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Lysophosphatidic acid species (LPA) are lipid bioactive signaling molecules that have been recently implicated in the modulation of emotional and motivational behaviors. The present study investigates the consequences of either genetic deletion or pharmacological blockade of lysophosphatidic acid receptor-1 (LPA1) in alcohol consumption.The experiments were performed in alcohol-drinking animals by using LPA1-null mice and administering the LPA1 receptor antagonist Ki16425 in both mice and rats.In the two-bottle free choice paradigm, the LPA1-null mice preferred the alcohol more than their wild-type counterparts. Whereas the male LPA1-null mice displayed this higher preference at all doses tested, the female LPA1-null mice only consumed more alcohol at 6% concentration. The male LPA1-null mice were then further characterized, showing a notably increased ethanol drinking after a deprivation period and a reduced sleep time after acute ethanol administration. In addition, LPA1-null mice were more anxious than the wild-type mice in the elevated plus maze test. For the pharmacological experiments, the acute administration of the antagonist Ki16425 consistently increased ethanol consumption in both wild-type mice and rats; while it did not modulate alcohol drinking in the LPA1-null mice and lacked intrinsic rewarding properties and locomotor effects in a conditioned place preference paradigm. In addition, LPA1-null mice exhibited a marked reduction on the expression of glutamate-transmission-related genes in the prefrontal cortex similar to those described in alcohol-exposed rodents.Results suggest a relevant role for the LPA/LPA1 signaling system in alcoholism. In addition, the LPA1-null mice emerge as a new model for genetic vulnerability to excessive alcohol drinking. The pharmacological manipulation of LPA1 receptor arises as a new target for the study and treatment of alcoholism.

Treball Final de Grau. Grau en Psicologia. Codi: PS1048. Curs acadèmic 2016/2017 El alcohol es la droga más aceptada y consumida en el mundo, la cual puede causarte un alto nivel de dependencia, a causa, principalmente, del efecto reforzante que produce en tu cerebro. En el presente trabajo nos vamos a centrar en la importancia que tiene el salsolinol en nuestro organismo tras el consumo de alcohol, así pues, el objetivo es aceptar o refutar la siguiente hipótesis: Un producto de la condensación de acetaldehído y dopamina es el responsable del efecto reforzante del etanol. Es decir, el salsolinol, como producto derivado de la condensación no enzimática de acetaldehído y dopamina, es el responsable del reforzamiento positivo. Aparece tras el consumo de etanol, y gracias a la metabolización de este. Todavía no se sabe el mecanismo de acción del salsolinol, pero sabemos que juega un papel importante a la hora de crear dependencia, llegando a pensar que el alcohol actúa como una prodroga. El salsolinol es una molécula reforzante, más potente que el acetaldehído y el etanol. The alcohol is the drug most accepted and consumed in the world, which can cause a high level of dependence, to reason, principally, of the reinforcing effect that produces in your brain. In the present work, we us go to focus in the importance that salsolinol has in our organism after consume alcohol, this way so, the objective is to agree or to refuse the following hypothesis: A product of the condensation of acetaldehyde and dopamine is the responsible of the effect positive reinforcement of the ethanol. The salsolinol, as product derived from the non-enzymatically condenses of acetaldehyde and dopamine, is the responsible of the positive reinforcement. It appears after consume ethanol, and thanks to metabolizing of this one. The mechanism of action of the salsolinol is not yet known, but we know that it plays an important role in creating dependency, coming to think that alcohol acts as a prodrug. The salsolinol more reforcing molecule that acetaldehyde and ethanol.

The heavy metal thallium is an emerging pollutant among the most potentially toxic species to which human populations are exposed. Its harmful effects on living organisms are well-known at high doses, typical of acute intoxication. Its harmful effects at low doses are by far less known. In a previous paper, we reported a TlCl-induced metabolic shift to lactate and ethanol production in living hippocampal HN9.10e neurons that appeared after a single short exposure (48 h) at low doses (1-100 μg/L). This metabolic shift to lactate and ethanol suggests a marked impairment of cell bioenergetics. In this work, we provide detailed evidence for TlCl-induced changes of neuronal morphology and mitochondrial activity. Confocal microscopy and fluorescent probes were used to qualitatively and quantitatively analyze, at the subcellular level, living HN9.10e neurons during and after TlCl exposure. An early onset mitochondrial dysfunction appeared, associated with signs of cellular deregulation such as neurite shortening, loss of substrate adhesion, and increase of cytoplasmic calcium. The dose-dependent alteration of mitochondrial ROS (mtROS) level and of transmembrane mitochondrial potential (ΔΨm) has been observed also for very low TlCl doses (1 μg/L). The treatment with the ATP synthase inhibitor oligomycin revealed a severe impairment of the mitochondrial function, more significant than that measured by the simple quantification of the tetramethylrhodamine methyl ester (TMRM) fluorescence. These results highlight that mitochondria are a key subcellular target of TlCl neurotoxicity. The transmembrane mitochondrial potential was significantly correlated with the ethanol concentration in cell culture medium ( P < 0.001, r = -0.817), suggesting that ethanol could be potentially used as a biomarker of mitochondrial impairment.

AbstractThe possible effects on cognitive processes of external electric fields, such as those generated by power line pillars and household appliances are of increasing public concern. They are difficult to study experimentally, and the relatively scarce and contradictory evidence make it difficult to clearly assess these effects. In this study, we investigate how, why and to what extent external perturbations of the intrinsic neuronal activity, such as those that can be caused by generation, transmission and use of electrical energy can affect neuronal activity during cognitive processes. For this purpose, we used a morphologically and biophysically realistic three‐dimensional model of CA1 pyramidal neurons. The simulation findings suggest that an electric field oscillating at power lines frequency, and environmentally measured strength, can significantly alter both the average firing rate and temporal spike distribution properties of a hippocampal CA1 pyramidal neuron. This effect strongly depends on the specific and instantaneous relative spatial location of the neuron with respect to the field, and on the synaptic input properties. The model makes experimentally testable predictions on the possible functional consequences for normal hippocampal functions such as object recognition and spatial navigation. The results suggest that, although EF effects on cognitive processes may be difficult to occur in everyday life, their functional consequences deserve some consideration, especially when they constitute a systematic presence in living environments.

Various spinal cord stimulation (SCS) modes are used in the treatment of chronic neuropathic pain disorders. Conventional (Con) and Burst-SCS are hypothesized to exert analgesic effects through different stimulation-induced mechanisms. Preclinical electrophysiological findings suggest that stimulation intensity is correlated with the effectiveness of Burst-SCS. Therefore, we aimed to investigate the relation between amplitude (charge per second) and behavioral effects in a rat model of chronic neuropathic pain, for both Conventional Spinal Cord Stimulation (Con-SCS) and biphasic Burst-SCS.Animals (n = 12 rats) received a unilateral partial sciatic nerve ligation, after which they were implanted with quadripolar electrodes in the epidural space at thoracic level 13. Mechanical hypersensitivity was assessed using paw withdrawal thresholds (WTs) to von Frey monofilaments, at various SCS intensities (amplitudes) and multiple time points during 60 minutes of stimulation and 30 minutes post stimulation.Increasing amplitude was shown to improve the efficacy of Con-SCS, whereas the efficacy of Burst-SCS showed a non-monotonic relation with amplitude. Con-SCS at 66% MT (n = 5) and Burst-SCS at 50% MT (n = 6) were found to be equally effective in normalizing mechanical hypersensitivity. However, in the assessed time period Burst-SCS required significantly more mean charge per second to do so (p < 0.01). When applied at comparable mean charge per second, Con-SCS resulted in a superior behavioral outcome (p < 0.01), compared with Burst-SCS.Biphasic Burst-SCS requires significantly more mean charge per second in order to achieve similar pain relief, as compared with Con-SCS, in an experimental model of chronic neuropathic pain.

Although much is known about factors influencing short-term implementation, little is known about what factors are relevant for the long-term sustainment of innovations. In the Dutch National Quality Improvement Program for Palliative Care, innovations were implemented in 76 implementation projects.To give insight into the sustainment strategies used and factors facilitating and hindering sustainment.Online questionnaire with prestructured and open questions sent to the contact persons for 76 implementation projects, 2-6.5 years after the start.Information was gathered on 63 implementation projects (response 83%). Most projects took place in home care, general practices, and/or nursing homes. Sustainment was attained in 60% of the implementation projects. Six often applied strategies were statistically significantly related to sustainment: 1) realizing coherence between the innovation and the strategic policy of the organization; 2) arranging to have a specific professional responsible for the use of the innovation; 3) integrating the innovation into the organization's broader palliative care policy; 4) arranging accessibility of the innovation; 5) involving management in the implementation project; and 6) giving regular feedback about the implementation. In three-quarters of the projects, barriers and facilitators were encountered relating to characteristics of the care organizations, such as employee turnover and ratification of the project by the management.Applying the six strategies enhances sustainment. The organization plays a decisive role in the sustainment of innovations in palliative care. Engaging the management team in implementation projects from early onset is of utmost importance.

BackgroundEthanol (EtOH), one of the most widely consumed substances of abuse, can induce brain damage and neurodegeneration. EtOH is centrally metabolized into acetaldehyde, which has been shown to be responsible for some of the neurophysiological and cellular effects of EtOH. Although some of the consequences of chronic EtOH administration on cell oxidative status have been described, the mechanisms by which acute EtOH administration affects the brain's cellular oxidative status and the role of acetaldehyde remain to be elucidated in detail.MethodsSwiss CD‐I mice were pretreated with the acetaldehyde‐sequestering agent d‐penicillamine (DP; 75 mg/kg, i.p.) or the antioxidant lipoic acid (LA; 50 mg/kg, i.p.) 30 minutes before EtOH (2.5 g/kg, i.p.) administration. Animals were sacrificed 30 minutes after EtOH injection. Glutathione peroxidase (GPx) mRNA levels; GPx and glutathione reductase (GR) enzymatic activities; reduced glutathione (GSH), glutathione disulfide (GSSG), glutamate, g‐L‐glutamyl‐L‐cysteine (Glut‐Cys), and malondialdehyde (MDA) concentrations; and protein carbonyl group (CG) content were determined in whole‐brain samples.ResultsAcute EtOH administration enhanced GPx activity and the GSH/GSSG ratio, while it decreased GR activity and GSSG concentration. Pretreatment with DP or LA only prevented GPx activity changes induced by EtOH.ConclusionsAltogether, these results show the capacity of a single dose of EtOH to unbalance cellular oxidative homeostasis.

Background: Fatigue is a frequently reported and disabling symptom in multiple sclerosis (MS). Objective: To investigate the effectiveness of an individual energy conservation management (ECM) intervention on fatigue and participation in persons with primary MS-related fatigue. Methods: A total of 86 severely fatigued and ambulatory adults with a definite diagnosis of MS were randomized in a single-blind, two-parallel-arm randomized clinical trial to the ECM group or the information-only control group in outpatient rehabilitation departments. Blinded assessments were carried out at baseline and at 8, 16, 26 and 52 weeks after randomization. Primary outcomes were fatigue (fatigue subscale of Checklist Individual Strength – CIS20r) and participation (Impact on Participation and Autonomy scale – IPA). Results: Modified intention-to-treat analysis was based on 76 randomized patients (ECM, n = 36; MS nurse, n=40). No significant ECM effects were found for fatigue (overall difference CIS20r between the groups = −0.81; 95% confidence interval (CI), −3.71 to 2.11) or for four out of five IPA domains. An overall unfavourable effect was found in the ECM group for the IPA domain social relations (difference between the groups = 0.19; 95% CI, 0.03 to 0.35). Conclusion: The individual ECM format used in this study did not reduce MS-related fatigue and restrictions in participation more than an information-only control condition.