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

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 12 mg/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 (8 mg/kg, i.p.) which behavioral effects in this model are well characterized. Individually housed mice were exposed to anosmic standard opponents 30 min 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 4 mg/kg to 12 mg/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.

Papel de la oxitocina en la regulación de la agresión / Role of oxytocin in the regulation of aggression

La oxitocina (Oxt) es un neuropéptido especialmente relevante por su implicación en las conductas sociales y de afiliación, incluyendo la regulación de la conducta agresiva. En este artículo presentamos una revisión actualizada que examina la relación entre la Oxt y la agresión en modelos animales. La recopilación de artículos se realizó a través de una búsqueda combinada en las bases de datos Web of Knowledge, Scopus y Pubmed (1990-septiembre 2016). Los resultados de estos estudios incluyen evidencias que proceden de la administración de Oxt intranasal, intracerebral, intracerebroventricular, o sus antagonistas, de estudios de lesión, microdiálisis, así como de trabajos con animales modificados genéticamente. En conjunto, los resultados indican que tanto en roedores machos como en hembras la Oxt modula la agresión, aunque no siempre lo hace en el mismo sentido. Se concluye que en la agresión ofensiva la Oxt ejerce generalmente un papel inhibitorio sobre la agresión, mientras que en la agresión maternal se ha observado tanto un papel facilitador como inhibidor, dependiendo de diferentes factores. Se sugiere la necesidad de analizar las variables contextuales e individuales que podrían estar modulando la acción de la Oxt sobre la agresión (AU)

Oxytocin (Oxt) is a neuropeptide particularly relevant for its involvement in social and affiliation behaviours, including the regulation of aggressive behaviours. An updated review is presented, examining the relationships between oxytocin and aggression in animal models. The articles for review were gathered using a combined search on Web of Knowledge, Scopus, and PubMed databases (from 1990 to September 2016). The results of these studies include evidence derived from intranasal, intraventricular and intra-cerebro-ventricular Oxt administration, or from antagonist drugs, lesion studies, microdialysis, as well as works with genetically modified animals. Overall, the results indicate that Oxt modulates aggression both in male and female rodents, although it does not always act in the same direction. It is concluded that Oxt generally exerts an inhibitory role in offensive aggression, whereas in maternal aggression both a facilitating as well as an inhibitor role has been observed, depending on different factors. It is suggested that there is a need to analyse the contextual and individual variables that might be modulating the Oxt action in aggression (AU)

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.

Estudio de la instigación social en un modelo de agresión inducida por aislamiento: efectos de la administración de JNJ16259685, un antagonista de receptores mGlu1 / Study of the Social Instigation in a Model of Isolation-Induced Aggression: Effects of JNJ16259685 Administration, an mGlu1 Receptor Antagonist

La instigación social intensifica la conducta agresiva permitiendo observar niveles más extremos de agresión. Estudios recientes indican que el receptor metabotrópico del glutamato mGlu1 está implicado en la regulación de la conducta agresiva en un modelo de agresión inducida por aislamiento. El objetivo de este trabajo fue evaluar los efectos de la administración de un antagonista del receptor mGlu1 (JNJ16259685) sobre la conducta agresiva normal e intensificada, utilizando instigación social en un modelo animal de agresión inducida por aislamiento. Varios grupos de animales aislados fueron expuestos a 5 minutos de instigación social, recibiendo la mitad de ellos JNJ16259685 (0.5 mg/kg, ip) o vehículo. Las interacciones agonísticas de 10 min de duración se realizaron en un área neutral 30 min después de la inyección. Dichos encuentros fueron grabados en vídeo para el posterior análisis etológico de diez categorías conductuales. La instigación redujo la latencia de ataque y aumentó la frecuencia y duración de los ataques frente a los animales no instigados. La administración de JNJ16259685 redujo de forma significativa la conducta agresiva en ambos casos, sugiriendo la implicación del receptor mGlu1 en la modulación de la agresión normal e intensificada.

Social instigation intensifies aggressive behavior in rodents allowing observe more extreme levels of aggression. Recent studies indicate that glutamate metabotropic receptor 1 (mGlu1) are involved in the regulation of aggressive behavior in isolation-induced aggression model. The object of this work was to examine social instigation in an animal model of isolation-induced aggression and assess the anti-aggressive effects of an mGlu1 receptor antagonist (JNJ16259685) on normal and heightened aggressive behavior. Several groups of individually housed mice were exposed to 5 minutes of social instigation, and half of them received an acute administration ofJNJ16259685 (0.5 mg/kg, ip) or vehicle. Ten minute of dyadic interactions were staged between a singly housed and an anosmic mouse in a neutral area 30 min after drug or vehicle administration. The encounters were videotaped for subsequent analysis of ten ethological behavioural categories. Social instigation reduced latency of attack and increased the frequency and duration of attacks against not instigated animals. JNJ16259685 administration significantly reduced aggressive behavior in both cases, suggesting the involvement of mGlu1 receptor in the modulation of normal and heightened aggression.

Efectos de la administración de LY354740, un agonista selectivo del grupo II de receptores metabotrópicos de glutamato, sobre la conducta agresiva en ratones / Effects of LY354740, a selective agonist of Glutamate metabotropic group II receptors, on aggressive behavior in mice

Estudios recientes han demostrado una implicación de los receptores metabotrópicos mGlu1 y mGlu5 en la regulación de la conducta agresiva. Este trabajo examina el efecto de la administración de LY354740 (4-16 mg/kg ip), un agonista selectivo de los receptores metabotrópicos del grupo II (mGlu2/3), en encuentros agonísticos entre ratones macho, utilizando un modelo de agresión inducida por aislamiento. Treinta minutos tras la administración del fármaco, se llevaron a cabo interacciones agonísticas de 10 min de duración entre un animal aislado y un oponente anósmico en un área neutral. Dichos encuentros fueron grabados, para su posterior análisis etológico, estimándose el tiempo pasado por los ratones en cada una de diez categorías conductuales. LY354740 (12 y 16 mg/kg) redujo significativamente las conductas ofensivas, sin afectar la motilidad, en comparación con el grupo control. Estos resultados sugieren una implicación de los receptores mGlu del grupo II, en la modulación de la agresión.

Recent studies have demonstrated that glutamate metabotropic receptors mGlu1 and mGlu5 are involved in the regulation of aggressive behaviour. This study examines the effect of the administration of LY354740 (4-16 mg/kg i.p.), a selective group II metabotropic receptors agonist (mGlu2/3), using an isolation-induced aggression model. Individually housed mice were exposed to anosmic opponents 30 min after drug administration. Ten min of diadic interactions were staged between a singly housed and an anosmic mouse in a neutral area. The encounters were videotaped and the accumulated time allocated by subjects to ten broad behavioural categories was estimated using an ethologically based analysis. LY354740 (12 and 16 mg/kg) significantly reduced offensive behaviours, without affecting immobility, as compared with the control group. These results suggest an implication of mGlu group II receptors in the modulation of aggression.

Papel del glutamato en la regulación de la conducta agresiva en modelos animales / Role of glutamate in regulating aggresive behavior in animal models

En este trabajo se presenta una revisión actualizada del papel del glutamato en la regulación de la conducta agresiva. El glutamato es el principal neurotransmisor excitador en el sistema nervioso central. Una vez liberado desde las vesículas presinápticas, se une a receptores postsinápticos ionotrópicos (NMDA, AMPA y kainato). Asimismo, activa receptores metabotrópicos (mGluR) que modulan su liberación, la respuesta postsináptica, así como la actividad de otras sinapsis. Tanto los receptores ionotrópicos como los receptores metabotrópicos (mGlu) de glutamato han sido implicados en la modulación de la conducta agresiva en modelos animales. En este sentido, estudios recientes han encontrado una reducción de la agresión en ratones que carecen de la subunidad GluR-A de los receptores AMPA. Asimismo, los receptores mGlu del grupo I (mGlu1 y mGlu5) han sido también claramente involucrados en la regulación de la agresión en roedores, utilizando un modelo animal de agresión inducida por aislamiento. Estos resultados sugieren una marcada implicación del glutamato en el control de la conducta agresiva (AU)

The present article provides an updated review of the role of glutamate in regulating aggressive behavior. Glutamate is the main excitatory neurotransmitter in the central nervous system. Once released from the presynaptic vesicles, glutamate binds to postsynaptic ionotropic receptors (NMDA, AMPA and kinate). Likewise, glutamate activates metabotropic receptors (mGluR) that modulate its release, postsynaptic response, and the activity of other synapses. Both ionotropic and metabotropic receptors (mGlu) of glutamate have been implicated in the modulation of aggressive behavior in animal models. Recent studies have found reduced aggression in rats lacking the GluR-A subunit of AMPA receptors. Group I mGlu receptors (mGlu1 and mGlu5) have also been clearly implicated in the regulation of aggression in rodents in an animal model of isolation-induced aggression. These results suggest that glutamate is significantly involved in the regulation of aggressive behavior (AU)

Papel de las subunidades alfa del receptor GABAA en la regulación de la conducta agresiva / Role of alpha subunits of the GABAA receptor in the regulation of aggressive behavior

El ácido gamma-aminobutírico (GABA) es el principal neurotransmisor inhibidor del sistema nervioso, y realiza sus principales acciones farmacológicas mediante el receptor ionotrópico GABAA, cuya composición más frecuente es la formada por la combinación de subunidades (α1)2(β2)2γ2. Las características farmacológicas del receptor GABAA parecen depender de la subunidad alfa que se encuentre en cada subtipo de receptor. Aunque numerosos estudios han implicado al receptor de GABAA en la modulación de la conducta agresiva, aún no conocemos el papel preciso que las distintas subunidades alfa tienen en la agresión. La razón principal es la dificultad para conseguir ligandos que muestren selectividad específica por las subunidades alfa. La introducción de nuevas estrategias que incluyen el uso de modelos animales knock-out y knock-in, el empleo de ligandos con actividad agonista parcial frente a total y los nuevos compuestos con eficacia selectiva abren nuevos horizontes en el estudio del grado de participación que tienen las distintas subunidades alfa del receptor GABAA en la agresión (AU)

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain and exerts its main actions via ionotropic GABAA receptors, the most abundant subunit combination being (α1)2(β2)2γ2. The pharmacological characteristics of GABAA receptor appear to depend on the alpha subunit, which is present in each receptor subtype. Although numerous studies have implicated GABAA receptors in the modulation of aggressive behavior, the precise role of the distinct alpha subunits in aggression is not well characterized. The main reason is the difficulty of obtaining ligands that exhibit specific selectivity for the α-subunits. The introduction of new strategies that include the use of "knock-out" and "knock-in" animal models, the use of ligands with partial versus total agonist activity, as well as the existence of new compounds with selective efficacy open new perspectives for studying the degree of involvement of the distinct alpha subunits in aggression (AU)

Behavioural profile of selective ligands for mGlu7 and mGlu8 glutamate receptors in agonistic encounters between mice / Perfil conductual de ligandos selectivos para los receptores de glutamato mGlu7 y mGlu8 en encuentros agonísticos entre ratones

Evidence is accumulating for a role of glutamate transmission in aggression modulation. Recent studies indicate that glutamate metabotropic receptors (mGlu1 and mGlu5) are involved in the regulation of aggressive behaviour. However, to date, the possible role of mGlu7 and mGlu8 receptors has not been explored. In this work, we analyze the effect of acute administration of AMN082 (0.5-4mg/kg, ip) and (S)-3,4-DCPG (2.5-10 mg/kg, ip), selective ligands for the mGlu7 and mGlu8 receptors, respectively, on agonistic encounters between male mice. Individually housed mice were exposed to anosmic opponents 60 or 30 min after drug administration. Ten min of dyadic interactions were staged between a singly housed and an anosmic mouse in a neutral area. The encounters were videotaped and the accumulated time allocated by subjects to ten broad behavioural categories was estimated using anethologically based analysis. The highest dose of AMN082 (4 mg/kg) significantly reduced offensive behaviours (threat and attack), as compared with the control group, without depressing motility, whereas (S)-3,4-DCPG did not produce significant behavioural changes. Overall, these results suggest that mGlu7 receptors (but not mGlu8) may be implicated in the modulation of aggression (AU)

Existe una evidencia creciente de la implicación del glutamato en la modulación de la agresión. Estudios recientes indican que los receptores metabotrópicos de glutamato (mGlu1 y mGlu5) están involucrados en la regulación de la conducta agresiva. Sin embargo, el posible papel de los receptores mGlu7 y mGlu8 no ha sido aún examinado. En este trabajo analizamos el efecto de la administración aguda de AMN082 (0.5-4 mg/kg) y (S)-3,4-DCPG (2.5-10 mg/kg), ligandos selectivos para los receptores mGlu7 y mGlu8, respectivamente, sobre los encuentros agonísticos entre ratones machos. Se llevaron a cabo interacciones agonísticas de 10 minutos de duración entre un animal aislado y un oponente anósmico en un área neutral, tras 60 y 30 minutos de la administración de ambos fármacos. Dichos encuentros fueron grabados en vídeo para su análisis etológico mediante un programa de ordenador, estimándose el tiempo pasado por los ratones en cada una de diez categorías conductuales. AMN082 (4 mg/kg) redujo significativamente las conductas ofensivas, sin disminuirla motilidad, en comparación con el grupo control, mientras que la administración de (S)-3,4-DCPG no produjo cambios conductuales significativos. Estos resultados sugieren que los receptores mGlu7(pero no los mGlu8) podrían estar implicados en la modulación de la agresión (AU)

Behavioural profile of selective ligands for mGlu7 and mGlu8 glutamate receptors in agonistic encounters between mice.

Evidence is accumulating for a role of glutamate transmission in aggression modulation. Recent studies indicate that glutamate metabotropic receptors (mGlu1 and mGlu5) are involved in the regulation of aggressive behaviour. However, to date, the possible role of mGlu7 and mGlu8 receptors has not been explored. In this work, we analyze the effect of acute administration of AMN082 (0.5-4 mg/kg, ip) and (S)-3,4-DCPG (2.5-10 mg/kg, ip), selective ligands for the mGlu7 and mGlu8 receptors, respectively, on agonistic encounters between male mice. Individually housed mice were exposed to anosmic opponents 60 or 30 min after drug administration. Ten min of dyadic interactions were staged between a singly housed and an anosmic mouse in a neutral area. The encounters were videotaped and the accumulated time allocated by subjects to ten broad behavioural categories was estimated using an ethologically based analysis. The highest dose of AMN082 (4 mg/kg) significantly reduced offensive behaviours (threat and attack), as compared with the control group, without depressing motility, whereas (S)-3,4-DCPG did not produce significant behavioural changes. Overall, these results suggest that mGlu7 receptors (but not mGlu8) may be implicated in the modulation of aggression.

Effects of (RS)-3,4-DCPG, a mixed AMPA antagonist/mGluR8 agonist, on aggressive behavior in mice.

INTRODUCTION: Ionotropic and metabotropic (mGlu) receptors of glutamate have been suggested to be involved in the modulation of aggression. Thus, recent studies found reduced aggression in AMPA-type glutamate receptor GluR-A subunit-deficient mice. Likewise, mGlu1 and 5 receptors have also been implicated in aggression regulation. (RS)-3,4-DCPG is a mixed antagonist of AMPA receptors and an agonist of mGluR8. The AMPA antagonist activity of this compound is determined by its R isomer while the S isomer is responsible for its mGluR8 agonistic properties. METHODS: We analyzed the effects of (RS)-3,4-DCPG (5, 10 and 20mg/kg, ip) on agonistic encounters between male mice. Individually housed mice were exposed to anosmic opponents 30 min after drug administration. Ten min of dyadic interactions were staged between a singly housed and an anosmic mouse in a neutral area. The encounters were videotaped and the accumulated time allocated by subjects to 10 broad behavioral categories was estimated using an ethologically based analysis. RESULTS AND CONCLUSIONS: The results indicated that (RS)-3,4-DCPG produced no significant behavioral changes, suggesting that antagonism of AMPA receptors by the R isomer and stimulation of mGluR8 by the S isomer do not act synergistically on aggression in the racemic form of 3,4-DCPG.

Actualización del papel de la enzima MAO-A en la regulación de la conducta agresiva / Update of the role of the MAO-A enzyme in regulating aggressive behavior

La monoaminooxidasa A (MAO-A) es una enzima que regula la degradación metabólica de serotonina y noradrenalina en el sistema nervioso. Ambos neurotransmisores han sido claramente involucrados en la modulación de la agresión. De hecho, el sistemas erotoninérgico representa uno de los principales sistemas de neurotransmisión relacionado con la aparición de conductas impulsivas y violentas. En este trabajo se presenta una revisión actualizada del papel de la enzima MAO-A en la regulación de la conducta agresiva, tanto en animales de experimentación como en humanos (AU)

Monoamine oxidase A (MAO-A) is an enzyme that regulates the metabolic degradation of serotonin andnoradrenaline in the nervous system. Both neurotransmitters are clearly involved in modulating aggression. Indeed, the serotonergic system is one of the main neurotransmission systems related to the appearance of impulsive and violent behaviors. The present article provides an updated review of the role of the MAO-A enzyme in regulating aggressive behavior in experimental animals and humans (AU)

Efectos de la administracion de MPEP, un antagonista selectivo de los receptores de glutamato mGlu5, sobre la memoria espacial en ratones / Effects of administration of MPEP, a selective mglu5 receptor antagonist, on spatial memory in mice

Estudios recientes han mostrado que la inhibición de los receptores mGlu5 perjudica el aprendizaje espacial evaluado con una tarea en el laberinto acuático con ratones, lo que indica una implicación de estos receptores en el aprendizaje y la memoria. En un intento por esclarecer la participación de los receptores mGlu5 en los procesos de aprendizaje, hemos examinado los efectos de 2-metil-6-(feniletinil)piridina (MPEP; 10 mg/kg, intraperitoneal), un antagonista selectivo de los receptores de glutamato mGlu5, en el aprendizaje espacial de ratones macho de la cepa OF.1. Para ello, empleamos una tarea de aprendizaje en el laberinto de hoyos adaptada a ratón, que nos permite valorar simultáneamente la memoria de trabajo (MT) y la memoria de referencia (MR) espacial. El laberinto de hoyos consiste en un campo abierto que consta de 16 hoyos. Durante los ensayos, la misma configuración de 4 hoyos reforzados permanece constante durante el entrenamiento. Los animales deberían aprender a visitar sólo las localizaciones reforzadas y hacerlo una sola vez, recordando la lista de lugares ya visitados para evitar las revisitas. Nuestros resultados mostraron que los ratones adquirieron fácilmente este hábito a los 5 días (4 ensayos por día). El último día, 30 min antes del entrenamiento, los animales fueron tratados con solución salina (grupo control) o con MPEP. No encontramos diferencias significativas entre ambos grupos. Estos hallazgos indican que la administración aguda de MPEP (10 mg/kg) no afecta la MT y la MR espacial en ratones macho. Se hacen necesarios otros estudios con mayores dosis del fármaco y otras situaciones de prueba para confirmar estos resultados

Recent studies have found that mGlu5 receptor blockade impairs spatial learning tested in a water maze task in mice, suggesting that these receptors might play a role in learning and memory. To clarify the involvement of mGlu5 receptors in spatial learning processes, we examined the effects of 2-methyl-6-(phenylethylnyl) pyridine (MPEP; 10 mg/kg, i.p.), a selective mGlu5 receptor antagonist, on spatial learning in male mice of the OF.1 strain. To do this, we adapted a hole-board-learning task to mice. This task allows simultaneous assessment of spatial working memory (WM) and reference memory (RM) performance. The hole-board apparatus consists of an open-field with a 16-hole floor. During the trials, a configuration of 4 holes baited with a food pellet was unchanged throughout training. The animals had to learn to visit only baited locations and to visit them only once, remembering a list of places already visited in order to avoid revisits. Our results showed that the mice readily acquired this task within 5 days (4 trials per day). On the last day, 30 minutes before training, the animals were administered either saline solution (control group) or MPEP. No significant differences were found between the two groups. These findings indicate that acute administration of MPEP (10 mg/kg) did not affect spatial WM or RM in male mice. Further studies with higher doses of the drug and other test situations are required to confirm these results (AU)

JNJ16259685, a selective mGlu1 antagonist, suppresses isolation-induced aggression in male mice.

mGlu1 receptors are present in brain regions involved in aggression modulation. This study examines the effects of 3-4-Dihydro-2H-pyrano[2,3-b]quinolin-7-yl-(cis-4-methoxycyclohexyl)-methanone (JNJ16259685; 0.125, 0.25, 0.5, 1, 2, 4 and 8 mg/kg, i.p), a selective antagonist of the mGlu1 receptors, on agonistic interactions between male mice. Individually housed mice were exposed to anosmic "standard opponents" 30 min after drug administration. Ten minutes of diadic interactions was staged between a singly housed and an anosmic mouse in a neutral area. The encounters were videotaped and the accumulated time allocated by subjects to ten broad behavioural categories was estimated using an ethologically based analysis. JNJ16259685 (all doses) produced a significant reduction of offensive behaviours (threat and attack), without affecting immobility. These findings suggest for the first time a role for mGlu1 receptors in aggression regulation.

Effects of SB-205384, a positive modulator of α3-subunit-containing GABA-A receptors, on isolation-induced aggression in male mice / Efectos del SB-205384, un modulador positivo de los receptores GABA-A que contienen la subunidad α3, sobre la agresión inducida por aislamiento en ratones machos

GABA-A receptors are involved in the control of aggressive behaviour. Various studies suggest a role for a1-containing GABA-A receptors in modulating aggression. However, the possible involvement of a3 subunit of GABA-A receptors has not been examined. In this study, we analysed the effect of SB-205384 (0.5-4 mg/kg, i.p), a positive modulator of GABA-A receptors containing a3 subunit, on agonistic behaviour elicited by isolation in male mice. Half of the mice were housed during 30 days and employed as experimental or control animals; the remainder were used as «opponents» and were temporally rendered anosmic by zinc sulphate. Individually housed mice were exposed to anosmic opponents in a neutral area 30 minutes after the drug administration and encounters were videotaped and evaluated using an ethopharmacologically-based analysis. The results indicated that SB-205384 did not produce any significant behavioural changes, suggesting that GABA-A receptors which contain the α3 subunit may not be involved in the modulation of aggression (AU)

Los receptores GABA-A están involucrados en el control de la conducta agresiva. Diversos estudios sugieren un papel de los receptores GABA-A que contienen la subunidad a1 en la modulación de la agresión. Sin embargo, la posible implicación de los receptores que contienen la subunidad a3 no ha sido examinada. En este trabajo analizamos el efecto de la administración de SB-205384 (0.5-4 mg/kg, i.p), un modulador positivo de los receptores GABA-A que contienen la subunidad a3, sobre la conducta agonística en ratones machos, utilizando un modelo de agresión inducida por aislamiento. La mitad de los ratones fueron aislados durante 30 días y empleados como animales experimentales o controles; la otra mitad fueron utilizados como «oponentes», siendos anosmiados temporalmente mediante sulfato de zinc. Treinta minutos después de la administración del fármaco se llevaron a cabo interacciones agonísticas de diez minutos de duración entre un animal aislado y un oponente anósmico en un área neutral, grabadas en vídeo para su posterior análisis etológico/conductual mediante ordenador. Los resultados indicaron que el SB-205384 no produjo cambios conductuales significativos, sugiriendo que los receptores GABA-A que contienen la subunidad α3 podrían no estar implicados en la modulación de la agresión (AU)

Effects of SB-205384, a positive modulator of alpha3-subunit-containing GABA-A receptors, on isolation-induced aggression in male mice.

GABA-A receptors are involved in the control of aggressive behaviour. Various studies suggest a role for a1-containing GABA-A receptors in modulating aggression. However, the possible involvement of a3 subunit of GABA-A receptors has not been examined. In this study, we analysed the effect of SB-205384 (0.5-4 mg/kg, i.p), a positive modulator of GABA-A receptors containing a3 subunit, on agonistic behaviour elicited by isolation in male mice. Half of the mice were housed during 30 days and employed as experimental or control animals; the remainder were used as <> and were temporally rendered anosmic by zinc sulphate. Individually housed mice were exposed to anosmic opponents in a neutral area 30 minutes after the drug administration and encounters were videotaped and evaluated using an ethopharmacologically-based analysis. The results indicated that SB-205384 did not produce any significant behavioural changes, suggesting that GABA-A receptors which contain the a3 subunit may not be involved in the modulation of aggression.

Farmacología y aspectos conductuales del receptor a5/GABA-A / Pharmacology and behavioral aspects of the 5/GABA-A receptor

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Efectos de la administración de (RS)-2-cloro-5-hidroxifenilglicina (CHPG) sobre la conducta agonística en ratones / Effects of (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) on agonistic behavior in mice

Diversos trabajos han implicado a los receptores ionotrópicos de glutamato (especialmente NMDA y AMPA) en la modulación de la conducta agresiva en modelos animales. En contraste, el papel de los receptores metabotrópicos de glutamato (mGlu) es menos conocido. Los receptores mGlu5 se localizan en altas concentraciones en estructuras del sistema límbico implicadas en procesos emocionales, como la agresión. Este estudio examina el efecto de administrar (RS)-2-cloro-5-hidroxifenilglicina (CHPG, 0,75; 1,5; 3; 6 y 12 mg/kg), un agonista selectivo de los receptores mGlu5, sobre la conducta agonística en ratones machos utilizando un modelo animal de agresión inducida por aislamiento. Ratones aislados individualmente fueron enfrentados a oponentes anósmicos en un área neutral 30 min después de la administración del fármaco. Además de otras conductas, se evaluaron las conductas agresivas (amenaza y ataque) y exploratorias durante 10 min utilizando un análisis etológico. Los resultados indicaron que la administración de CHPG no produjo efectos significativos en la conducta agonística con ninguna de las dosis utilizadas; estos resultados pueden deberse a diversos factores, como las características propias del ligando utilizado (agonista parcial contra agonista total), el rango de dosis elegido o el intervalo utilizado entre la administración del fármaco y la evaluación de sus efectos (AU)

Several studies have indicated that ionotropic glutamate receptors (especially NMDA and AMPA) are involved in the modulation of aggressive behavior in animal models. In contrast, the role of metabotropic glutamate receptors (mGlu) is less well known. mGlu5 receptors are found in high concentrations in the limbic brain structures implicated in emotional behaviors, including aggression. This study examines the effects of CHPG (0.75, 1.5, 3, 6 and 12 mg/kg, ip), a selective mGlu5 receptor agonist, on agonistic behavior elicited by isolation in male mice. Individually housed mice were exposed to an anosmic opponent in a neutral area 30 min after drug administration. In addition to other behaviors, aggressive (threat and attack) and exploratory behaviors were evaluated for 10 min using an ethologically based analysis. The results indicate that CHPG administration produced no significant effects on agonistic behavior at any of the doses used. These findings could be related to several factors such as the specific characteristics of the ligand used (partial vs total agonist), the chosen dose range, or the interval between drug administration and the evaluation of its effects (AU)

Anti-aggressive effects of GHB in OF.1 strain mice: involvement of dopamine D2 receptors.

Numerous studies indicate that gamma-hydroxybutyric acid (GHB) influences the endogenous dopamine system. Both GHB and most dopaminergic D(2) receptor antagonists are effective anti-aggressive agents in animal models. The present study aimed to investigate the effects of GHB on agonistic behaviour and to implicate D(2) dopamine receptor on these behaviours. For this purpose, the effects of GHB (80, 120 and 160 mg/kg, IP) and tiapride (60 mg/kg) administered alone or in combination were examined on agonistic behaviour elicited by 'isolation' in male mice. Individually housed mice were exposed to anosmic "standard opponents" 30 min after drug administration, and the encounters were videotaped and evaluated using an ethologically based analysis. The administration of 80 and 120 mg/kg of GHB reduced threat without impairing motor activity, but the administration of 160 mg/kg of GHB or the co-administration of GHB+tiapride (a selective D(2) receptor antagonist) significantly reduced threat and attack but concomitantly increased immobility. The co-administration of GHB+tiapride had different effects to those observed by the administration of these drugs separately. It is concluded that the anti-aggressive effect of GHB appears to be mediated, at least in part, by D(2) dopamine receptors. This anti-dopaminergic activity is an indirect effect, probably induced by the activation of GHB receptors of low affinity, and in this way, this compound would reduce levels of dopamine without blockading of D(2) postsynaptic dopamine receptors.

Anxiolytic-like activity of SB-205384 in the elevated plus maze test in mice / Actividad ansiolítica del sb-205384 en el laberinto elevado en cruz en ratones

Recent studies point to a major role for a2-containing GABA-A receptors in modulating anxiety. However, the possible implication of GABA-A receptors containing the a3 subunit on anxiety is less known. The aim of this study was to examine the effects of SB-205384 (0.5-4 mg/kg, ip), an a3 subunit positive modulator of GABA-A receptor, on anxiety tested in the elevated plus-maze in male mice, using classical and ethological parameters. Mice treated with SB-205384 showed an increase in the frequency of entries and the time spent in open arms, as well as a reduction in the time spent in closed arms, as compared with the control group. A notable increase of «head-dipping» unprotected and a reduction of «stretched-attend posture» protected was also evident. These findings indicate that SB-205384 exhibits an anxiolytic-like profile in the elevated plus-maze test, suggesting that GABA-A receptors which contain the a3 subunit might be involved in regulation anxiety

Recientes investigaciones indican que los receptores GABA-A que contienen subunidades a2 desempeñan un importante papel en la modulación de la ansiedad. Sin embargo, la posible implicación de los receptores GABA-A que contienen la subunidad a3 es menos conocida. El objetivo de este trabajo fue examinar los efectos del SB-205384 (0.5-4 mg/kg, ip), un modulador positivo de los receptores GABA-A que contienen la subunidad a3, sobre la ansiedad evaluada en el laberinto elevado en cruz en ratones machos, utilizando parámetros clásicos y etiológicos. Los animales tratados con SB-205384 mostraron un incremento en la frecuencia de entradas y el tiempo pasado en brazos abiertos, así como una reducción en el tiempo pasado en los brazos cerrados del laberinto, en comparación con el grupo control. Igualmente, se observó un notable aumento en la frecuencia de «head-dipping» desprotegidos y una disminución del número de «stretched-attend posture» protegidos. Estos resultados indican que el SB-205384 exhibe un perfil ansiolítico en el test de laberinto elevado en cruz, sugiriendo que los receptores GABA-A que contienen la subunidad a3 podrían estar involucrados en la regulación de la ansiedad

Anxiolytic-like activity of SB-205384 in the elevated plus-maze test in mice.

Recent studies point to a major role for alpha2-containing GABA-A receptors in modulating anxiety. However, the possible implication of GABA-A receptors containing the alpha3 subunit on anxiety is less known. The aim of this study was to examine the effects of SB-205384 (0.5-4 mg/kg, i.p.), an alpha3 subunit positive modulator of GABA-A receptor, on anxiety tested in the elevated plus-maze in male mice, using classical and ethological parameters. Mice treated with SB-205384 showed an increase in the frequency of entries and the time spent in open arms, as well as a reduction in the time spent in closed arms, as compared with the control group. A notable increase of "head-dipping" unprotected and a reduction of "stretched-attend posture" protected was also evident. These findings indicate that SB-205384 exhibits an anxiolytic-like profile in the elevated plus-maze test, suggesting that GABA-A receptors which contain the alpha3 subunit might be involved in regulation of anxiety.