El moviment veïnal a Palma: una experiència d'aprenentatge per l'acció

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Galanin (1-15) enhances the behavioral effects of fluoxetine in the forced swimming test: a new therapeutic strategy against depression

The selective serotonergic (5- HT) reuptake inhibitors, including Fluoxetine (FLX), are the most commonly used for treatment of major depression. However, the understanding of the mechanism of action of FLX beyond its effect of elevating 5-HT is limited. The interaction between 5-HT system and neuropeptides signaling could be a key aspect. The neuropeptide Galanin(1-15) [GAL(1-15)], induced a strong depression-like and anxiogenic-like effects in the forced swimming test (FST), the tail suspension test, the open field and the light/dark test. The GALR1-GALR2 heteroreceptor complexes in the dorsal hippocampus and in the dorsal raphe were involved in these effects. We have analyzed the effect of GAL(1–15) on FLX-mediated responses in the FST. We tested the involvement of GALR in the GAL(1–15) effect with the selective GALR2 antagonist M871 and using siRNA GALR2 or GALR1 knockdown rats. Groups of rats received three injections of sc FLX(2.5mg/Kg) or FLX(10mg/Kg) and a single icv injection of a threshold dose of GAL(1-15)(1nmol) 15 minutes before the FST. In a second set of experiments, we determined the involvement of GALR1 and GALR2 in the effect of GAL(1-15) on FLX-mediated action. Groups of rats received three injections of sc FLX(10mg/kg), a single icv injection of GAL(1-15) (1nmol) and the GALR2 antagonist M871 (3nmol) icv alone or in combination. Also, in siRNA GALR1 or GALR2 knockdown rats we coadministered FLX(10mg/Kg) and GAL(1-15)(1nmol). The coadministration of sc FLX(2.5mg/Kg) and icv injection of GAL(1-15)(1nmol) induced antidepressant-like effects with a significant decrease in the immobility (p<0.05). Moreover, an increase in the swimming time (p <0.05) was also observed. The strong enhancement by GAL(1-15) of the antidepressant-like effects mediated by FLX was validated using the effective dose of FLX 10mg/kg. Icv GAL(1-15) significantly decreased the immobility time induced by the effective dose of FLX(10mg/kg) by 50% in the FST (p<0.05). Moreover, an increase of the swimming time by about 40% versus FLX(10mg/kg) group was also observed (p<0.01). The GALR2 antagonist M871 3nmol significantly blocked the GAL(1–15)-induced reduction of the immobility time (p<0.05), and increase in the swimming time (p<0.01) found after coadministration of icv injection of GAL(1-15) and sc FLX(10mg/kg) in the FST. The coadministration of sc FLX(10mg/kg) and icv injection of GAL(1-15) in siRNA GALR1 or GALR2 knockdown animals did not produce a further reduction of the immobility time and a further increase in the swimming time compared to FLX alone. In the current study we describe for the first time that GAL(1-15) enhances the antidepressant-like effects induced by FLX in the FST. Indications were also obtained for the involvement of a GALR1/GALR2 heteroreceptor complex in the GAL (1-15)-mediated actions based on the use of the specific GALR2 antagonist M871 and icv injections of GALR1 siRNA or GALR2 siRNA producing a reduction of GALR1 or GALR2, respectively. The results open up the possibility to use GAL(1-15) as for a combination therapy with FLX as a novel strategy for treatment of depression. This work was supported by grants awarded by Spanish Ministry of Economy (SAF2016-79008-P),Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Sex-related differences of cAMP-specific PDE4B3 mRNA in oligodendrocytes following systemic inflammation

Sex-related differences have been observed in the incidence and severity of several neurological diseases and in sepsis in humans. Cyclic adenosine monophosphate (cAMP) has been shown to play an important role in modulating the inflammatory environment during neuroinflammation and importantly in protecting myelin from excitotoxic cell death. Considering the sexual dimorphism in the functional properties of oligodendrocytes and the importance of a systemic inflammation in the progression of multiple sclerosis, we focused on identifying possible sex-related differences in the alterations previously reported for the two phosphodiesterase4B (PDE4B) splice-variants (PDE4B2 and PDE4B3) mRNA expression during innate neuroinflammation. PDE4A, PDE4B, and PDE4D are present in oligodendrocytes and we have previously reported that PDE4B3 mRNA is readily expressed in both oligodendrocytes and neurons. In this study, we analyzed the influence of an intraperitoneal lipopolysaccharide injection on the distribution pattern and expression levels of the PDE4B mRNA splicing variants in both male and female mice brains. Clear differences were observed in PDE4B2 and PDE4B3 mRNA expression levels in males compared with females in a time-dependent manner. Furthermore, we observed that the clear downregulation of PDE4B3 mRNA was reflected in a lower percentage of oligodendrocytes positive for this transcript which correlated with a decrease in inducible cAMP early repressor expression in female corpus callosum. © 2012 Wiley Periodicals, Inc.Grant sponsor: Spanish Ministerio de Educación y Ciencia; Grant number: SAF2006-10243; Grant sponsor: Ministerio de Ciencia e Innovación; Grant numbers: SAF 2009-11052, PI-10/01874; Grant sponsor: Generalitat de Catalunya; Grant number: SGR2009/220; Grant sponsor: FEDER Funds (European Union).Peer Reviewe

The human area postrema and other nuclei related to the emetic reflex express cAMP phosphodiesterases 4B and 4D

Phosphodiesterase 4 (PDE4) inhibitors, i.e. rolipram, are being extensively investigated as therapeutic agents in several diseases. Emesis is one of the most common side effects of PDE4 inhibitors. Given the fact that the area postrema is considered the chemoreceptor trigger zone for vomiting, the present study investigates the regional distribution and cellular localization of the four gene transcripts of the PDE4 subfamily (PDE4A, PDE4B, PDE4C and PDE4D) in human brainstem. In situ hybridization histochemistry was used to locate the mRNA distribution of the four PDE4 subfamilies in the area postrema and related nuclei of human postmortem brainstem. We have found that in the brainstem PDE4B and PDE4D mRNA expression is abundant and distributed not only in neuronal cells, but also in glial cells, and on blood vessels. The hybridization signals for PDE4B and PDE4D mRNAs in the area postrema were stronger than those in any other nuclei in the brainstem. They were also found in vomiting-related nuclei such as the nucleus of the solitary tract and the dorsal vagal motor nucleus. These findings suggest that cAMP signaling modification in the area postrema could mediate the emetic effects of PDE4 inhibitors in human brainstem.This work was supported by grants from Ministerio de Educación y Ciencia and Fondo Europeo de Desarrollo Regional (SAF2006-10243). F.M. was on sabbatical leave from Hirosaki University School of Medicine. S.P.-T. was recipient of a predoctoral fellowship from CIRIT (Generalitat de Catalunya).Peer Reviewe

Cognitive impairment induced by delta9-tetrahydrocannabinol occurs through heteromers between cannabinoid CB1 and serotonin 5-HT2A receptors

Delta-9-tetrahydrocannabinol (THC), the main psychoactive compound of marijuana, induces numerous undesirable effects, including memory impairments, anxiety, and dependence. Conversely, THC also has potentially therapeutic effects, including analgesia, muscle relaxation, and neuroprotection. However, the mechanisms that dissociate these responses are still not known. Using mice lacking the serotonin receptor 5-HT2A, we revealed that the analgesic and amnesic effects of THC are independent of each other: while amnesia induced by THC disappears in the mutant mice, THC can still promote analgesia in these animals. In subsequent molecular studies, we showed that in specific brain regions involved in memory formation, the receptors for THC and the 5-HT2A receptors work together by physically interacting with each other. Experimentally interfering with this interaction prevented the memory deficits induced by THC, but not its analgesic properties. Our results highlight a novel mechanism by which the beneficial analgesic properties of THC can be dissociated from its cognitive side effects