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28 Pags., 1 Tabl., 3 Figs. The definitive version is available at: http://onlinelibrary.wiley.com/journal/10.1111/%28ISSN%291755-0238 ; Background and Aims: Most optical devices for indirect measurement of leaf area index (LAI) from canopy-transmitted light are tailored for homogeneous canopies, thus limiting their application to discontinuous canopies such as vertically trained vineyards. This study evaluates the influence of sun position on the reliability of LAI estimates provided by a ceptometer and proposes a measurement protocol for use of such instruments on vineyards under direct illumination. Methods and Results: Ceptometer readings at several sun elevation and azimuth angles were recorded in two fields. LAI estimated at different sun positions using several measurement protocols were then compared against destructive leaf area measurements. The best results when the sun position departs from the zenith (sun elevation < 40°) were achieved by reading the transmitted, photosynthetically active radiation in all the inter-row spaces, whereas measurements below the vines were suitable only when the sun illuminates close to the zenith. Conclusions: The homogeneity of the canopy fraction measured along the ceptometer at each individual reading is a major requirement in order to obtain non-biased LAI estimates. Therefore, the protocol followed to measure the transmitted photosynthetically active radiation at every sun position proved critical for the accuracy of LAI determination. Significance of Study This study provides guidelines for reducing LAI uncertainties associated with vineyard canopy structure in LAI estimation with linear array optical devices such as ceptometers. ; This research was funded by the Government of Aragon, Spain, as part of a demonstration project, and by the Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria (INIA) under research project RTA 2005-00230-00-00, and a grant for author Raúl López-Lozano. ; Peer reviewed

In this paper we discuss the consensus view on the use of qualifying biomarkers in drug safety, raised within the frame of the XXIV meeting of the Spanish Society of Clinical Pharmacology held in Málaga (Spain) in October, 2011. The widespread use of biomarkers as surrogate endpoints is a goal that scientists have long been pursuing. Thirty years ago, when molecular pharmacogenomics evolved, we anticipated that these genetic biomarkers would soon obviate the routine use of drug therapies in a way that patients should adapt to the therapy rather than the opposite. This expected revolution in routine clinical practice never took place as quickly nor with the intensity as initially expected. The concerted action of operating multicenter networks holds great promise for future studies to identify biomarkers related to drug toxicity and to provide better insight into the underlying pathogenesis. Today some pharmacogenomic advances are already widely accepted, but pharmacogenomics still needs further development to elaborate more precise algorithms and many barriers to implementing individualized medicine exist. We briefly discuss our view about these barriers and we provide suggestions and areas of focus to advance in the field. ; The work in the author's laboratory is financed by Grants PS09/00943, PS09/00469, PS09/01384, FIS-FEDER-PI081913, RETICS RIRAAF RD07/0064/0016, REDINSCOR RD06/0003/0015, TERCEL RD06/010/0017, RTA RD06/0001/1009, CIBERehD and CIBERobn from Instituto de Salud Carlos III, Madrid, Spain, and by Grants SAF10/16549 from Ministerio de Ciencia y Tecnología, CTS-6470 from Consejeria de Salud, Junta de Andalucía, Spain, and GR10068 from Junta de Extremadura, Spain. Financed in part with FEDER funds from the European Union. IMI-JU is partly funding the research activities under the SAFE-T project (Grant Agreement No 115003). ; Peer reviewed ; Peer Reviewed

9 páginas, 4 figuras, 2 tablas.-- El PDF es la versión post-print. ; [Background and Aims]: The objective of this study was to test whether the mean values of several root morphological variables were related to the ability to develop root-borne shoots and/or shoot-borne roots in a wide range of vascular plants. [Methods]: A comparative study was carried out on the 123 most common plant species from eroded lands in north-east Spain. After careful excavations in the field, measurements were taken of the maximum root depth, absolute and relative basal root diameter, specific root length (SRL), and the root depth/root lateral spread ratio on at least three individuals per species. Shoot-rooting and root-sprouting were observed in a large number of individuals in many eroded and sedimentary environments. The effect of life history and phylogeny on shoot-rooting and root-sprouting abilities was also analysed. [Key Results]: The species with coarse and deep tap-roots tended to be root-sprouting and those with fine, fasciculate and long main roots (which generally spread laterally), tended to be shoot-rooting. Phylogeny had an important influence on root system morphology and shoot-rooting and root-sprouting capacities. However, the above relations stood after applying analyses based on phylogenetically independent contrasts (PICs). [Conclusions]: The main morphological features of the root system of the study species are related to their ability to sprout from their roots and form roots from their shoots. According to the results, such abilities might only be functionally viable in restricted root system morphologies and ecological strategies. ; This study was supported by the Spanish Ministry of Science and Technology, projects AMB93-0806, REN2002-02635/ GLO and RTA 2005-00100. J. G. C. and S. P. were supported by a grant from the Government of Aragon (BMA 15/93) and a FPU scholarship (AP-2001-2311, MEC, Spain), respectively. ; Peer reviewed

En el presente texto se analiza el proyecto de la Sociedad de la Información tal como ha sido formulado por la Comisión Eu ropea y por la Organización para la Cooperación y el De s a r rollo Ec o n ó m i c o. Como iniciativa política, la llamada Sociedad de la Información está basada en el dominio de las ideas fuerza de la desregulación, la liberalización y la competitividad internacional. En un nivel económico, el proyecto es sostén del modo de desarrollo informacional, en el que la información aparece como el revulsivo productivo medular en las últimas tres décadas. Para realizar el análisis de un proyecto que es al mismo tiempo un proceso social, se propone un marco explicativo articulado por la economía política de la comunicación y se discute tanto el abordaje culturalista como el tecnologista. El artículo sostiene que la Sociedad de la Información no puede ser entendida sino i n s e rta en el contexto de las tensiones y conflictos desencadenados en su desarrollo. ; This text analyses the Information Society Project just the way it has been formulated by the Eu ropean Commission and the Eu ropean Cooperation and De velopment Organisation. As a political initiative, the so-called Information Society is based upon the domain of ideas such as: deregularization force, liberalisation and international competi t i veness. In an economic level, the project supports the informational development way, w h e re information has appeared as a medullary production revulsive in last three decades. In order to pre p a re the analysis of a project that, at the same time, is a social process this text suggests an explanation frame articulated by communication political economy. Whether cultural or technological approaches are discussed. This article affirms that Information Society cannot be understood but implemented into the strain and conflict context caused during its development.

One aspect of the addictive process that has not been thoroughly investigated is the consequence of the frustrated state occurring when the drug is not available. The present study aimed to validate a novel operant model of frustrated expected reward in mice. C57BL/6J mice were trained in operant conditioning maintained by chocolate-flavoured pellets or cocaine. After the completion of high rates of responding on a progressive ratio schedule, the reward was unexpectedly withheld. The consequences of this frustrated behaviour on anxiety, aggressiveness, perseveration, extinction and reinstatement were investigated. Mice exposed to the frustrated event perseverated in the operant responses and showed increased aggressiveness in the resident-intruder test. These animals also showed higher rates of cue-induced reinstatement of drug seeking. The present study provides a reliable operant model in mice to evaluate a frustrated state following reward unavailability. This animal model could be useful to study the behavioural and neurochemical consequences related to the emotional states generated during the omission of a highly expected reward. ; This work was supported by the DG Research of the European Commission (PHECOMP, no. LHSM-CT-2007—037669 and GENADDICT, no. LSHM-CT-2004—05166), the Spanish 'Instituto de Salud Carlos III' (RTA, no. RD06/001/001), the Spanish 'Ministerio de Ciencia e Innovación' (no. SAF2007-64062), the Spanish 'Ministerio de Sanidad, Política Social e Igualdad' (Plan/nNacional Sobre Drogas, no. 2009/026), the Catalan Government (SGR2009-00131), the ICREA Foundation (ICREA Academia-2008). A.B. was supported by an FI pre-doctoral fellowship of the Catalan Government; J.G.-C. was supported by a 'Juan de la Cierva' postdoctoral fellowship from the Spanish 'Ministerio de Ciencia e Innovación'; and E.M.-G. was supported by a 'Sara Borrell' post-doctoral fellowship from the Spanish 'Instituto de Salud Carlos III'. Partial support from FEDER funds is also acknowledged

Injury to peripheral nerves often leads to abnormal pain states (hyperalgesia, allodynia and spontaneous pain), which can remain long after the injury heals. Although opioid agonists remain the gold standard for the treatment of moderate to severe pain, they show reduced efficacy against neuropathic pain. In addition to analgesia, opioid use is also associated with hyperalgesia and analgesia tolerance, whose underlying mechanisms share some commonalities with nerve injury-induced hypersensitivity. Here, we reviewed up-to-day research exploring the contribution of mu-opioid receptor (MOR) on the pathophysiology of neuropathic pain and on analgesic opioid actions under these conditions. We focused on the specific contributions of MOR populations at peripheral, spinal and supraspinal level. Moreover, evidences of neuroplastic changes that may underlie the low efficacy of MOR agonists under neuropathic pain conditions are reviewed and discussed. Sensitization processes leading to pain hypersensitivity, molecular changes in signalling pathways triggered by MOR and glial activation are some of these mechanisms elicited by both nerve injury and opioid exposure. Nerve injury-induced pain hypersensitivity might be masking the initial analgesic effects of opioid agonists, and alternatively, sustained opioid treatment to individuals already suffering from neuropathic pain could aggravate their pathophysiological state. Finally, some combined therapies that can increase opioid analgesic effectiveness in neuropathic pain treatment are highlighted. SIGNIFICANCE: This review provides evidence of the low benefit of opioid monotherapy in neuropathic pain and analyses the reasons of this reduced effectiveness. Opioid agonists along with drugs targeted to block the sensitization processes induced by MOR stimulation might result in a better management of neuropathic pain. ; We acknowledge the financial support of the European Commission FP7. Grant Number: #HEALTH‐F2‐2013‐602891; Spanish Ministry of Science, Innovation and Universities. Grant Number: #SAF2017‐84060‐R‐AEI/FEDER‐UE; Instituto de Salud Carlos III. Grant Number: RETICS/RTA #RD16/0017; Catalan Government AGAUR. Grant Numbers: #ICREA Acadèmia‐2015, #2017‐SGR‐669; Spanish MECD

11 páginas, 3 figuras, 5 tablas. ; [Background and Aims]: Plants from gypsum habitats are classified as gypsophiles and gypsovags. The former include both narrow endemics limited to small gypsum areas and regionally dominant gypsophiles growing in gypsum areas of large regions, whereas gypsovags are plants that can grow both in gypsum and non-gypsum soils. Factors controlling the distribution of gypsum plants are still not fully understood. [Methods]: To assess how the different types of gypsum plants deal with the stressful conditions of gypsum substrates, comparisons were made of the leaf chemical composition of four gypsovags, five regionally dominant gypsophiles and four narrow gypsum endemics growing in two massive gypsum areas of the Iberian Peninsula. [Key Results]: The chemical composition of gypsovags was clearly different from regionally dominant gypsophiles, while the chemical composition of narrow-gypsophile endemics was more similar to the chemical composition of gypsovags than to that of regionally dominant gypsophiles. Regionally dominant gypsophiles showed higher concentrations of ash, Ca, S, N, Mg P and Na, whereas gypsovags and local gypsophile endemics displayed higher concentrations of C and greater C : N ratios. [Conclusions]: Such differences suggest that the three groups of gypsum plants follow diverse ecological strategies. It is suggested that regionally dominant gypsophiles might fit the 'specialist' model, being species specifically adapted to gypsum, whereas both gypsovags and narrow-gypsophile endemics might fit the 'refuge' model, being stress-tolerant species that find refuge on gypsum soils from competition. The analysis of the leaf chemical composition could be a good predictor of the degree of plants specialization to gypsum soils. ; R.M. and S.P. were funded by a Post-doctoral and a FPU fellowship, respectively (SEUI – MEC, Spain). This study was supported by the MEC (Spanish Government; research project RTA 2005–00100), the MCT (Spanish Government; research projects CGL2006–11619/HID, CGL2004– 04919-C02-01/HID, REN2003–08678/HID) and by REMEDINAL, a research network financed by the Autonomous Government of Madrid. ; Peer reviewed

BACKGROUND: Hypocretin (orexin) signaling is involved in drug addiction. In this study, we investigated the role of these hypothalamic neuropeptides in nicotine withdrawal by using behavioral and neuroanatomical approaches. METHODS: Nicotine withdrawal syndrome was precipitated by mecamylamine (2 mg/kg, subcutaneous) in C57BL/6J nicotine-dependent mice (25 mg/kg/day for 14 days) pretreated with the hypocretin receptor 1 (Hcrtr-1) antagonist SB334867 (5 and 10 mg/kg, intraperitoneal), the hypocretin receptor 2 antagonist TCSOX229 (5 and 10 mg/kg, intraperitoneal), and in preprohypocretin knockout mice. c-Fos expression was analyzed in several brain areas related to nicotine dependence by immunofluorescence techniques. Retrograde tracing with rhodamine-labeled fluorescent latex microspheres was used to determine whether the hypocretin neurons project directly to the paraventricular nucleus of the hypothalamus (PVN), and SB334867 was locally administered intra-PVN (10 nmol/side) to test the specific involvement of Hcrtr-1 in this brain area during nicotine withdrawal./nRESULTS: Somatic signs of nicotine withdrawal were attenuated in mice pretreated with SB334867 and in preprohypocretin knockout mice. No changes were found in TCSOX229 pretreated animals. Nicotine withdrawal increased the percentage of hypocretin cells expressing c-Fos in the perifornical, dorsomedial, and lateral hypothalamus. In addition, the increased c-Fos expression in the PVN during withdrawal was dependent on hypocretin transmission through Hcrtr-1 activation. Hypocretin neurons directly innervate the PVN and the local infusion of SB334867 into the PVN decreased the expression of nicotine withdrawal. CONCLUSIONS: These data demonstrate that hypocretin signaling acting on Hcrtr-1 in the PVN plays a crucial role in the expression of nicotine withdrawal. ; This work was supported by the Instituto de Salud Carlos III grants #PI07/0559,/n#PI10/00316, and #RD06/001/001 (RTA-RETICS), by the Spanish Ministry of Science/nand Technology (Consolider-C, #SAF2007-64062), the Catalan Government/n(SGR2009-00731), and by the Catalan Institution for Research and Advanced Studies/n(ICREA Academia program). A Plaza-Zabala is a recipient of a predoctoral fellowship/nfrom the Spanish Ministry of Education

BACKGROUND: The treatment of neuropathic pain is unsatisfactory at the present moment and the sigma 1 receptor has been identified as a new potential target for neuropathic pain. The aim of this study was to use an operant self-administration model to reveal the potential interest of a new sigma 1 receptor antagonist, S1RA, in chronic pain that was developed in mice by a partial ligation of the sciatic nerve. METHODS: Once that chronic pain had reached a steady state, mice were trained to maintain an operant behaviour to self-administer S1RA. The possible abuse liability of the analgesic compound was determined by evaluating operant self-administration in sham-operated mice. The influence of S1RA on the anhedonic state related to chronic pain was also evaluated by measuring the preference for palatable drink (2% sucrose solution) using a recently validated and highly sensitive behavioural device. RESULTS: Nerve-injured mice, but not sham-operated animals, acquired the operant responding to obtain S1RA (6 mg/kg/infusion). After 10 days of S1RA self-administration, neuropathic pain was significantly reduced in nerve-injured mice. In addition, an anhedonic state was revealed in nerve-injured mice by a decreased consumption of palatable drink, which was significantly attenuated by S1RA (25 mg/kg). CONCLUSIONS: These results reveal the analgesic efficacy of the sigma antagonist, S1RA, in neuropathic pain associated with an improvement of the emotional negative state and that was devoided of reinforcing effects. The operant responses evaluated in this new mouse model can have a high predictive value to estimate the clinical benefit/risk ratio of new analgesic compounds to treat chronic pain, such as S1RA. ; S1RA was provided by Esteve as a gift within research projects funded by the CENIT program (CEN-20061005) from the Centro para el Desarollo Technológico Industrial from the Spanish Ministry of Science and Innovation (#SAF2007-64062), "Redes temáticas de investigación cooperativa en salud (RETICS) del Instituto de Salud Carlos III (RD06/001/001). Red de trastornos adictivos (RTA)", the Catalan Government (SGR2009-00131), the ICREA Foundation (ICREA Academia-2008) and the DG Research of the European Commission (PHECOMP, #LSHM-CT-2007-037669)

BACKGROUND: Cannabis is the most widely used illicit drug in the world. Although there is a high prevalence of users who seek treatment for cannabis dependence, no accepted pharmacologic treatment is available to facilitate and maintain abstinence. The hypocretin/orexin system plays a critical role in drug addiction, but the potential participation of this system in the addictive properties of cannabinoids is unknown. METHODS: We investigated the effects of hypocretins in the intravenous self-administration of the synthetic cannabinoid agonist WIN55,212-2 using hypocretin receptor-1 (Hcrtr-1) and hypocretin receptor-2 antagonists and Hcrtr-1 knockout mice. Additional groups of mice were trained to obtain water to rule out operant responding impairments. Activation of hypocretin neurons was analyzed by using double-label immunofluorescence of FosB/ΔFosB with hypocretin-1. Microdialysis studies were performed to evaluate dopamine extracellular levels in the nucleus accumbens after acute Δ(9)-tetrahydrocannabinol administration.RESULTS: Systemic administration of the Hcrtr-1 antagonist SB334867 reduced intravenous self-administration of WIN55,212-2, as well as the maximum effort to obtain a WIN55,212-2 infusion, as revealed under a progressive ratio schedule. This role of Hcrtr-1 in the reinforcing and motivational properties of WIN55,212-2 was confirmed in Hcrtr-1 knockout mice. Contingent, but not noncontingent, WIN55,212-2 self-administration increased the percentage of hypocretin cells expressing FosB/ΔFosB in the lateral hypothalamus. The enhancement in dopamine extracellular levels in the nucleus accumbens induced by Δ(9)-tetrahydrocannabinol was blocked in mice lacking the Hcrtr-1. CONCLUSIONS: /nThese findings demonstrate that Hcrtr-1 modulates the reinforcing properties of cannabinoids, which could have a clear therapeutic interest. ; This work was supported by the Instituto de Salud Carlos III grants, #PI07/0559, #PI10/00316 and #RD06/001/001 (RTA-RETICS), by the Spanish Ministry of Science and Technology, Consolider-C #SAF2007-64062 and #SAF2011-29864, the Catalan Government (SGR2009-00731), and by the Catalan Institution for Research and Advanced Studies (ICREA Academia program). África Flores is recipient of a predoctoral fellowship from the Spanish Ministry of Education

Regional trade agreements (RTAs) are important instruments of the world trade system, which have been increasingly developed in recent decades, since they complement the existing World Trade Organization (WTO) and WTO+ agreements and allow taking into account the specificities of regions. The principle of ensuring non-discriminatory trade is the main principle of multilateral trade of the WTO, or in other words, observes the rule of not favoring one trading partner over another. RTAs are, in fact, an exception to this approach, as it is the signatories that enjoy more favorable market access conditions. At the same time, the WTO recognizes the legitimate role of RTAs in facilitating trade between their parties, but requires that they not create barriers to trade with third parties. RTAs cover more than half of world trade, and new transcontinental agreements have been concluded in recent years: the Comprehensive and Progressive Agreement for Trans-Pacific Partnership, the Comprehensive Regional Economic Partnership, and the African Continental Free Trade Area. There are different types of RTAs in international cooperation, ranging from free trade agreements to common markets, including between countries of a territorially contiguous or transcontinental nature, based on WTO and WTO+ agreements or protectionist in nature. The article reflects the consequences for the national economies of developing countries, it is revealed that the European Union in the RTAs is actively promoting its values as the absolute truth for all peoples and nations, and their non-acceptance is considered as a factor causing possible restrictions. Other developed economies have also imposed obligations on signatories in terms of ensuring the transformation of the national economies of developing countries, but in recent years this trend has weakened somewhat. China, initiating the RTA, pursues the realization of its national interests, without imposing any political, mental or social aspects, and at the same time is ready to develop mutually acceptable compromises. The transformation of RTАs in modern conditions is carried out in three basic directions: preference for the preservation of full sovereignty by the signatory countries; the inclusion of articles that condition the promotion of sustainable development; control and monitoring to ensure compliance with labor safety regulations, non-damage to the ecological environment, as well as the use of tools of responsible corporate business conduct.

The statistics of road accidents in the world is presented. The most probable causes and consequences of accidents on roads were analyzed. Devices, allowing to minimize losses in vehicle collisions were proposed. To solve the problem of safe movement of vehicles on roads is the topical issue. For this, it is necessary to study and analyze the statistics of road accidents and to identify the key factors, which cause fatal accidents or injuries. To develop the complex of measures and modern devices, allowing to avoid collisions and minimize losses in accidents is pressing problem. Road accidents are the most dangerous threat to human health around the world. Damage from road traffic accidents (RTA) exceeds the damage from all other transport accidents (aircrafts, ships, trains, etc.) together. Road accidents are one of the major global threats to human health and life. The problem is aggravated by the fact that victims of accidents are as a rule young and healthy (before the accident) people. According to the WHO, in the world 1.2 million people die and about 50 million are injured in road accidents each year. More than 27,000 die on Russian roads, and more than 40,000 on USA roads. In terms of the number of vehicles, these figures mean 70 dead in road accidents in Russia or 15 dead in the USA in a year for each 100 000 vehicles. According to statistical estimates, more than 3 million people died in accidents on U.S. roads since the beginning of the XX century that exceeds all USA losses (650,000) in all military conflicts (since 1774). ; Представлена статистика дорожно-тарнспортных происшествий в мире. Проанализировано наиболле вероятносные причины и последствия аварий на дорогах. Предложены устройства позволяющие минимизировать потери при столкновениях транспортних средств. В работе изучено и проанализировано статистику дорожно-транспортных происшествий и выявлены основные факторы, при которых происходят аварии с летальным исходом или травматизмом. ; Представлена статистика дорожньо-тарнспортних пригод в світі. Проаналізовано наібольш імовірносні причини і наслідки аварій на дорогах. Запропоновано пристрої які дозволяють мінімізувати втрати при зіткненнях транспортних засобів. У роботі вивчено і проаналізовано статистику дорожньо-транспортних пригод та виявлено основні чинники, при яких відбуваються аварії з летальним результатом або травматизмом.

The statistics of road accidents in the world is presented. The most probable causes and consequences of accidents on roads were analyzed. Devices, allowing to minimize losses in vehicle collisions were proposed. To solve the problem of safe movement of vehicles on roads is the topical issue. For this, it is necessary to study and analyze the statistics of road accidents and to identify the key factors, which cause fatal accidents or injuries. To develop the complex of measures and modern devices, allowing to avoid collisions and minimize losses in accidents is pressing problem. Road accidents are the most dangerous threat to human health around the world. Damage from road traffic accidents (RTA) exceeds the damage from all other transport accidents (aircrafts, ships, trains, etc.) together. Road accidents are one of the major global threats to human health and life. The problem is aggravated by the fact that victims of accidents are as a rule young and healthy (before the accident) people. According to the WHO, in the world 1.2 million people die and about 50 million are injured in road accidents each year. More than 27,000 die on Russian roads, and more than 40,000 on USA roads. In terms of the number of vehicles, these figures mean 70 dead in road accidents in Russia or 15 dead in the USA in a year for each 100 000 vehicles. According to statistical estimates, more than 3 million people died in accidents on U.S. roads since the beginning of the XX century that exceeds all USA losses (650,000) in all military conflicts (since 1774). ; Представлена статистика дорожно-тарнспортных происшествий в мире. Проанализировано наиболле вероятносные причины и последствия аварий на дорогах. Предложены устройства позволяющие минимизировать потери при столкновениях транспортних средств. В работе изучено и проанализировано статистику дорожно-транспортных происшествий и выявлены основные факторы, при которых происходят аварии с летальным исходом или травматизмом. ; Представлена статистика дорожньо-тарнспортних пригод в світі. Проаналізовано наібольш імовірносні причини і наслідки аварій на дорогах. Запропоновано пристрої які дозволяють мінімізувати втрати при зіткненнях транспортних засобів. У роботі вивчено і проаналізовано статистику дорожньо-транспортних пригод та виявлено основні чинники, при яких відбуваються аварії з летальним результатом або травматизмом.

Cocaine addiction causes serious health problems, and no effective treatment is available yet. We previously identified a genetic risk variant for cocaine addiction in the PLCB1 gene and found this gene upregulated in postmortem brains of cocaine abusers and in human dopaminergic neuron-like cells after an acute cocaine exposure. Here, we functionally tested the contribution of the PLCB1 gene to cocaine addictive properties using Plcb1+/- mice. First, we performed a general phenotypic characterization and found that Plcb1+/- mice showed normal behavior, although they had increased anxiety and impaired short-term memory. Subsequently, mice were trained for operant conditioning, self-administered cocaine for 10 days, and were tested for cocaine motivation. After extinction, we found a reduction in the cue-induced reinstatement of cocaine-seeking behavior in Plcb1+/- mice. After reinstatement, we identified transcriptomic alterations in the medial prefrontal cortex of Plcb1+/- mice, mostly related to pathways relevant to addiction like the dopaminergic synapse and long-term potentiation. To conclude, we found that heterozygous deletion of the Plcb1 gene decreases cue-induced reinstatement of cocaine-seeking, pointing at PLCB1 as a possible therapeutic target for preventing relapse and treating cocaine addiction. ; This work was supported by the Spanish 'Ministerio de Economía y Competitividad-MINECO' (#SAF2017-84060-RAEI/FEDER-UE), the Spanish 'Instituto de Salud Carlos III, RETICS-RTA' (#RD12/0028/0023), the 'Generalitat de Catalunya, AGAUR' (#2017 SGR-669), 'ICREA-Acadèmia' (#2015) and the Spanish 'Ministerio de Sanidad, Servicios Sociales e Igualdad/Plan Nacional Sobre Drogas' (#PNSD-2017I068) to RM, 'Fundació La Marató-TV3' (#2016/20-30) and 'Plan Nacional Sobre Drogas of the Spanish Ministry of Health' (#PNSD-2019I006) to EMG, Spanish 'Ministerio de Ciencia, Innovación y Universidades' (#RTI2018-100968-B-100), Spanish 'Ministerio de Economía y Competitividad' (#SAF2015-68341-R), 'AGAURGeneralitat de Catalunya' (#2017-SGR-738) and Spanish 'Ministerio de Sanidad, Servicios Sociales e Igualdad/Plan Nacional Sobre Drogas' (#PNSD-2017I050) to BC and (#PNSD-2020I042) to NFC. The research leading to these results has also received funding from the European Union H2020 Program [H2020/2014-2020] under grant agreements n° 667302 (CoCA), 643051 (MiND) and 728018 (Eat2beNICE). JCD was supported by the H2020 CoCA and Eat2beNICE projects

The neuropeptide oxytocin (OXT) plays a critical role in the regulation of social and emotional behaviors. OXT plays a role in stress response and in drug reward, but to date no studies have evaluated its implication in the long-lasting increase of the motivational effects of cocaine induced by repeated social defeat (RSD). During the social defeat procedure, 1 mg/kg of OXT was administered 30 min before each episode of RSD. Three weeks after the last defeat, the effects of cocaine on the conditioned place preference (CPP), locomotor sensitization and the self-administration (SA) paradigms were evaluated. The influence of OXT on the levels of BDNF in the prefrontal cortex (PFC), striatum and hippocampus was also measured. Our results confirm that raising the levels of OXT during social defeat stress can block the long-lasting effects of this type of stress. OXT counteracts the anxiety induced by social defeat and modifies BDNF levels in all the structures we have studied. Moreover, OXT prevents RSD-induced increases in the motivational effects of cocaine. Administration of OXT before each social defeat blocked the social defeat-induced increment in the conditioned rewarding effects of cocaine in the CPP, favored the extinction of cocaine-associated memories in both the CPP and SA, and decreased reinstatement of cocaine-seeking behavior in the SA. In conclusion, the long-lasting effects of RSD are counteracted by administering OXT prior to stress, and changes in BDNF expression may underlie these protective effects. ; This work was supported by the Ministerio de Economía y Competitividad, Dirección General de Investigación, [grant numbers PSI2014-51847-R and PSI 2017-83023-R]; Spanish Ministry of Economy, Innovation and Competiveness (SAF2016-75347-R). Instituto de Salud Carlos III, Red de Trastornos Adictivos (RTA) [grant numbers RETICS RD06/0001/1006; RD12/0028/0005; and RD/16/0017/0010] and Unión Europea, Fondos FEDER "A way to build Europe". The Department of Experimental and Health Sciences (UPF) is an "Unidad de Excelencia María de Maeztu" funded by the MINECO (Ref. MDM2014-0370). A.C-Z received CONACYT grant from the Government of Mexico. M.A.L. and C.F.P received FPU grant from the Spanish Ministry of Economy, Innovation and Competiveness (15/02492 and 14/02279).