Mercedes Martín-López

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

GABAA 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 GABAA 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 ip) 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 GABAA 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 LY379268, A Selective Agonist of mGLu2/3 Receptors, onIsolation-Induced Aggression in Male Mice

Recent studies indicate that glutamate metabotropic receptors (mGlu) 1 and 5 are involved in the regulation of aggressive behaviour. Brain distribution of mGlu2/3 receptors suggests that they may also play important roles in emotional responses, including aggression. This study examines the effects of LY379268 (0.254 mg/kg, ip), a selective agonist of the mGlu2/3 receptors, on agonistic interactions between male mice using an animal model of isolation-induced aggression. Individually housed mice were exposed to anosmic “standard 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. LY379268 (2 mg/kg) significantly reduced attack behaviour, as compared with the control group, without affecting immobility, whereas the highest dose of the drug (4 mg/kg) also decreased offensive behaviours (threat and attack), but with a marked increase of immobility (non-selective effect). These results indicate that mGlu2/3 receptors might be implicated in the modulation of aggression.

Efectos de la administración de (RS)-3,4-DCPG, un antagonista mixto de los receptores AMPA y agonista de los receptores mGlu8, en la conducta agresiva de los ratones

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.

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.

P.1.h.015 Differential effect of c-Fos activation associated with JNJ16259685 after an agonistic encounter as compared with grouped mice

Results: HMA movement was significantly impaired after one week of cobalt chloride administration (p = 0.006), with a 19.3% decrease compared to baseline. HMA movement was also decreased by 13% after riboflavin administration, but the change did not reach statistical significance (p = 0.08). VMA movement was decreased by 34.5% after repeated riboflavin administration, which was statistically significant (p = 0.004). None of the other tested substances induced a modification in VMA. The Rotarod test revealed an impaired balance in the Co group (p = 0.04), with a 7.3% decrease; no statistical differences were observed in the other groups when compared with baseline or with control. Conclusion: Due to the fact that riboflavin appears more efficient on VMA, we can say that it acts similar to a psychotropic drug on motor activity. Cobalt chloride appears to impair motor learning, due to the fact that, in general, mice improve their performance over time with training, whereas in our study, the Cobalt-treated mice were unable to maintain balance for the duration of the Rotarod test. Taken together, our results show that some mitochondrial mediators influence spontaneous activity and balance, whereas others have no effect, possibly due to the fact that they modulate different mitochondrial complexes.

Actualización del papel de la enzima MAO-A en la regulación de la conducta agresiva

La monoaminooxidasa A (MAO-A) es una enzima que regula la degradacion metabolica de serotonina y noradrenalina en el sistema nervioso. Ambos neurotransmisores han sido claramente involucrados en la modulacion de la agresion. De hecho, el sistema serotoninergico representa uno de los principales sistemas de neurotransmision relacionado con la aparicion de conductas impulsivas y violentas. En este trabajo se presenta una revision actualizada del papel de la enzima MAO-A en la regulacion de la conducta agresiva, tanto en animales de experimentacion como en humanos.

Efectos de la administración de (RS)-2-cloro-5-hidroxifenilglicina (CHPG) sobre la conducta agonística en ratones

Diversos trabajos han implicado a los receptores ionotropicos de glutamato (especialmente NMDA y AMPA) en la modulacion de la conducta agresiva en modelos animales. En contraste, el papel de los receptores metabotropicos de glutamato (mGlu) es menos conocido. Los receptores mGlu5 se localizan en altas concentraciones en estructuras del sistema limbico implicadas en procesos emocionales, como la agresion. 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 agonistica en ratones machos utilizando un modelo animal de agresion inducida por aislamiento. Ratones aislados individualmente fueron enfrentados a oponentes anosmicos en un area neutral 30 min despues de la administracion del farmaco. Ademas de otras conductas, se evaluaron las conductas agresivas (amenaza y ataque) y exploratorias durante 10 min utilizando un analisis etologico. Los resultados indicaron que la administracion de CHPG no produjo efectos significativos en la conducta agonistica con ninguna de las dosis utilizadas; estos resultados pueden deberse a diversos factores, como las caracteristicas propias del ligando utilizado (agonista parcial contra agonista total), el rango de dosis elegido o el intervalo utilizado entre la administracion del farmaco y la evaluacion de sus efectos.