Análogos de las benztropinas como agentes terapéuticos para la adicción a la cocaína: Estudios preclínicos en modelos animales de conducta adictiva

La adicción a cocaína es un fenómeno de gran importancia clínica y social. Las consecuencias negativas que produce el abuso de estas sustancias son significativas, incluyendo problemas médicos, psicosociales y laborales para los individuos afectados. Además, su abuso está asociado a tasas incrementadas de crimen y violencia. La dependencia se caracteriza por tasas elevadas de recaída en un patrón cíclico de búsqueda y consumo. Estas recaídas pueden producirse incluso después de períodos prolongados de abstinencia. Dadas estas premisas, uno de los principales objetivos de nuestro trabajo es la identificación de fármacos que puedan atenuar el deseo compulsivo (“craving”) de consumir y reducir la incidencia de recaídas en animales experimentales. Además de mitigar el craving, estos fármacos deberían poseer un escaso o nulo potencial de abuso y carecer de los fuertes efectos psicoestimulantes característicos de estas drogas. La búsqueda de nuevas medicaciones para el tratamiento de la adicción se ha centrado en la identificación de sustancias que actúen como sustitutos de la droga estimulante produciendo efectos similares en la transmisión dopaminérgica y/o ejerciendo acciones antagonistas que impidan la unión al transportador de dopamina. La mayoría de los esfuerzos se han centrado en el diseño de moléculas que mimeticen la unión al transportador pero con un menor efecto estimulante y una acción farmacológica más duradera. Los estudios presentados han caracterizado el potencial de abuso y e terapéutico de dos análogos derivados de la benzotropina (BZT), el AHN 1-055 y el JHW 007. Estas moléculas se caracterizan por tener una alta afinidad por el DAT y una pauta lenta y duradera de acción farmacológica. Para llevar a cabo el trabajo administramos cada uno de los análogos en combinación con cocaína o anfetamina empleando diferentes modelos animales de adicción a psicoestimulantes tales como actividad locomotora, sensibilización, preferencia de lugar condicionada (CPP) y autoadministración (SA), acompañados de tecnicas de Western blot. Los resultados de estos ensayos han mostrado que ambos análogos no se comportan como estimulantes clásicos, mostrando significativamente menor capacidad estimulante a la vez que atenúan o bloquean completamente algunos de los efectos, tanto comportamentales como neurobiológicos inducidos tanto por los psicoestimulantes. Además, se muestran evidencias de que el tratamiento sustitutivo con el AHN-1055 como reduce la vulnerabilidad de recaída en individuos consumidores, apoyando la hipótesis de que pueden ser moléculas apropiadas para el tratamiento de la adicción a los psicoestimulantes

Retrieval-Extinction and Relapse Prevention: Rewriting Maladaptive Drug Memories?

Addicted individuals are highly susceptible to relapse when exposed to drug-associated conditioned stimuli (CSs; "drug cues") even after extensive periods of abstinence. Until recently, these maladaptive emotional drug memories were believed to be permanent and resistant to change. The rediscovery of the phenomenon of memory reconsolidation-by which retrieval of the memory can, under certain conditions, destabilize the previously stable memory before it restabilizes in its new, updated form-has led to the hypothesis that it may be possible to disrupt the strong maladaptive drug-memories that trigger a relapse. Furthermore, recent work has suggested that extinction training "within the reconsolidation window" may lead to a long-term reduction in relapse without the requirement for pharmacological amnestic agents. However, this so-called "retrieval-extinction" effect has been inconsistently observed in the literature, leading some to speculate that rather than reflecting memory updating, it may be the product of facilitation of extinction. In this mini review article, we will focus on factors that might be responsible for the retrieval-extinction effects on preventing drug-seeking relapse and how inter-individual differences may influence this therapeutically promising effect. A better understanding of the psychological and neurobiological mechanisms underpinning the "retrieval-extinction" paradigm, and individual differences in boundary conditions, should provide insights with the potential to optimize the translation of "retrieval-extinction" to clinical populations

Basal ganglia, drug addiction and the neuroscience of maladaptive habits

The mammalian brain has developed memory systems mediating rigid, yet evolutionarily adaptive patterns of responding to invariant environmental stimuli and internal demands. Such memory systems promote the recall of specific response templates and the execution of inflexible actions to liberate buffering capacity for performing conscious, explicit cognitive processing. The dopamine-innervated neostriatum is central to the ability to learn such consistent associations between stimuli and actions implicitly. Controlled by their outcome when initially learned, actions succumb through iteration to the influence of triggering stimuli and progressively detach themselves from the pleasurable results originally produced, thereby becoming pervasive habits. This might be the case for drug-seeking and drug-taking behaviours, actions learned in part through dopamine-dependent drug-induced reinforcement when the drug is first experienced. With extended drug use, however, drugseeking actions might become conditioned to, and triggered by, specific exteroceptive stimuli and/or affective states, gradually becoming irrepressible forms of responding. We will review neuroanatomical, neuropharmacological and behavioural evidence suggesting that the basal ganglia play a prominent role in the shaping of drug addiction, here regarded as a pathological modification of otherwise adaptive habit learning systems mediated by the basal ganglia.peer-reviewe

Withdrawal from Extended, Intermittent Access to A Highly Palatable Diet Impairs Hippocampal Memory Function and Neurogenesis: Effects of Memantine.

BACKGROUND: Compulsive eating can be promoted by intermittent access to palatable food and is often accompanied by cognitive deficits and reduction in hippocampal plasticity. Here, we investigated the effects of intermittent access to palatable food on hippocampal function and neurogenesis. METHODS: Male Wistar rats were either fed chow for 7 days/week (Chow/Chow group), or fed chow intermittently for 5 days/week followed by a palatable diet for 2 days/week (Chow/Palatable group). Hippocampal function and neurogenesis were assessed either during withdrawal or following renewed access to palatable food. Furthermore, the ability of the uncompetitive N-methyl-d-aspartate receptor (NMDAR) antagonist memantine to prevent the diet-induced memory deficits and block the maladaptive feeding was tested. RESULTS: Palatable food withdrawn Chow/Palatable rats showed both a weakened ability for contextual spatial processing and a bias in their preference for a "novel cue" over a "novel place," compared to controls. They also showed reduced expression of immature neurons in the dentate gyrus of the hippocampus as well as a withdrawal-dependent decrease of proliferating cells. Memantine treatment was able both to reverse the memory deficits and to reduce the excessive intake of palatable diet and the withdrawal-induced hypophagia in food cycling rats. CONCLUSIONS: In summary, our results provide evidence that withdrawal from highly palatable food produces NMDAR-dependent deficits in hippocampal function and a reduction in hippocampal neurogenesis

A Tangible Educative 3D Printed Atlas of the Rat Brain

[EN] In biology and neuroscience courses, brain anatomy is usually explained using Magnetic Resonance (MR) images or histological sections of different orientations. These can show the most important macroscopic areas in an animals¿ brain. However, this method is neither dynamic nor intuitive. In this work, an anatomical 3D printed rat brain with educative purposes is presented. Hand manipulation of the structure, facilitated by the scale up of its dimensions, and the ability to dismantle the ¿brain¿ into some of its constituent parts, facilitates the understanding of the 3D organization of the nervous system. This is an alternative method for teaching students in general and biologists in particular the rat brain anatomy. The 3D printed rat brain has been developed with eight parts, which correspond to the most important divisions of the brain. Each part has been fitted with interconnections, facilitating assembling and disassembling as required. These solid parts were smoothed out, modified and manufactured through 3D printing techniques with poly(lactic acid) (PLA). This work presents a methodology that could be expanded to almost any field of clinical and pre-clinical research, and moreover it avoids the need for dissecting animals to teach brain anatomy.This work was supported in part by the Spanish Ministerio de Economia y Competitividad (MINECO) and FEDER funds under grants BFU2015-64380-C2-2-R (D.M.) and BFU2015-64380-C2-1-R and EU Horizon 2020 Program 668863-SyBil-AA grant (S.C.). S.C. acknowledges financial support from the Spanish State Research Agency, through the "Severo Ochoa" Programme for Centres of Excellence in R&D (ref. SEV-2013-0317). D.R.Q. was supported by grant "Ayudas para la formacion de personal investigador (FPI)" from the Vicerrectorado de Investigacion, Innovacion y Transferencia of the Universitat Politecnica de Valencia.Quiñones, DR.; Ferragud-Agulló, J.; Pérez Feito, R.; García Manrique, JA.; Canals-Gamoneda, S.; Moratal, D. (2018). A Tangible Educative 3D Printed Atlas of the Rat Brain. Materials. 11(9):1531-1542. https://doi.org/10.3390/ma11091531S15311542119Perrin, R. J., Fagan, A. M., & Holtzman, D. M. (2009). Multimodal techniques for diagnosis and prognosis of Alzheimer’s disease. Nature, 461(7266), 916-922. doi:10.1038/nature08538Linden, D. E. J. (2012). The Challenges and Promise of Neuroimaging in Psychiatry. Neuron, 73(1), 8-22. doi:10.1016/j.neuron.2011.12.014Teipel, S., Drzezga, A., Grothe, M. J., Barthel, H., Chételat, G., Schuff, N., … Fellgiebel, A. (2015). Multimodal imaging in Alzheimer’s disease: validity and usefulness for early detection. The Lancet Neurology, 14(10), 1037-1053. doi:10.1016/s1474-4422(15)00093-9Woo, C.-W., Chang, L. J., Lindquist, M. A., & Wager, T. D. (2017). Building better biomarkers: brain models in translational neuroimaging. Nature Neuroscience, 20(3), 365-377. doi:10.1038/nn.4478Ivanov, I. (2017). The Neuroimaging Gap - Where do we go from Here? Acta Psychopathologica, 03(03). doi:10.4172/2469-6676.100090Kastrup, O., Wanke, I., & Maschke, M. (2005). Neuroimaging of infections. NeuroRX, 2(2), 324-332. doi:10.1602/neurorx.2.2.324Preece, D., Williams, S. B., Lam, R., & Weller, R. (2013). «Let»s Get Physical’: Advantages of a physical model over 3D computer models and textbooks in learning imaging anatomy. Anatomical Sciences Education, 6(4), 216-224. doi:10.1002/ase.1345Zheng, Y., Yu, D., Zhao, J., Wu, Y., & Zheng, B. (2016). 3D Printout Models vs. 3D-Rendered Images: Which Is Better for Preoperative Planning? 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Three-Dimensional Printing and Medical Imaging: A Review of the Methods and Applications. Current Problems in Diagnostic Radiology, 45(1), 2-9. doi:10.1067/j.cpradiol.2015.07.009Michalski, M. H., & Ross, J. S. (2014). The Shape of Things to Come. JAMA, 312(21), 2213. doi:10.1001/jama.2014.9542Ratto, M., & Ree, R. (2012). Materializing information: 3D printing and social change. First Monday, 17(7). doi:10.5210/fm.v17i7.3968Rengier, F., Mehndiratta, A., von Tengg-Kobligk, H., Zechmann, C. M., Unterhinninghofen, R., Kauczor, H.-U., & Giesel, F. L. (2010). 3D printing based on imaging data: review of medical applications. International Journal of Computer Assisted Radiology and Surgery, 5(4), 335-341. doi:10.1007/s11548-010-0476-xMannoor, M. S., Jiang, Z., James, T., Kong, Y. L., Malatesta, K. A., Soboyejo, W. O., … McAlpine, M. C. (2013). 3D Printed Bionic Ears. Nano Letters, 13(6), 2634-2639. doi:10.1021/nl4007744Guy, J. R., Sati, P., Leibovitch, E., Jacobson, S., Silva, A. C., & Reich, D. S. (2016). Custom fit 3D-printed brain holders for comparison of histology with MRI in marmosets. Journal of Neuroscience Methods, 257, 55-63. doi:10.1016/j.jneumeth.2015.09.002Friston, K. J., Holmes, A. P., Worsley, K. J., Poline, J.-P., Frith, C. D., & Frackowiak, R. S. J. (1994). Statistical parametric maps in functional imaging: A general linear approach. Human Brain Mapping, 2(4), 189-210. doi:10.1002/hbm.460020402Flandin, G., & Novak, M. J. U. (2013). fMRI Data Analysis Using SPM. fMRI, 51-76. doi:10.1007/978-3-642-34342-1_6Mueller, B. (2012). Additive Manufacturing Technologies – Rapid Prototyping to Direct Digital Manufacturing. Assembly Automation, 32(2). doi:10.1108/aa.2012.03332baa.010Gulanová, J., Kister, I., Káčer, N., & Gulan, L. (2018). A Comparative Study of various AM Technologies Based on Their Accuracy. Procedia CIRP, 67, 238-243. doi:10.1016/j.procir.2017.12.206D’Urso, P. S., Barker, T. M., Earwaker, W. J., Bruce, L. J., Atkinson, R. L., Lanigan, M. 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A Critical Period for Prefrontal Network Configurations Underlying Psychiatric Disorders and Addiction

The medial prefrontal cortex (mPFC) has been classically defined as the brain region responsible for higher cognitive functions, including the decision-making process. Ample information has been gathered during the last 40 years in an attempt to understand how it works. We now know extensively about the connectivity of this region and its relationship with neuromodulatory ascending projection areas, such as the dorsal raphe nucleus (DRN) or the ventral tegmental area (VTA). Both areas are well-known regulators of the reward-based decision-making process and hence likely to be involved in processes like evidence integration, impulsivity or addiction biology, but also in helping us to predict the valence of our future actions: i.e., what is “good” and what is “bad.” Here we propose a hypothesis of a critical period, during which the inputs of the mPFC compete for target innervation, establishing specific prefrontal network configurations in the adult brain. We discuss how these different prefrontal configurations are linked to brain diseases such as addiction or neuropsychiatric disorders, and especially how drug abuse and other events during early life stages might lead to the formation of more vulnerable prefrontal network configurations. Finally, we show different promising pharmacological approaches that, when combined with the appropriate stimuli, will be able to re-establish these functional prefrontocortical configurations during adulthood

Electrochemical analysis of gildings in Valencia altarpieces: a cross-age study since fifteenth until twentieth century, Journal of Solid State Electrochemistry

[EN] The application of the voltammetry of microparticles methodology to the study of gildings in paintings and architectural ornaments is described. Nanosamples from pieces from different churches of the Comunitat Valenciana (Spain) covering since the fifteenth century until nowadays were studied upon attachment to graphite electrodes in contact with aqueous HCl and H2SO4 electrolytes. Electrochemical measurements, combined with field emission scanning electron microscopy X-ray microanalysis (FESEM-EDX) and atomic force microscopy (AFM) data, denoted that a common manufacturing technique was used with minimal variations along time. The relationship between specific voltammetric features associated to bulk gold and active surface sites, however, changed monotonically with time, thus suggesting the possibility of age monitoring.Financial support from the MINECO Projects CTQ2014-53736-C3-1-P, CTQ2014-53736-C3-2-P and MAT2015-65445-C2-2-R, which are supported with ERDF funds is gratefully acknowledged. Likewise financial support of the Comunidad de Madrid and structural funds of the EU through Programa Geomateriales 2 ref. S2013/MIT-2914 is acknowledged. The authors thank the Seccion de Investigacion Arqueologica Municipal de Valencia for kindly authorizing sampling to carry out this research. The authors also thank Dr. Jose Luis Moya Lopez and Mr. Manuel Planes Insausti (Microscopy Service of the Universitat Politecnica de Valencia) for their technical support.Ferragud Adam, JV.; Piquero-Cilla, J.; Domenech Carbo, MT.; Guerola Blay, V.; Company Climent, J.; Domenech Carbo, A. (2016). Electrochemical analysis of gildings in Valencia altarpieces: a cross-age study since fifteenth until twentieth century, Journal of Solid State Electrochemistry. Journal of Solid State Electrochemistry. 21(5):1477-1487. https://doi.org/10.1007/s10008-017-3512-8S14771487215Le Goff J (1991) El hombre medieval. Alianza Editorial, MadridValero-Cuenca A (2011) El oro: símbolo de lo trascendente en la pintura gótica. Su capacidad como elemento transformador, espiritual y plástico. Archivo de Arte Valenciano XCII. Real Academia de Bellas Artes de San Carlos, ValènciaRodriguez-López A, Khandekar N, Gates G, Newman R (2007) Materials and techniques of a Spanish Renaissance panel painting. Stud Conserv 52:81–100Chao R, Heginbotham A, Lee L, Chiari G (2014) Materials and techniques of gilding on a suite of French eighteenth-century chair. Stud Conserv 59:102–112Alfonso-Muñoz M, Ferragut-Adam X, Guerola-Blay V, Roig-Picazo MP (2008) Intervención en la ornamentación dorada del espacio central y acceso sur de la Basílica de la Virgen de los Desamparados de Valencia. Arché 3:117–126Antonelli F, Lazzarini L, Cancellere S, Tesser E (2016) Study of the deteriortion products, gilding, and polychromy of the stones of the Scuola Grande Di San Marco’s façade in Venice. Stud Conserv 61:74–85Toniolo L, Colombo C, Bruni S, Fermo P, Casoli A, Palla G, Bianchi CL (1998) Gilded stuccoes of the Italian baroque. Stud Conserv 43:201–208De Quinto ML (1984) Los batihojas artesanos del oro. Editora Nacional, MadridLópez-Zamora E (2007) Estudio de los materiales y procedimientos del dorado a través de las fuentes literarias antiguas: aplicación en las decoraciones de pinturas castellanas sobre tabla. PhD Thesis. Universidad Complutense de Madrid, MadridHerranz E (2000) El arte de dorar, 6th edn. 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Actualización y adaptación a la docencia híbrida de la asignatura Documentación y Metodología Científica del Grado en Farmacia

[EN] The concern of the teaching staff to improve the teaching quality of the Scientific Documentation and Methodology subject that is taught in the first year of the Degree in Pharmacy (and double degree in Pharmacy and Human Nutrition and Dietetics) at the University of Valencia has been permanent with the development of three innovation projects during three consecutive courses and the creation of the Manual Documentation and Methodology in Health Sciences. The innovation generated includes the reformulation of both the content and the teaching methodology of the subject, based on the Flipped Classroom modality and focusing the contents around the construction of a monographic work by the students on a pertinent topic of the teaching program. In a complementary way, and given the hybrid teaching circumstances of the 2020-2021 academic year, innovative initiatives have been developed focused on creating virtual or blended learning environments and promoting continuous evaluation of students in order to cause positive and verifiable effects in learning. At the same time, we have considered essential to know the degree of acceptance and involvement of the students regarding the implementation of the new teaching modalities.[ES] La inquietud del profesorado por mejorar la calidad docente de la asignatura Documentación y Metodología Científica que se imparte en el primer curso del Grado en Farmacia (y doble grado en Farmacia y Nutrición Humana y Dietética) de la Universidad de Valencia ha sido permanente con el desarrollo de tres proyectos de innovación durante tres cursos consecutivos y la creación del manual Documentación y Metodología en Ciencias de la Salud. La innovación generada incluye la reformulación tanto del contenido como de la metodología docente de la asignatura, basándonos en la modalidad Flipped Classroom y centrando los contenidos en torno a la construcción de un trabajo monográfico por parte de los alumnos sobre un tema pertinente del programa docente. De forma complementaria y ante las circunstancias de docencia híbrida del curso académico 2020-2021, se han desarrollado iniciativas innovadoras enfocadas a la creación de entornos de aprendizaje virtuales o semipresenciales y a fomentar la evaluación continua de los estudiantes con el fin de provocar efectos positivos y constatables en el aprendizaje. Paralelamente hemos considerado imprescindible conocer el grado de aceptación e implicación del alumnado respecto a la implantación de las nuevas modalidades docentes.Lucas Domínguez, R.; Vidal Infer, A.; Ferragud Domingo, C.; Valderrama Zurian, JC.; Cuenca Lorente, M. (2021). Actualización y adaptación a la docencia híbrida de la asignatura Documentación y Metodología Científica del Grado en Farmacia. En IN-RED 2021: VII Congreso de Innovación Edicativa y Docencia en Red. Editorial Universitat Politècnica de València. 1387-1401. https://doi.org/10.4995/INRED2021.2021.13719OCS1387140

Identification of vegetal species in wooden objects using in situ microextraction-assisted voltammetry of microparticles

[EN] A method for identifying vegetal species in wooden objects using microextraction-assisted voltammetry of microparticles is described. The proposed methodology, aimed at facilitating tasks of patrimony conservation, is based on the recording of the voltammetric response of microparticulate films of compounds resulting from microextraction with organic solvents (ethanol, acetone, and chloroform) of micro- or sub-microsamples of wood in contact with aqueous buffers. Upon application of bivariate and multivariate chemometric techniques, the obtained voltammetric responses led us to identify different taxonomic groups from the characteristic voltammetric profiles. Application to a series of samples of wooden objects of cultural heritage of different European and American provenances dated to ca. 375¿ 350 BC and to historical periods, namely 14th and 17¿19th centuries, is describedFinancial support from the MICIN Projects CTQ2014-53736-C3-1-P and CTQ2014-53736-C3-2-P, which are also supported with ERDF funds, is gratefully acknowledged. Thanks to the Museum of Prehistory of Valencia, especially to the director Helena Bonet.Domenech-Carbo, A.; Domenech Carbo, MT.; Ferragud-Adam, X.; Ortiz-Miranda, AS.; Montoya, N.; Pasies -Oviedo, T.; Peiró-Ronda, MA.... (2017). Identification of vegetal species in wooden objects using in situ microextraction-assisted voltammetry of microparticles. Analytical Methods. 9(13):2041-2048. https://doi.org/10.1039/c7ay00323dS2041204891