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.

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 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.

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.

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.

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.

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.

Anxiogenic-like activity of L-655,708, a selective ligand for the benzodiazepine site of GABA(A) receptors which contain the alpha-5 subunit, in the elevated plus-maze test.

GABA(A) receptor is a transmembrane hetero-oligomeric protein which consists of five subunits, the combination of which confers unique pharmacological properties to the receptor. L-655,708 is a new ligand selective for GABA(A) receptors containing an alpha-5 subunit. It is a partial inverse agonist that exhibits a 100-fold higher affinity for alpha-5 containing receptors, compared with alpha-1 containing receptors. The aim of this study was to examine the effects of L-655,708 (0.625-5 mg/kg i.p.) on anxiety tested in the elevated plus-maze in male mice. A number of classical parameters were collected: (a) Open arm duration; (b) Closed arm duration; (c) Central platform duration; (d) Open arm frequency; (e) Closed arm frequency; and (f) Total number of entries in the arms. Likewise, different ethological measures were also obtained (rears, head-dipping [HD], stretched attend posture [SAP] and grooming). Mice treated with L-655,708 showed a marked increase in the frequency of entries and the time spent in closed arms, as well as a reduction in the frequency of entries and the time spent in open arms, as compared with the control group. Unprotected HDs were also significantly decreased after treatment with the drug. Overall, these results indicate that L-655,708 could exhibit an anxiogenic-like profile in the elevated plus-maze test. This ligand is selective for GABA(A) receptors containing an alpha-5 subunit, which is mainly expressed over the hippocampal formation, a region which has been involved in the modulation of anxiety.

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.

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.