M. Cavas

Effects of selective neuronal nitric oxide synthase inhibition on sleep and wakefulness in the rat

The role played by the unconventional messenger Nitric Oxide (NO) upon the sleep-wake cycle remains controversial. Evidence suggests a positive role of NO on Slow Wave Sleep (SWS) and Paradoxical Sleep (PS) regulation, favoring sleep. However, other studies have found a role of NO upon wakefulness and alertness, inhibiting sleep. Divergences have been explained in part because of the use of different inhibitors of nitric oxide synthases (NOS). The aim of this study is to analyse the effects of a highly selective neuronal NOS inhibitor (3-Bromo7-Nitroindazole) on sleep-wake states in rats. Male Wistar rats were stereotaxically prepared for polysomnography. 3-Bromo-7-Nitroindazole (10, 20, 40 mg/kg, i.p.) dissolved in DMSO 10% filled with saline, or vehicle (DMSO 10% in saline) was administered at the beginning of the light period. Three hours of polygraphic recordings were evaluated for stages of vigilance. Results show dose-dependent effects of 3-Bromo7-Nitroindazole upon sleep: 10 mg/kg decreases duration and number of episodes of deep SWS, increasing duration of light SWS. 20 mg/kg decreased duration of light and deep SWS, while active and quiet wake increased. Deep SWS and PS latency increased. Number of episodes of PS decreased, as well as number of cycles of sleep and time spent asleep. 40 mg/kg reduced duration of deep SWS and increased mean episode duration of light SWS. Therefore, sleep states are affected by selective inhibition of nNOS, reducing in all cases deep SWS. These results support the hypothesis that nitric oxide, produced by nNOS, is involved in sleep processes, favoring sleep.

Coadministration of l-NOARG and tiapride: Effects on catalepsy in male mice

This study was designed to determine the possible potentiation of catalepsy behavior after coadministration of N(G)-nitro-L-arginine (L-NOARG), an inhibitor of nitric oxide synthase (NOS), and tiapride, a specific antagonist for D2 receptors, in male mice. Catalepsy was measured by the bar test. Two successive evaluations were carried out 60 and 90 min after injections. The induction of catalepsy following coadministration of L-NOARG (25 and 50 mg/kg) and tiapride (200 mg/kg) was significantly higher than the sum of catalepsy scores after administration of L-NOARG and tiapride separately. Coadministration of L-NOARG and tiapride produced a clear potentiation of their effects on catalepsy in mice. These results underline the view that nitric oxide (NO) interacts with central dopamine D2 transmission.

Effects of selective dopamine D4 receptor antagonist, L-741,741, on sleep and wakefulness in the rat.

The influence of the dopamine system upon sleep/wake states is not fully understood. To date, the role of dopamine D4 receptor has not been studied. The aim of this work is to study the influence of dopamine D4 receptor upon sleep/wake states in male rats. Male Wistar rats were implanted with electroencephalography and electromyography electrodes for sleep recording. Sleep/wake times were compared in rats first treated with control solution (vehicle) and the day after treated with a potent and highly selective D4 dopamine receptor antagonist. L-741,741 (1.5, 3, 6 mg/kg) or vehicle solution (10% DMSO in saline) was administered intraperitoneally at the beginning of the light period. Subsequently, 3 h of polysomnography were recorded and sleep-wake parameters evaluated. For statistical comparisons, Wilcoxon ranges test was performed. L-741,741 (1.5 mg/kg) only increased Light Slow Wave Sleep (SWS). 3 mg/kg enhanced Quiet Waking (QW) increasing number of episodes, whereas Active Waking (AW) was reduced decreasing mean episode duration. 6 mg/kg reduced number of episodes of Deep SWS and increased its latency. Light SWS was decreased reducing number of episodes and their duration. Total time spent asleep was reduced and time spent in AW was increased. REM latency was increased. These results suggest a role for D4 receptors in the regulation of wake and sleep.

Cytochrome Oxidase Activity of the Suprachiasmatic Nucleus and Pineal Gland in Rats with Portacaval Shunt

Rhythmic behavioral and biochemical changes have been observed in both human and animal models with hepatic insufficiency. The basis of all these alterations is the principal endogenous pacemaker, the suprachiasmatic nucleus. The aim of this work, therefore, is to determine cytochrome c oxidase activity, a marker of neuronal activity and oxidative metabolism, in this nucleus in rats with portacaval shunt. In order to do this, this enzyme was histochemically marked and quantified by computer-assisted optical densitometry. Results show a reduced cytochrome oxidase activity in the suprachiasmatic nucleus in animals with portacaval shunts and, inversely, an increase in oxidative metabolism in the pineal gland, another circadian structure. However, the activity measured in a noncircadian brain structure, the hippocampus, which served as a control, showed no changes with surgery. Additionally, locomotor activity was assessed by actimeters and revealed a clearly reduced activity in animals with portacaval shunt. We conclude that the suprachiasmatic nucleus is possibly involved in the rhythmic changes associated with hepatic insufficiency.

Effects of MPEP, a selective metabotropic glutamate mGlu5 ligand, on sleep and wakefulness in the rat.

Metabotropic glutamate receptors (mGlu) have been implicated in the regulation of physiological and behavioral processes. Pharmacological evidence involves group I mGlu receptors in the regulation of emotional states and antagonism of these receptors has been proposed as a novel class of anxiolytic drugs having also antidepressant effects. Here, the effects of mGlu5 receptor selective modulation on sleep and wake states are explored. 32 male Wistar rats were implanted with electrodes for recording sleep and wake states. 2-Methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP hydrochloride, 5, 10, and 20 mg/kg, i.p.), a potent, selective and systemically active mGlu5 receptor negative allosteric modulator, or vehicle was administered 1 h after the beginning of the light period. Sleep recordings were conducted for 3 h. MPEP (5, 10, and 20 mg/kg) significantly suppressed rapid eye movement (REM) sleep, decreasing the number of episodes and mean episode duration, and increased its latency. A reduction of light and deep slow wave sleep (SWS) latency was observed in the groups receiving 10 or 20 mg/kg, increasing latency to first wakefulness episode. 10 mg/kg of MPEP also increased non rapid eye movement sleep (NREM). The present results suggest that mGlu5 receptors might be involved in sleep regulation, more specifically in REM sleep, and drugs that block these receptors could potentially benefit the treatment of pathologies were REM sleep is enhanced.

Acidos grasos omega-3 y enfermedades neuropsiquiátricas

Los acidos grasos poliinsaturados omega-3 desempenan un destacado papel en el correcto funcionamiento de la membrana neuronal. Numerosos estudios sugieren que el consumo de suplementos de estos compuestos (especialmente acido eicosapentanoico [EPA] y acido docosahexanoico [DHA]) podria producir una mejoria clinica en algunas enfermedades neuropsiquiatricas. En este trabajo se presenta una revision actualizada de la evidencia disponible en relacion con el uso de acidos grasos omega-3 en el tratamiento de la esquizofrenia, la depresion, el trastorno bipolar y otras enfermedades neuropsiquiatricas.

Effects of para-methoxyamphetamine (PMA) on agonistic encounters between male mice

ABSTRACT Para‐methoxyamphetamine (PMA) is a synthetic drug chemically similar to the recreational drug 3,4‐methylenedioxy‐methamphetamine (MDMA or “ecstasy”) and often replaces MDMA in tablets that show an “ecstasy” logo. PMA displays a higher toxic potential than MDMA, but the behavioral profile of PMA has been scarcely studied in animal models. Here we evaluated the effects of PMA (2, 4, 8, and 12mg/kg, i.p.) on agonist encounters between male mice using an ethopharmacological approach, the isolation‐induced aggression model. Likewise, since PMA and MDMA share common mechanisms of action, we compared the behavioral profile of PMA with that induced by MDMA (8mg/kg, i.p.) which behavioral effects in this model are well characterized. Individually housed mice were exposed to anosmic standard opponents 30min after drug administration. The encounters were videotaped and evaluated using an ethologically based analysis. PMA (all doses) significantly reduced offensive behaviors (threat and attack), however, a detailed behavioral analysis suggests that the observed antiaggressive effect seems to be unspecific, showing a complex dose‐dependent behavioral profile. Thus, antiaggresive actions observed after the administration of the lowest dose were accompanied by increases in social investigation, avoidance/flee behaviors and non‐social explorations, together with a reduction of digging behavior. This pattern reflects both approach‐contact behaviors and avoidance‐flee behaviors. From 4mg/kg to 12mg/kg, the increase in social investigation previously observed disappears, and there is a slight increase in immobility, together with a different behavioral pattern that suggests anxiogenic effects of PMA, similar to those reported after the administration of MDMA. The higher doses of PMA exhibit a behavioral profile very similar to that observed in animals treated with MDMA, with the exception of the immobility produced by PMA. These findings show for the first time the non‐specific antiaggressive profile of PMA in the model of aggression induced by isolation in male mice. HIGHLIGHTSUnlike the MDMA, PMAs action on aggression has not yet been assessed.PMA drastically reduced aggressive behavior in male mice, but unspecifically.PMA (2mg/kg) shows both approach‐contact behaviors and avoidance‐flee behaviors.PMA (4–12mg/kg) increased immobility behaviors and showed an anxiogenic profile.MDMA shows an antiaggressive‐anxiogenic profile, but does not produce immobility.

Selective agonism of mGlu8 receptors by (S)-3,4-dicarboxyphenylglycine does not affect sleep stages in the rat

BACKGROUND Metabotropic glutamate receptors (mGlu) play a role in a number of physiological processes and behaviors, as well as in certain pathological conditions and diseases. New drugs targetting mGlu receptors are being developed with treatment purposes. Recent data indicates that glutamate is involved in sleep, and pharmacological manipulation of distinct subtypes of mGlu receptors affect sleep. Here the consequences of selective pharmacological agonism of mGlu8 receptor upon sleep and wakefulness are explored for the first time. METHODS 32 male Wistar rats were stereotaxically prepared for polysomnography. (S)-3,4-dicarboxyphenylglycine (S)-3,4-DCPG (5, 10, and 20mg/kg, ip), a selective and potent mGlu8 receptor agonist, or physiological saline was administered one hour after the light period began. RESULTS Compared to control vehicle, (S)-3,4-DCPG, did not affect, at any of the doses given, the sleep and wakefulness parameters examined in the general analysis of the three hours of recording. Drug effects across time were studied analyzing three one-hour time blocks, control and experimental groups did not show any significant difference in the sleep and wakefulness parameters analyzed. Latency to sleep stages did not significantly vary between vehicle and treatment groups. CONCLUSIONS Results indicate that pharmacological activation of mGlu8 receptor by (S)-3,4-DCPG (5, 10, 20mg/kg, ip) does not affect sleep and wakefulness in the rat, suggesting that pharmacological agonism of these receptors may not influence sleep. Further research is needed to verify whether new drugs acting on these receptors lack of effect upon sleep and wakefulness.