El paper dels receptors de la dopamina, l'adenosina i l'NMDA en l'activitat motora de l'animal d'experimentació

Se sap des de fa temps que els receptors dopaminèrgics estriatals tenen un paper fonamental en la modulació de 1'activitat motora. Recentment, hem trobat resultats que mostren 1'existencia d'interaccions especifiques entre subtipus de receptors de l'adenosina i de la dopamina al cervell dels mamifers. A través d'aquestes interaccions, que tenen lloc en neurones estriatals concretes, el neuromodulador adenosina inhibeix 1'activitat motora. Aquest mecanisme sembla ser el principal responsable dels efectes psicomotors dels antagonistes adenosínics com la cafeïna. En aquest treball també es revisen una sèrie de resultats experimentals que demostren la implicació dels receptors de NMDA en la modulació de l'activitat motora. Aquest resultats suggereixen que, a part de 1'estriat i d'altres ganglis basals, hi ha altres estructures subcorticals, com probablement 1'hipocamp, involucrades en aquesta modulaci

Anàlisis del consum de combustible i emissions de sofre en un vaixell de cabotatge que consumeixi fuel-oil : Comparació de les possibles solucions per a les emissions

L’objectiu d’aquest treball és aprofundir en el coneixement d’un motor marí real cremant fuel-oil, les normatives que els regeixen i calcular les principals característiques d’aquest referents a la generació de gasos d’escapament. Realitzar un estudi sobre l’abocament del diòxid de sofre a l’atmosfera provocat per la combustió de combustibles fòssils, les normatives que ho regulen, dimensionament d’aquests i les repercussions que aquest té sobre el medi ambient, la naturalesa i les persones. Un cop aquests factors són conegut amb claredat, trobar les principals solucions que existeixen en l’actualitat per a resoldre o minimitzar aquest problema. L’estructura del treball ha seguit un ordre lògic on s’ha estudiat des del punt més bàsic i general i s’ha anat aprofundint. Inicialment es presenta l’embarcació del treball i poc a poc es va concretant en tots els temes relacionats per a acabar descrivint els principals mètodes per reduir les emissions de sofre a l’atmosfera i proposant una solució real

Sepulcres i enterraments a la Dertosa tardoantiga. Les excavacions del carrer de la Mercè (Tortosa, Baix Ebre)

En els darrers anys el nostre coneixement de les àrees d’enterrament tardoantigues a la ciutat de Dertosa ha augmentat significativament, gràcies sobretot a les excavacions que s’han produït a la zona del barranc del Rastre. En aquest estudi presentem les dades de caire funerari obtingudes de les excavacions efectuades al carrer de la Mercè entre els anys 2009 i 2010. És destacable la troballa d’un conjunt de sepulcres de cista del segle VI cobertes amb grans lloses de pedra. Aquesta modalitat d’enterrament, la qual ha d’estar destinada a personatges d’un rang social elevat, no s’havia documentat fins ara a Tortosa.In recent years, our knowledge about the late Roman burial areas of the city of Dertosa has increased significantly mainly due to the excavations that have been carried out in the Rastre ravine area. In this paper we present the data of funeral type obtained from the excavations of Mercè street between 2009 and 2010. Is remarkable the finding of a VIth century set of stone slab graves covered by ashlars. This type of burial, which must be reserved for individuals of high social rank, was unknown in Tortosa until now

Blockade of adenosine A2A receptors prevents protein phosphorylation in the striatum induced by cortical stimulation

©2006 Society for NeurosciencePrevious studies have shown that cortical stimulation selectively activates extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and immediate early gene expression in striatal GABAergic enkephalinergic neurons. In the present study, we demonstrate that blockade of adenosine A2A receptors with caffeine or a selective A2A receptor antagonist counteracts the striatal activation of cAMP– protein kinase A cascade (phosphorylation of the Ser845 residue of the glutamate receptor 1 subunit of the AMPA receptor) and mitogenactivated protein kinase (ERK1/2 phosphorylation) induced by the in vivo stimulation of corticostriatal afferents. The results indicate that A2A receptors strongly modulate the efficacy of glutamatergic synapses on striatal enkephalinergic neurons.This work was supported by the Intramural Research Program of the National Institutes of Health, National Institute on Drug Abuse, Department of Health and Human Services

Presynaptic adenosine receptor heteromers as key modulators of glutamatergic and dopaminergic neurotransmission in the striatum

Adenosine plays a very significant role in modulating striatal glutamatergic and dopaminergic neurotransmission. In the present essay we first review the extensive evidence that indicates this modulation is mediated by adenosine A1 and A2A receptors (A1Rs and A2ARs) differentially expressed by the components of the striatal microcircuit that include cortico-striatal glutamatergic and mesencephalic dopaminergic terminals, and the cholinergic interneuron. This microcircuit mediates the ability of striatal glutamate release to locally promote dopamine release through the intermediate activation of cholinergic interneurons. A1Rs and A2ARs are colocalized in the cortico-striatal glutamatergic terminals, where they form A1R-A2AR and A2AR-cannabinoid CB1 receptor (CB1R) heteromers. We then evaluate recent findings on the unique properties of A1R-A2AR and A2AR-CB1R heteromers, which depend on their different quaternary tetrameric structure. These properties involve different allosteric mechanisms in the two receptor heteromers that provide fine-tune modulation of adenosine and endocannabinoid-mediated striatal glutamate release. Finally, we evaluate the evidence supporting the use of different heteromers containing striatal adenosine receptors as targets for drug development for neuropsychiatric disorders, such as Parkinson's disease and restless legs syndrome, based on the ability or inability of the A2AR to demonstrate constitutive activity in the different heteromers, and the ability of some A2AR ligands to act preferentially as neutral antagonists or inverse agonists, or to have preferential affinity for a specific A2AR heteromer

El paper dels receptors de la dopamina, l'adenosina I l'NMDA en l'activitat motora de l'animal d'experimentació

Se sap des de fa temps que els receptors dopaminèrgics estriatals tenen un paper fonamental en la modulació de 1'activitat motora. Recentment, hem trobat resultats que mostren 1'existencia d'interaccions especifiques entre subtipus de receptors de l'adenosina i de la dopamina al cervell dels mamifers. A través d'aquestes interaccions, que tenen lloc en neurones estriatals concretes, el neuromodulador adenosina inhibeix 1'activitat motora. Aquest mecanisme sembla ser el principal responsable dels efectes psicomotors dels antagonistes adenosínics com la cafeïna. En aquest treball també es revisen una sèrie de resultats experimentals que demostren la implicació dels receptors de NMDA en la modulació de l'activitat motora. Aquest resultats suggereixen que, a part de 1'estriat i d'altres ganglis basals, hi ha altres estructures subcorticals, com probablement 1'hipocamp, involucrades en aquesta modulaci

Adenosine A1-A2A Receptor Heteromer as a Possible Target for Early-Onset Parkinson's Disease

Parkinson's disease (PD) is a progressive, neurodegenerative disorder that affects ~1% of individuals over the age of 60, which turns to 5% in subjects up to 85 years (de Lau and Breteler, 2006). On the other hand, a form of PD, called early-onset PD (EOPD), arises at an earlier age (<45; Bonifati et al., 2005; Ylikotila et al., 2015). EOPD patients generally display a slower progression of the disease and present a better response to dopaminergic treatments; however, they may finally develop a full PD symptomatology (i.e., bradykinesia, resting tremor, muscular rigidity and postural instability, drug-induced dyskinesia; Olgiati et al., 2016)

Prefrontal cortex-driven dopamine signals in the striatum show unique spatial and pharmacological properties

Dopamine (DA) signals in the striatum are critical for a variety of vital processes, including motivation, motor learning, and reinforcement learning. Striatal DA signals can be evoked by direct activation of inputs from midbrain DA neurons (DANs) as well as cortical and thalamic inputs to the striatum. In this study, we show that in vivo optogenetic stimulation of prelimbic (PrL) and infralimbic (IL) cortical afferents to the striatum triggers an increase in extracellular DA concentration, which coincides with elevation of striatal acetylcholine (ACh) levels. This increase is blocked by a nicotinic ACh receptor (nAChR) antagonist. Using single or dual optogenetic stimulation in brain slices from male and female mice, we compared the properties of these PrL/IL-evoked DA signals with those evoked by stimulation from midbrain DAN axonal projections. PrL/IL-evoked DA signals are undistinguishable from DAN evoked DA signals in their amplitudes and electrochemical properties. However, PrL/IL-evoked DA signals are spatially restricted and preferentially recorded in the dorsomedial striatum. PrL/IL-evoked DA signals also differ in their pharmacological properties, requiring activation of glutamate and nicotinic ACh receptors. Thus, both in vivo and in vitro results indicate that cortical evoked DA signals rely on recruitment of cholinergic interneurons, which renders DA signals less able to summate during trains of stimulation and more sensitive to both cholinergic drugs and temperature. In conclusion, cortical and midbrain inputs to the striatum evoke DA signals with unique spatial and pharmacological properties that likely shape their functional roles and behavioral relevance.Fil: Adrover, Martín Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres"; Argentina. National Institutes of Health; Estados UnidosFil: Shin, Jung Hoon. National Institutes of Health; Estados UnidosFil: Quiroz, Cesar. National Institutes of Health; Estados UnidosFil: Ferré, Sergi. National Institutes of Health; Estados UnidosFil: Lemos, Julia C.. National Institutes of Health; Estados UnidosFil: Alvarez, Veronica A.. National Institutes of Health; Estados Unido

Past, present and future of A(2A) adenosine receptor antagonists in the therapy of Parkinson's disease

Several selective antagonists for adenosine A2A receptors (A2AR) are currently under evaluation in clinical trials (phases I to III) to treat Parkinson's disease, and they will probably soon reach the market. The usefulness of these antagonists has been deduced from studies demonstrating functional interactions between dopamine D2 and adenosine A2A receptors in the basal ganglia. At present it is believed that A2AR antagonists can be used in combination with the dopamine precursor L-DOPA to minimize the motor symptoms of Parkinson's patients. However, a considerable body of data indicates that in addition to ameliorating motor symptoms, adenosine A2AR antagonists may also prevent neurodegeneration. Despite these promising indications, one further issue must be considered in order to develop fully optimized antiparkinsonian drug therapy, namely the existence of (hetero)dimers/oligomers of G protein-coupled receptors, a topic that is currently the focus of intense debate within the scientific community. Dopamine D2 receptors (D2Rs) expressed in the striatum are known to form heteromers with A2A adenosine receptors. Thus, the development of heteromer-specific A2A receptor antagonists represents a promising strategy for the identification of more selective and safer drugs