co-administered with zolpidem, a synergistic effect was observed as the combination produced an increase in NREMS time and bouts duration. These findings confirm further that 5-HT₂A antagonists promote the maintenance of sleep, and suggest that combining a 5-HT₂A antagonist with a short-acting hypnotic may be a useful strategy for the treatment of insomnia.

Le Moyen Atlas marocain est une région climatiquement sensible aux variations des masses d’air de la mer Méditerranée, du désert du Sahara et de l’océan Atlantique. Cette région recèle plusieurs retenues d’eaux naturelles généralement à l’abri des perturbations anthropiques. Une carotte sédimentaire d’environ 10 mètres de longueur extraite du centre du lac Iffer a fourni un enregistrement des conditions paléoclimatiques et paléohydrologiques du Moyen Atlas durant les derniers 6 500 ans. L’étude de la granulométrie, la géochimie élémentaire ainsi que la mesure des teneurs en carbone organique, des carbonates et de la susceptibilité magnétique des sédiments montrent que la séquence est formée d’une alternance de sédiments détritiques et de sédiments relativement riches en matière organique d’origine terrestre et aquatique liée aux conditions climatiques et environnementales régionales.Les résultats montrent que :– la base de la séquence, dont l’âge remonterait à ~6 500 ans BP, est formée de sables carbonatés qui témoignent des conditions climatiques arides associées aux faibles apports hydriques,– la période 4 600-2 000 ans BP est caractérisée par l’installation de conditions climatiques plus humides traduites par des hauts niveaux lacustres entrecoupés par des événements relativement arides de courtes durées,– à partir de 2 000 ans BP, on assiste à une anthropisation qui se traduit par le recul des forêts et l’intensification des activités agricoles. Cette déforestation est indiquée par un déséquilibre total des profils pédologiques (érosion des sols) et par des flux détritiques très importants arrivant dans le lac. Moroccan middle Atlas is a climatically sensitive area to the influence of Mediterranean sea, Saharan desert and Atlantic ocean air masses. It encloses several natural small lakes preserved from anthropogenic perturbations. A ten-meter-long core from Iffer lake provided a record of palaeoclimatic and paleohydrologic conditions in the Middle Atlas during the last 6 500 years. Magnetic susceptibility, organic and inorganic geochemistry and granulometry show that lake sediments contain detrital silt layers rich in organic matter alternating with marl layers rich in authigenic carbonates linked to the regional climatic variability.The main results are:– lacustrine records started at about 6 500 years BP with yellowish carbonate-rich sands corresponding to the lake settlement. This period was characterized by warm and dry climate,– the 4 600-2 000 years BP period is characterized by the establishment of wetter climatic conditions with high lake level levels interspersed by relatively abrupt dry events,– during the last 2 000 years, the human impact due to increasing pastoral and agricultural activities caused the decline of forest. This deforestation is indicated by a strong disequilibrium of pedological profiles (erosion of soils) and high detrital inputs in the lake.

The objective of the present study was to compare the awakening effects of two newly discovered H₃ receptor antagonists (i.e. SAR110894 and SAR110068) with those of reference H₃ receptor ligands (i.e. ciproxifan, ABT-0239 and GSK189254) and classical psychostimulants (i.e. amphetamine and modafinil) by using EEG recording in rats during their light phase. Results showed that SAR110068 (10 and 30 mg/kg, p.o.) increased wakefulness and decreased slow wave sleep to a similar degree than ciproxifan (10 mg/kg, i.p.), ABT-0239 (10 mg/kg, p.o.) and GSK189254 (10 mg/kg, p.o.), while SAR110894 (3-30 mg/kg, p.o.) did not modify significantly any of the sleep/wakefulness parameters. Time-course analysis revealed that the awakening effects of GSK189254 lasted for about 1h, while ciproxifan, ABT-0239 and SAR110068 produced such effects for 3-4 h. The magnitude of the awakening effects of the psychostimulants, amphetamine (3 mg/kg, i.p.) and modafinil (300 mg/kg, i.p.), was dramatically higher than with the H₃ compounds, and they lasted for 5 and 6 h, respectively. However, unlike the H₃ receptor antagonists, both psychostimulants produced a strong increase in theta (θ) rhythm, which is indicative of CNS side effects, such as hyperactivity or abnormal excitation. In conclusion, this study provides further evidence to support the potential use of H₃ receptor antagonists in the treatment of vigilance and sleep-wake disorders such as narcolepsy.

SSR181507 ((3-exo)-8-benzoyl-N-(((2S)7-chloro-2,3-dihydro-1,4-benzodioxin-1-yl)methyl)-8-azabicyclo(3.2.1)octane-3-methanamine monohydrochloride) is a novel tropanemethanamine benzodioxane that displays antagonist activity at dopamine D(2) receptors and agonist activity at 5-HT(1A) receptors. SSR181507 antagonized apomorphine-induced climbing in mice and stereotypies in rats (ED(50) of 2 and 3.4 mg/kg i.p., respectively) and blocked D-amphetamine-induced hyperlocomotion in rats at lower doses (0.3-1 mg/kg i.p.). At 1-10 mg/kg, it was found to disrupt active avoidance in mice. SSR181507 did not induce catalepsy in rats (MED>60 mg/kg i.p.) and antagonized (3-10 mg/kg i.p.) haloperidol-induced catalepsy. SSR181507 was also active in two models sensitive to antidepressant/anxiolytic drugs: in a guinea-pig pup/mother separation test, it decreased (1-3 mg/kg i.p.) the time spent vocalizing during the separation episode, and in a lithium-induced taste aversion procedure in rats, it partially reversed (3 mg/kg i.p.) the decrease of intake of a saccharin solution. Furthermore, SSR181507 increased (3 mg/kg i.p.) the latency time to paradoxical sleep in rats, an effect commonly observed with antidepressants. Coadministration of the selective 5-HT(1A) blocker SL88.0338 produced catalepsy and antagonized the effects of SSR181507 in the depression/anxiety tests, confirming the view that activation of 5-HT(1A) receptors confers an atypical profile on SSR181507, and is responsible for its antidepressant/anxiolytic properties. Finally, SSR181507 (1-3 mg/kg) did not affect memory performance in a Morris water maze task in rats. The pharmacological profile of SSR181507 suggests that it should control the symptoms of schizophrenia, in the absence of extrapyramidal signs and cognitive deficits, with the additional benefit of antidepressant/anxiolytic activities.

a UMR CNRS 6538 ‘‘Domaines Oceaniques’’, Institut Universaire Europeen de la Mer, Universite de Bretagne Occidentale, place Nicolas Copernic, 29280 Plouzane, France b EP 1748 CNRS, Equipe Hydrologie, Paleohydrologie et Paleoenvironnement, Universite Paris-Sud, Bâtiment 504, 91405 Orsay Cedex, France c Laboratoire d’Hydrogeologie, Universite d’Avignon et des Pays du Vaucluse, 33 rue Louis Pasteur, 8400 Avignon Cedex, France d 3 Rue des Ajoncs, 64160 Morlaas, France e CEREGE, B.P. 80, 13545 Aix-en-Provence Cedex 04, France f Laboratoire ‘‘Environnements sedimentaires et Stratigraphie’’, Universite de Perpignan, 52 avenue de Villeneuve, 66860 Perpignan, France g Department of Geology and Geophysics, Addis Ababa University, P.O. Box 1176, Addis Ababa, Ethiopia h Royal Belgian Institute of Natural Sciences, Freshwater Biology, Vautierstraat 29, B-1000 Brussels, Belgium i Department of Earth Sciences, Via Universita 4, 41100 Modena, Italy