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Ap.: VII pDigitalización. Vitoria-Gasteiz : Fundación Sancho el Sabio, 200

Rethinking the Use of Antidepressants to Treat Alcohol Use Disorders and Depression Comorbidity: The Role of Neurogenesis

Patients with alcohol use disorders (AUDs) are frequently treated with antidepressant drugs (ADs), but clinical evidence of their efficacy is contradictory. Considering that ADs are thought to produce their therapeutic effects partially by increasing hippocampal plasticity and neurogenesis (HN), and that both AUDs and depression share a potential for the disruption of these neuroplastic processes, one could reasonably wonder whether the poor efficacy of AD treatment could be explained by the inability of these drugs to exert their proper action in patients suffering from AUD or depression. In order to further clarify this question, this chapter aims to examine available data regarding the effect of ADs on behavioral and HN alterations related to alcohol abstinence, as a key period in which the treatment would be implemented and in which their potential effects on alcohol-related problems remain under controversy

La influencia de las actitudes lingüísticas sobre las valoraciones online de los clientes de hoteles

En la mayoría de actividades de servicios la satisfacción de los clientes depende, en gran medida, de su interacción directa con los prestadores de los mismos. En el caso del turismo, con frecuencia dicha interacción se produce entre personas cuyos idiomas maternos son diferentes. En este contexto, conceptos como la acomodación, las expectativas y las actitudes lingüísticas o la proximidad cultural enriquecen las posibilidades de análisis de la conducta y satisfacción de los turistas. En este trabajo se presenta un proyecto de investigación en curso cuyo objetivo último es profundizar en un planteamiento interdisciplinar que integre elementos de índole cultural-lingüística en el análisis económico-empresarial del turismo. En particular, se aplica la técnica del Análisis de contenido a los comentarios realizados por huéspedes de alojamientos hoteleros en la plataforma de reservas online Booking.com para determinar en qué medida las diferencias culturales influyen sobre la satisfacción con el servicio recibido.In most service activities, customer satisfaction depends to a large extent on its direct interaction with service providers. In the case of tourism, such interaction often occurs between people whose mother tongues are different. In this context, concepts such as accommodation, expectations and linguistic attitudes or cultural proximity enrich the possibilities of analyzing the behavior and satisfaction of tourists. This paper presents an ongoing research project whose ultimate goal is to deepen an interdisciplinary approach that integrates cultural and linguistic elements in the economic-business analysis of tourism. In particular, the Content Analysis technique is applied to comments made by hotel guests on the online booking platform Booking.com to determine the extent to which cultural differences influence satisfaction with the received service

Role of the Galanin N--terminal fragment (1-15) in anhedonia: involvement of the dopaminergic mesolimbic system

Anhedonia is a core feature of depressive disorders. The galanin N-terminal fragment (1-15) plays a role in mood regulation since it induces depression and anxiogenic-like effects in rats. In this study, we analysed galanin N-terminal fragment (1-15) actions in anhedonic-like behaviours in rats using operant and non-operant tests and the areas involved with these effects. Galanin N-terminal fragment (1-15) effects were analysed in saccharin self-administration, sucrose preference, novelty-suppressed feeding and female urine sniffing tests. The areas involved in galanin N-terminal fragment (1-15)-mediated effects were studied with positron emission tomography for in vivo imaging, and we analysed the ventral tegmental area and nucleus accumbens. Galanin N-terminal fragment (1-15) had effects on the mRNA expression of the dopamine transporters Dat and Vmat2; the C-Fos gene; the dopamine receptors D1, D2, D3, D5; and the galanin receptors 1 and 2. Galanin N-terminal fragment (1-15) at a concentration of 3 nmol induced a strong anhedonia-like phenotype in all tests. The involvement of galanin receptor 2 was demonstrated with the galanin receptor 2 antagonist M871 (3 nmol). The 18F-fluorodeoxyglucose positron emission tomography images indicated the action of galanin N-terminal fragment (1-15) over several nuclei of the limbic system. Galanin N-terminal fragment (1-15)-mediated effects also involved changes in the expression of Dat, Vmat2, D3 and galanin receptors in the ventral tegmental area as well as the expression of C-Fos, D1, D2 and D3 and TH immunoreactivity in the nucleus accumbens. Our results indicated that galanin N-terminal fragment (1-15) exerts strong anhedonic-like effects and that this effect was accompanied by changes in the dopaminergic mesolimbic system. These results may provide a basis for the development of novel therapeutic strategies using galanin N-terminal fragment (1-15) analogues for the treatment of depression and reward-related diseases

The effect of Galanin N-Terminal fragment (1-15) in anhedonia: Involvement of the dopaminergic mesolimbic system.

The Galanin N-terminal fragment (1-15) [GAL(1-15)] induces depressant- and anxiogenic-like actions in behavioral tests and these effects were significantly stronger than the ones induced by Galanin. Since anhedonia is a core feature of depression, we have analyzed GAL(1-15) actions in two anhedonic-like behavior tests: saccharin Self-administration and Sucrose Preference test (SPT). In order to investigate whether the effect of GAL(1–15) was associated with the reward circuit, we have studied the GAL(1-15) actions over the mesolimbic system by the expression of the C-Fos, Dat, Vmat2 and Dopamine and GAL receptors genes in VTA and NAc. GAL(1-15) 3nmol significantly decreased the number of reinforcement of saccharin self-administer (p<0.01), while 1nmol lacked effect. GAL(1-15) also significantly reduced the number of reinforcement (p<0.01) compared with GAL. The GALR2 antagonist M871 significantly blocked (p<0.05) the decrease in the number of saccharin reinforcements induced by GAL(1-15). In the SPT, GAL(1-15) decreased the sucrose intake 8 (p<0.05) and 24 hours (p<0.01) after administration. GAL(1-15) at a dose of 3 nmol produced a significant decrease in the mRNA levels of Dat and Vmat2 (p<0.05) and an increase in the D3 receptor (p<0.05) in VTA. In the NAc, GAL(1-15) induced a significant decrease in the expression of C-Fos (p<0.05) mRNA and a significantly increased the mRNA expression of D1 (p<0.05), D2 (p<0.05) and D3 (p<0.05). In the current study, we described for the first time that GAL(1-15) induced a strong anhedonia-like phenotype in several behavioral tests, confirming an important role of this neuropeptide in anhedonia, moreover, the dopaminergic mesolimbic system was described as a key region in GAL(1-15)-mediated action on anhedonia. These results may give the basis for the development of novel therapeutic strategies using GAL(1-15) for treatment of depression and reward-related diseases.This study was supported by SpanishSAF2016-79008 and PPIT.UMA.B1.2017/17. Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

Role of the satiety factor oleoylethanolamide in alcoholism

Oleoylethanolamide (OEA) is a satiety factor that controls motivational responses to dietary fat. Here we show that alcohol administration causes the release of OEA in rodents, which in turn reduces alcohol consumption by engaging peroxisome proliferator-activated receptor-alpha (PPAR-α). This effect appears to rely on peripheral signaling mechanisms as alcohol self-administration is unaltered by intracerebral PPAR-α agonist administration, and the lesion of sensory afferent fibers (by capsaicin) abrogates the effect of systemically administered OEA on alcohol intake. Additionally, OEA is shown to block cue-induced reinstatement of alcohol-seeking behavior (an animal model of relapse) and reduce the severity of somatic withdrawal symptoms in alcohol-dependent animals. Collectively, these findings demonstrate a homeostatic role for OEA signaling in the behavioral effects of alcohol exposure and highlight OEA as a novel therapeutic target for alcohol use disorders and alcoholism

Sudden cessation of fluoxetine before alcohol drinking reinstatement alters microglial morphology and TLR4/inflammatory neuroadaptation in the rat brain

Preclinical studies on the efects of abrupt cessation of selective serotonin reuptake inhibitors (SSRIs), a medication often prescribed in alcohol use disorder (AUD) patients with depression, results in alcohol consumption escalation after resuming drinking. However, a potential neuroinfammatory component on this escalation remains unexplored despite the immunomodulatory role of serotonin. Here, we utilized a rat model of 14-daily administration of the SSRI fuoxetine (10 mg/kg/day) along alcohol self-administration deprivation to study the efects of fuoxetine cessation on neuroinfammation after resuming alcohol drinking. Microglial morphology and infammatory gene expression were analyzed in prelimbic cortex, striatum, basolateral amygdala and dorsal hippocampus. Results indicated that alcohol drinking reinstatement increased microglial IBA1 immunoreactivity and altered morphometric features of activated microglia (fractal dimension, lacunarity, density, roughness, and cell area, perimeter and circularity). Despite alcohol reinstatement, fuoxetine cessation modifed microglial morphology in a brain region-specifc manner, resulting in hyper-ramifed (spatial complexity of branching), reactive (lower heterogeneity and circularity)-like microglia. We also found that microglial cell area correlated with changes in mRNA expression of chemokines (Cx3cl1/fractalkine, Cxcl12/SDF1α, Ccl2/MCP1), cytokines (IL1β, IL6, IL10) and the innate immune toll-like receptor 4 (TLR4) in dorsal hippocampus. Specifcally, TLR4 correlated with microglial spatial complexity assessed by fractal dimension in striatum, suggesting a role in process branching. (...)Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. Funding for open access charge: Universidad de Málaga/CBUA. RETICS Red de Trastornos Adictivos, Instituto de Salud Carlos III (ISCIII), Ministerio de Ciencia e Innovación and European Regional Development Funds-European Union (ERDF-EU) (Grant No. RD16/0017/0001); ISCIII, ERDF-EU (Grant No. PI17/02026, Grant No. PI19/01577); Ministerio de Sanidad, Delegación de Gobierno para el Plan Nacional sobre Drogas (Grant No. PND 2020/048, Grant No. PND 2019/040, Grant No. PND 2018/044, Grant No. PND 2018/033); and Consejería de Salud y Familia, Junta de Andalucía (Neuro-RECA, Grant No. RIC-0111–2019). JS (Grant No. CPII17/00024), FJP (Grant No. CPII19/00022) and AS (Grant No. CPII19/00031) hold “Miguel Servet II” research contracts from the National System of Health, ISCIII, ERDF-EU. FJP also holds a “Nicolas Monardes” contract from Servicio Andaluz de Salud, Consejería de Salud y Familia, Junta de Andalucía (Grant No. C1-0049–2019). PR (Grant No. CP19/00068) hold “Miguel Servet I” research contracts from the National System of Health, ISCIII, ERDF-EU. The funding sources had no further role in study design; in the collection, analysis and interpretation of data; in writing of the report; and in the decision to submit the paper for publication

Effects of Galanin N-Terminal fragment (1-15) in the anhedonic behavioural tests in rats.

The Galanin N-terminal fragment (1-15)[GAL(1-15)] induces depressant- and anxiogenic-like actions in behavioural tests in rats. Since anhedonia is a core feature of depression, we have analyzed GAL(1-15) actions in anhedonic-like behaviour tests: saccharin Self-administration, Sucrose Preference test (SPT), Novelty suppressed feeding (NSF) and Female urine sniffing test (FUST). Three sets of experiments were conducted in the saccharin Self-administration. First, a dose-response curve of GAL(1-15) 1nmol, 3nmol or vehicle was performed. We have also compared the effects in the number of saccharine reinforcements of GAL 3nmol and GAL(1-15) 3nmol. In the last experiments, rats received GAL(1-15) 3nmol and the GALR2 antagonist M871 3nmol. In SPT, NSF and FUST we have analyzed the effects of GAL(1-15) 3nmol in the sucrose intake and preference, the latency of the first feeding episode and the female urine sniffing duration respectively. GAL(1-15)3nmol significantly decreased the number of reinforcement of saccharin self-administer (p<0.01), while 1nmol lacked effect. GAL(1-15) also significantly reduced the number of reinforcement (p<0.01) compared with GAL. The GALR2 antagonist significantly blocked (p<0.05) the decrease in the number of saccharin reinforcements induced by GAL(1-15). The administration of GAL(1-15) decreased the sucrose intake 8 (p<0.05) and 24 hours (p<0.01) In the SPT, increased the latency of feeding (p<0.001) in the NSF and significantly decreased sniffing duration in the FUST. All these results indicate that GAL(1-15) induces a strong anhedonia-like phenotype in several behavioural tests, confirming an important role of this neuropeptide in anhedonia.This study was supported by Spanish SAF2016-79008 , PI-0083-2019 and UMA18-FEDERJA-008. Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech

The dopaminergic mesolimbic system are involved in the anhedonic-like effects produced by galanin (1-15) in rats.

Galanin (1-15)[GAL(1-15)] induces depressant- and anxiogenic-like actions in several behavioural tests. Recently, we described that GAL(1-15) induces an anhedonic-like effect in saccharine self-administration and sucrose preference test in rats. In order to investigate whether the effect of GAL(1–15) in anhedonia was associated with the reward circuit, we have studied the GAL(1-15) actions over the mesolimbic system by PET for in vivo imaging and in the expression of the C-Fos, Dat, Vmat2 and Dopamine and Galanin receptors genes in VTA and NAc. In the PET experiments, the [18F]FDG at 30, 60 and 90min after GAL(1-15) administration was measure as indicative of brain glucose metabolism. In the qPCR experiments, groups of rats (n=5-6) were killed 1h after i.c.v. GAL(1-15) 3nmol or vehicle. The VTA and NAc were dissected and the mRNA expression of C-Fos, Dat, Vmat2 and D1, D2, D3, D5, GALR1, and GALR2 receptors were measured by RT-qPCR. The GAL(1-15) induced a decrease in [18F]FDG uptake in the hippocampus and thalamus at 30, 60 and 90min, and in the striatum at 30min, however, in the prefrontal cortex, an increase in [18F]FDG uptake was observed after 30 and 60min. GAL(1-15) at a dose of 3 nmol produced a significant decrease in the mRNA levels of Dat and Vmat2 (p<0.05) and an increase in the D3 receptor (p<0.05) in VTA. In the NAc, GAL(1-15) induced a significant decrease in the expression of C-Fos (p<0.05) mRNA and a significantly increased the mRNA expression of D1 (p<0.05), D2 (p<0.05) and D3 (p<0.05). These results suggest the involvement of the dopaminergic mesolimbic system, a key region for the reward system, in GAL(1-15)-mediated action on anhedonia. These results may give the basis for the development of novel therapeutic strategies using GAL(1-15) for treatment of depression and reward-related diseases.Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech. This study was supported by SpanishSAF2016-79008 and PPIT.UMA.B1.2017/17

Sex-Dimorphic Behavioral Alterations and Altered Neurogenesis in U12 Intron Splicing-Defective Zrsr1 Mutant Mice

Mutant mice with respect to the splicing factor Zrsr1 present altered spermatogenesis and infertility. To investigate whether Zrsr1 is involved in the homeostatic control that the hypothalamus exerts over reproductive functions, we first analyzed both differential gene and isoform expression and alternative splicing alterations in Zrsr1 mutant (Zrsr1mu) hypothalamus; second, we analyzed the spontaneous and social behavior of Zrsr1mu mice; and third, we analyzed adult cell proliferation and survival in the Zrsr1mu hypothalamus. The Zrsr1mu hypothalamus showed altered expression of genes and isoforms related to the glutathione metabolic process, synaptonemal complex assembly, mRNA transport, and altered splicing events involving the enrichment of U12-type intron retention (IR). Furthermore, increased IR in U12-containing genes related with the prolactin, progesterone, and gonadotropin-releasing hormone (GnRH) reproductive signaling pathway was observed. This was associated with a hyperactive phenotype in both males and females, with an anxious phenotype in females, and with increased social interaction in males, instead of the classical aggressive behavior. In addition, Zrsr1mu females but not males exhibited reduced cell proliferation in both the hypothalamus and the subventricular zone. Overall, these results suggest that Zrsr1 expression and function are relevant to organization of the hypothalamic cell network controlling behavior