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El pdf del artículo es la versión post-print. ; Despite the widespread use of antidepressant medications that block serotonin (5-hydroxytryptamine; 5-HT) and/or norepinephrine (NE) transporters, such as SSRIs (selective serotonin reuptake inhibitors) or SNRIs (serotonin and norepinephrine reuptake inhibitors), the underlying neurobiological basis of action of these agents is poorly understood. Increases in serotonergic function are hypothesized to have beneficial effects on depressive symptoms. However, which of the 14 different neuronal receptors sensitive to 5-HT accounts for the therapeutic effects of SSRIs and SNRIs remains undetermined. The development of drugs that activate or block specific 5-HT receptors may help to circumvent the two main limitations of current antidepressants: low efficacy and delayed onset of therapeutic action. What follows is a short summary of the author's views on this matter. © 2013 American Chemical Society. ; The author's research is supported by the Innovative Medicine Initiative Joint Undertaking under grant agreement n° 115008, of which resources are composed of EFPIA in-kind contribution and financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013). Support from the Generalitat de Catalunya (2009-SGR220) and the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM) is also acknowledged. ; Peer Reviewed

El pdf del artículo es la versión manuscrita de autor. ; The neurotransmitter serotonin (5-hdroxytryptamine; 5-HT) has been implicated in the pathophysiology and treatment of major depression since the serendipitous discovery of antidepressant drugs in the 1950s. However, despite the generalised use of serotonin-enhancing drugs, such as the selective serotonin reuptake inhibitors (SSRIs) and the dual serotonin and norepinephrine reuptake inhibitors (SNRIs), the exact neurobiological mechanisms involved in the therapeutic action of these drugs are poorly understood. Better knowledge of these mechanisms may help to identify new therapeutic targets and to overcome the two main limitations of current treatments: reduced efficacy and slowness of action. Here I review the preclinical and clinical evidence supporting the involvement of different 5-HT receptors in the therapeutic action of antidepressant drugs. Presynaptic 5-HT1A and 5-HT1B autoreceptors play a major detrimental role in antidepressant treatments, as their activation by the excess of the active (extracellular) 5-HT fraction produced by serotonin transporter (SERT) blockade reduces presynaptic serotonergic function. Conversely, stimulation of postsynaptic 5-HT1A receptors in corticolimbic networks appears beneficial for the antidepressant action. The 5-HT2 receptor family is also involved as 5-HT2A/2C receptor blockade improves the antidepressant action of SSRIs, and recent data suggest that 5-HT2B receptor activation enhances serotonergic activity. Less is known from the rest of postsynaptic 5-HT receptors. However, 5-HT3 receptor blockade augments the 5-HT increase evoked by SERT inhibition, and 5-HT4 receptor activation may have antidepressant effects on its own. Finally, blockade of 5-HT6 and 5-HT7 receptors appears also to augment the antidepressant effects of SERT inhibition. ; Supported by the Innovative Medicine Initiative Joint Undertaking under grant agreement no. 115008, of which resources are composed of EFPIA in-kind contribution and financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and by grant SAF 2012–35183 from the Ministerio de Economía y Competitividad. Support from the Generalitat de Catalunya (2009-SGR220) and the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM) is also acknowledged. ; Peer Reviewed

Rationale N-methyl-D-aspartate receptor (NMDA-R) hypofunction has been proposed to account for the pathophysiology of schizophrenia. Thus, NMDA-R blockade has been used to model schizophrenia in experimental animals. Acute and repeated treatments have been successfully tested; however, long-term exposure toNMDA-R antagonists more likely resembles the core symptoms of the illness. Objectives To explore whether schizophrenia-related behaviors are differentially induced by acute and subchronic phencyclidine (PCP) treatment in mice and to examine the neurobiological bases of these differences. Results Subchronic PCP induced a sensitization of acute locomotor effects. Spontaneous alternation in a T-maze and novel object recognition performance were impaired after subchronic but not acute PCP, suggesting a deficit in working memory. On the contrary, reversal learning and immobility in the tail suspension test were unaffected. Subchronic PCP significantly reduced basal dopamine but not serotonin output in medial prefrontal cortex (mPFC) and markedly decreased the expression of tyrosine hydroxylase in the ventral tegmental area. Finally, acute and subchronic PCP treatments evoked a different pattern of c-fos expression. At 1 h post-treatment, acute PCP increased c-fos expression in many cortical regions, striatum, thalamus, hippocampus, and dorsal raphe. However, the increased c-fos expression produced by subchronic PCP was restricted to the retrosplenial cortex, thalamus, hippocampus, and supramammillary nucleus. Four days after the last PCP injection, c-fos expression was still increased in the hippocampus of subchronic PCP-treated mice. Conclusions Acute and subchronic PCP administration differently affects neuronal activity in brain regions relevant to schizophrenia, which could account for their different behavioral effects ; This work has received support from the Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM (13INT4 intramural project), and the Innovative Medicine Initiative Joint Undertaking under grant agreement no. 115008 of which resources are composed of EFPIA in-kind contribution and financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) ; Peer Reviewed

[BACKGROUND] The role of inflammation in mood disorders has received increased attention. There is substantial evidence that cytokine therapies, such as interferon alpha (IFN-alpha), can induce depressive symptoms. Indeed, proinflammatory cytokines change brain function in several ways, such as altering neurotransmitters, the glucocorticoid axis, and apoptotic mechanisms. This study aimed to evaluate the impact on mood of initiating IFN-alpha and ribavirin treatment in a cohort of patients with chronic hepatitis C. We investigated clinical, personality, and functional genetic variants associated with cytokine-induced depression. [METHODS] We recruited 344 Caucasian outpatients with chronic hepatitis C, initiating IFN-alpha and ribavirin therapy. All patients were euthymic at baseline according to DSM-IV-R criteria. Patients were assessed at baseline and 4, 12, 24, and 48 weeks after treatment initiation using the Patient Health Questionnaire (PHQ), the Hospital Anxiety and Depression Scale (HADS), and the Temperament and Character Inventory (TCI). We genotyped several functional polymorphisms of interleukin-28 (IL28B), indoleamine 2,3-dioxygenase (IDO-1), serotonin receptor-1A (HTR1A), catechol-O-methyl transferase (COMT), glucocorticoid receptors (GCR1 and GCR2), brain-derived neurotrophic factor (BDNF), and FK506 binding protein 5 (FKBP5) genes. A survival analysis was performed, and the Cox proportional hazards model was used for the multivariate analysis. [RESULTS] The cumulative incidence of depression was 0.35 at week 24 and 0.46 at week 48. The genotypic distributions were in Hardy-Weinberg equilibrium. Older age (p = 0.018, hazard ratio [HR] per 5 years = 1.21), presence of depression history (p = 0.0001, HR = 2.38), and subthreshold depressive symptoms at baseline (p = 0.005, HR = 1.13) increased the risk of IFN-induced depression. So too did TCI personality traits, with high scores on fatigability (p = 0.0037, HR = 1.17), impulsiveness (p = 0.0200 HR = 1.14), disorderliness (p = 0.0339, HR = 1.11), and low scores on extravagance (p = 0.0040, HR = 0.85). An interaction between HTR1A and COMT genes was found. Patients carrying the G allele of HTR1A plus the Met substitution of the COMT polymorphism had a greater risk for depression during antiviral treatment (HR = 3.83) than patients with the CC (HTR1A) and Met allele (COMT) genotypes. Patients carrying the HTR1A CC genotype and the COMT Val/Val genotype (HR = 3.25) had a higher risk of depression than patients with the G allele (HTR1A) and the Val/Val genotype. Moreover, functional variants of the GCR1 (GG genotype: p = 0.0436, HR = 1.88) and BDNF genes (Val/Val genotype: p = 0.0453, HR = 0.55) were associated with depression. [CONCLUSIONS] The results of the study support the theory that IFN-induced depression is associated with a complex pathophysiological background, including serotonergic and dopaminergic neurotransmission as well as glucocorticoid and neurotrophic factors. These findings may help to improve the management of patients on antiviral treatment and broaden our understanding of the pathogenesis of mood disorders. ; This study was funded by the following Spanish grants: Instituto de Carlos III, Fondo de Investigaciones Sanitarias PSICOCIT-VHC-P110/01827 and PSIGEN-VHC-EC08/00201 (Dr Martín-Santos). It was co-financed by the ERDF, European Union "One way to make Europe," Ministerio de Economía y Competitividad (MTM2012-38067-C02-01), and the support of the Generalitat de Catalunya (SGR2009/1435/SGR2014/1411; Dr Martín-Santos). Dr Grande has received a research grant from Río Hortega Contract (CM12/00062), Instituto de Salud Carlos III, Spanish Ministry of Economy and Competiveness. ; Peer Reviewed

The prefrontal cortex (PFC) is involved in behavioural control and cognitive processes that are altered in schizophrenia. The brainstem monoaminergic systems control PFC function, yet the cells/networks involved are not fully known. Serotonin (5-HT) and norepinephrine (NE) increase PFC neuronal activity through the activation of α1-adrenergic receptors (α1ARs) and 5-HT2A receptors (5-HT2ARs), respectively. Neurochemical and behavioural interactions between these receptors have been reported. Further, classical and atypical antipsychotic drugs share nm in vitro affinity for α1ARs while having preferential affinity for D2 and 5-HT2ARs, respectively. Using double in situ hybridization we examined the cellular expression of α1ARs in pyramidal (vGluT1-positive) and GABAergic (GAD65/67-positive) neurons in rat PFC and their co-localization with 5-HT2ARs. α1ARs are expressed by a high proportion of pyramidal (59-85%) and GABAergic (52-79%) neurons. The expression in pyramidal neurons exhibited a dorsoventral gradient, with a lower percentage of α1AR-positive neurons in infralimbic cortex compared to anterior cingulate and prelimbic cortex. The expression of α1A, α1B and α1D adrenergic receptors was segregated in different layers and subdivisions. In all them there is a high co-expression with 5-HT2ARs (∼80%). These observations indicate that NE controls the activity of most PFC pyramidal neurons via α1ARs, either directly or indirectly, via GABAergic interneurons. Antipsychotic drugs can thus modulate the activity of PFC via α1AR blockade. The high co-expression with 5-HT2ARs indicates a convergence of excitatory serotonergic and noradrenergic inputs onto the same neuronal populations. Moreover, atypical antipsychotics may exert a more powerful control of PFC function through the simultaneous blockade of α1ARs and 5-HT2ARs. © 2012 CINP. ; This study was supported by the Innovative Medicine Initiative Joint Undertaking under grant agreement no. 115008 of which resources are composed of EFPIA in-kind contribution and financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013). Support from grant SAF 2007-62378 and Generalitat de Catalunya (2009-SGR220) and the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM) and the Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED) is also acknowledged. N. S. is supported by CIBERSAM. ; Peer Reviewed

© 2017 The New York Botanical Garden Crop genetic resources have been extensively collected in Europe in the last century, creating large, publicly available ex situ collections. While this huge genetic diversity is often underutilized, in recent decades, several initiatives have emerged at the local level to collect germplasm cultivated on farm. Uncoordinated actors often carry out these collecting missions without considering previously collected data. To explore whether new collecting missions are likely to be worthwhile, we studied the crop genetic resources conservation network in Catalonia by analyzing the passport data and geographical distribution of germplasm stored in seed banks. Moreover, to determine whether this germplasm was representative of the diversity cultivated on farm, we performed new collecting missions in four randomly selected areas in the European Union's Natura 2000 network and compared the results with the ex situ databases. Seed banks currently hold a large germplasm collection (2931 accessions), although most materials are conserved in private collections without regulated systems for seed regeneration and are not present as duplicates in the National Inventory. One important shortcoming of the ex situ network is that the germplasm conserved ex situ shows a low geographical coverage, representing only 35.3% of the municipalities in Catalonia. Our new missions allowed us to collect 234 accessions, mostly tomatoes (17.5%) and beans (16.2%). The ecological indicators' richness (both at species (S) and variety (V) levels), total abundance (A), and the Shannon-Weaver diversity index calculated at species (H2, considering the different accessions of each variety as a single population) and variety levels (H3, considering the intra-varietal genetic diversity) were higher in the newly collected germplasm than in the ex situ collections, suggesting that seed banks do not accurately represent the genetic diversity still cultivated on farm. Moreover, some important landraces from each area were absent or underrepresented in the ex situ collections. Thus, it is necessary to continue to devote efforts to collecting germplasm; better organization between actors and targeting specific species/varieties can increase the efficiency of new collecting missions. As a conclusion, we propose different criteria to guide new missions and to improve the network's conservation activities. ; Postprint (updated version)

© 2017 The New York Botanical Garden Crop genetic resources have been extensively collected in Europe in the last century, creating large, publicly available ex situ collections. While this huge genetic diversity is often underutilized, in recent decades, several initiatives have emerged at the local level to collect germplasm cultivated on farm. Uncoordinated actors often carry out these collecting missions without considering previously collected data. To explore whether new collecting missions are likely to be worthwhile, we studied the crop genetic resources conservation network in Catalonia by analyzing the passport data and geographical distribution of germplasm stored in seed banks. Moreover, to determine whether this germplasm was representative of the diversity cultivated on farm, we performed new collecting missions in four randomly selected areas in the European Union's Natura 2000 network and compared the results with the ex situ databases. Seed banks currently hold a large germplasm collection (2931 accessions), although most materials are conserved in private collections without regulated systems for seed regeneration and are not present as duplicates in the National Inventory. One important shortcoming of the ex situ network is that the germplasm conserved ex situ shows a low geographical coverage, representing only 35.3% of the municipalities in Catalonia. Our new missions allowed us to collect 234 accessions, mostly tomatoes (17.5%) and beans (16.2%). The ecological indicators' richness (both at species (S) and variety (V) levels), total abundance (A), and the Shannon-Weaver diversity index calculated at species (H2, considering the different accessions of each variety as a single population) and variety levels (H3, considering the intra-varietal genetic diversity) were higher in the newly collected germplasm than in the ex situ collections, suggesting that seed banks do not accurately represent the genetic diversity still cultivated on farm. Moreover, some important landraces from each area were absent or underrepresented in the ex situ collections. Thus, it is necessary to continue to devote efforts to collecting germplasm; better organization between actors and targeting specific species/varieties can increase the efficiency of new collecting missions. As a conclusion, we propose different criteria to guide new missions and to improve the network's conservation activities. ; Postprint (updated version)

[EN] The term "landrace" has generally been defined as a cultivated, genetically heterogeneous variety that has evolved in a certain ecogeographical area and is therefore adapted to the edaphic and climatic conditions and to its traditional management and uses. Despite being considered by many to be inalterable, landraces have been and are in a constant state of evolution as a result of natural and artificial selection. Many landraces have disappeared from cultivation but are preserved in gene banks. Using modern selection and breeding technology tools to shape these preserved landraces together with the ones that are still cultivated is a further step in their evolution in order to preserve their agricultural significance. Adapting historical landraces to present agricultural conditions using cutting-edge breeding technology represents a challenging opportunity to use them in a modern sustainable agriculture, as an immediate return on the investment is highly unlikely. Consequently, we propose a more inclusive definition of landraces, namely that they consist of cultivated varieties that have evolved and may continue evolving, using conventional or modern breeding techniques, in traditional or new agricultural environments within a defined ecogeographical area and under the influence of the local human culture. This includes adaptation of landraces to new management systems and the unconscious or conscious selection made by farmers or breeders using available technology. In this respect, a mixed selection system might be established in which farmers and other social agents develop evolved landraces from the variability generated by public entities. ; This work has been partially funded by the European Union's Horizon 2020 research and innovation program under grant agreements no. 634651 (TRADITOM) and no. 677379 (G2PSOL). ; Casañas Artigas, F.; Simo, J.; Casals, J.; Prohens Tomás, J. (2017). Toward an Evolved Concept of Landrace. Frontiers in Plant Science. 8. https://doi.org/10.3389/fpls.2017.00145 ; S ; 145 ...

© 2015 Elsevier Ltd. 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a natural hallucinogen, acting as a non-selective serotonin 5-HT1A/5-HT2A-R agonist. Psychotomimetic agents such as the non-competitive NMDA-R antagonist phencyclidine and serotonergic hallucinogens (DOI and 5-MeO-DMT) disrupt cortical synchrony in the low frequency range (<4 Hz) in rat prefrontal cortex (PFC), an effect reversed by antipsychotic drugs. Here we extend these observations by examining the effect of 5-MeO-DMT on low frequency cortical oscillations (LFCO, <4 Hz) in PFC, visual (V1), somatosensory (S1) and auditory (Au1) cortices, as well as the dependence of these effects on 5-HT1A-R and 5-HT2A-R, using wild type (WT) and 5-HT2A-R knockout (KO2A) anesthetized mice. 5-MeO-DMT reduced LFCO in the PFC of WT and KO2A mice. The effect in KO2A mice was fully prevented by the 5-HT1A-R antagonist WAY-100635. Systemic and local 5-MeO-DMT reduced 5-HT release in PFC mainly via 5-HT1A-R. Moreover, 5-MeO-DMT reduced LFCO in S1, Au1 and V1 of WT mice and only in V1 of KO2A mice, suggesting the involvement of 5-HT1A-R activation in the 5-MeO-DMT-induced disruption of V1 activity. In addition, antipsychotic drugs reversed 5-MeO-DMT effects in WT mice. The present results suggest that the hallucinogen action of 5-MeO-DMT is mediated by simultaneous alterations of the activity of sensory (S1, Au1, V1) and associative (PFC) cortical areas, also supporting a role of 5-HT1A-R stimulation in V1 and PFC, in addition to the well-known action on 5-HT2A-R. Moreover, the reversal by antipsychotic drugs of 5-MeO-DMT effects adds to previous literature supporting the usefulness of the present model in antipsychotic drug development. ; This work was supported by grants from Instituto de Salud Carlos III (PI09/1245 (P.C.), PI12/00156 (P.C.) and PI13/01390 (A.B.) (PN de I+D+I 2008-2011, ISCIII-Subdirección General de Evaluación y Fomento de la Investigación cofinanced by the European Regional Development Fund. "Una manera de hacer Europa"), SAF 2012-35183 (Spanish Ministry of Economy and Competitiveness, co-financed by European Regional Development Fund (ERDF), Centro de Investigación Biomédica en Red de Salud Mental, (CIBERSAM P82, 11INT3) and the Innovative Medicines Initiative Joint Undertaking (IMI) under Grant Agreement N° 115008 (NEWMEDS). IMI is a public-private partnership between the European Union and the European Federation of Pharmaceutical Industries and Associations. Support from the Generalitat de Catalunya (2014 SGR798) is also acknowledged. MR was supported by a IDIBAPS fellowship ; Peer Reviewed

A microdeletion at locus 15q13.3 is associated with high incidence rates of psychopathology, including schizophrenia. A mouse model of the 15q13.3 microdeletion syndrome has been generated (Df[h15q13]/+) with translational utility for modelling schizophrenia-like pathology. Among other deficits, schizophrenia is characterised by dysfunctions in prefrontal cortical (PFC) inhibitory circuitry and attention. Objectives: The objective of this study is to assess PFC-dependent functioning in the Df(h15q13)/+ mouse using electrophysiological, pharmacological, and behavioural assays. Method: Experiments 1¿2 investigated baseline firing and auditory-evoked responses of PFC interneurons and pyramidal neurons. Experiment 3 measured pyramidal firing in response to intra-PFC GABAAreceptor antagonism. Experiments 4¿6 assessed PFC-dependent attentional functioning through the touchscreen 5-choice serial reaction time task (5-CSRTT). Experiments 7¿12 assessed reversal learning, paired-associate learning, extinction learning, progressive ratio, trial-unique non-match to sample, and object recognition. Results: In experiments 1¿3, the Df(h15q13)/+ mouse showed reduced baseline firing rate of fast-spiking interneurons and in the ability of the GABAAreceptor antagonist gabazine to increase the firing rate of pyramidal neurons. In assays of auditory-evoked responses, PFC interneurons in the Df(h15q13)/+ mouse had reduced detection amplitudes and increased detection latencies, while pyramidal neurons showed increased detection latencies. In experiments 4¿6, the Df(h15q13)/+ mouse showed a stimulus duration-dependent decrease in percent accuracy in the 5-CSRTT. The impairment was insensitive to treatment with the partial ¿7nAChR agonist EVP-6124. The Df(h15q13)/+ mouse showed no cognitive impairments in experiments 7¿12. Conclusion: The Df(h15q13)/+ mouse has multiple dysfunctions converging on disrupted PFC processing as measured by several independent assays of inhibitory transmission and attentional function ; The research leading to these results has received support from the Innovative Medicine Initiative Joint Undertaking under grant agreement no. 115008 of which resources are composed of EFPIA in-kind contribution and financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013). The Behavioural and Clinical Neuroscience Institute is co-funded by the Medical Research Council and the Wellcome Trust. This study was also supported by the Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM). ; Peer Reviewed

Non-competitive NMDA receptor antagonists are widely used as pharmacological models of schizophrenia due to their ability to evoke the symptoms of the illness. Likewise, serotonergic hallucinogens, acting on 5-HT2A receptors, induce perceptual and behavioural alterations possibly related to psychotic symptoms. The neurobiological basis of these alterations is not fully elucidated. Data obtained in recent years revealed that the NMDA receptor antagonist phencyclidine (PCP) and the serotonergic hallucinogen 1-(2,5-dimethoxy-4-iodophenyl-2-aminopropane; DOI) produce a series of common actions in rodent prefrontal cortex (PFC) that may underlie psychotomimetic effects. Hence, both agents markedly disrupt PFC function by altering pyramidal neuron discharge (with an overall increase) and reducing the power of low frequency cortical oscillations (LFCO; < 4 Hz). In parallel, PCP increased c-fos expression in excitatory neurons of various cortical areas, the thalamus and other subcortical structures, such as the amygdala. Electrophysiological studies revealed that PCP altered similarly the function of the centromedial and mediodorsal nuclei of the thalamus, reciprocally connected with PFC, suggesting that its psychotomimetic properties are mediated by an alteration of thalamocortical activity (the effect of DOI was not examined in the thalamus). Interestingly, the observed effects were prevented or reversed by the antipsychotic drugs clozapine and haloperidol, supporting that the disruption of PFC activity is intimately related to the psychotomimetic activity of these agents. Overall, the present experimental model can be successfully used to elucidate the neurobiological basis of schizophrenia symptoms and to examine the potential antipsychotic activity of new drugs in development. ; Supported by the Innovative Medicines Initiative Joint Undertaking (IMI) under Grant Agreement No. 115008 (NEWMEDS). IMI is a public–private partnership between the European Union and the European Federation of Pharmaceutical Industries and Associations. Support from the following grants is also acknowledged: SAF 2012-35183 (Ministry of Economy and Competitiveness and European Regional Development Fund), PI09/1245 and PI12/00156 (PN de I+D+I 2008-2011, ISCIII-Subdireccion General de Evaluación y Fomento de la Investigación cofinanced by the European Regional Development Fund. 'Una manera de hacer Europa') and Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM (P82, 11INT3). Support from the Generalitat de Catalunya (SGR20093) is also acknowledged. P.C. is supported by the Researcher Stabilization Program of the Health Department of the Generalitat de Catalunya. M.R. is recipient of an IDIBAPS fellowship. ; Peer reviewed

Pentobarbital-anaesthetized male Wistar rats were infused with 6microgkg-1min-1 of noradrenaline. The infusion was supplemented with 8.5 mgkg-1min-1 of D-3-hydroxybutyrate (3-OHB) for 15 min in order to determine its effect on the adrenergic response of the rat. Plasma levels of noradrenaline rose to a plateau of approximately 50 nmoll-1 with infusion. In the group infused with noradrenaline alone, noradrenaline levels were maintained for 1h. Supplementation with 3-OHB induced a decrease in plasma noradrenaline level that was inversely correlated with 3-OHB level. Aortic and interscapular brown adipose tissue temperatures increased with noradrenaline infusion, but the rise was arrested by 3-OHB; replacing 3-OHB with glucose had no effect. Infusion of saline, glucose or 3-OHB in the absence of noradrenaline did not induce a rise in temperature in either tissue. Blood 3-OHB concentration increased to 1.2 mmoll-1 during 3-OHB infusion, decreasing rapidly at the end of infusion. Blood glucose levels increased with noradrenaline infusion; the presence of high 3-OHB levels decreased glucose concentration. The effects observed were transient and dependent on 3-OHB concentration; these effects may help explain most of the other effects of noradrenaline described here. The role of 3-OHB as a regulator of adrenergic responses seems to be part of a complex fail-safe mechanism which prevents wasting. ; This work was supported in part by the 'Fondo de Investigaciones Sanitarias' (projects 94/34-01 and 95/266) of the Government of Spain. ; Peer reviewed

In press. ; Current pharmacological treatments for major depressive disorder (MDD) are severely compromised by both slow action and limited efficacy. RNAi strategies have been used to evoke antidepressant-like effects faster than classical drugs. Using small interfering RNA (siRNA), we herein show that TASK3 potassium channel knockdown in monoamine neurons induces antidepressant-like responses in mice. TASK3-siRNAs were conjugated to cell-specific ligands, sertraline (Ser) or reboxetine (Reb), to promote their selective accumulation in serotonin (5-HT) and norepinephrine (NE) neurons, respectively, after intranasal delivery. Following neuronal internalization of conjugated TASK3-siRNAs, reduced TASK3 mRNA and protein levels were found in the brainstem 5-HT and NE cell groups. Moreover, Ser-TASK3-siRNA induced robust antidepressant-like behaviors, enhanced the hippocampal plasticity, and potentiated the fluoxetine-induced increase on extracellular 5-HT. Similar responses, yet of lower magnitude, were detected for Reb-TASK3-siRNA. These findings provide substantial support for TASK3 as a potential target, and RNAi-based strategies as a novel therapeutic approach to treat MDD. ; This work was supported by the following grants: SAF2015-68346-P (F.A.); SAF2013-48586-R (J.M.); SAF2016-75797-R (A.B.); Retos-Colaboración Subprograms RTC-2014-2812-1 and RTC-2015-3309-1 (A.B.); Ministry of Economy and Competitiveness (MINECO)—European Regional Development Fund (ERDF), UE; PI13/01390, Instituto de Salud Carlos III co-financed by ERDF (A.B.); IT616-13 Basque Government—ERDF (J.M.); 20003 NARSAD Independent Investigator (A.B.); and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM). CERCA Programme/Generalitat de Catalunya is also acknowledged. M.N.F. and A.F-C. are recipients of a fellowship from the Spanish Ministry of Education, Culture and Sport. ; Peer reviewed

Open Access: This work is licensed under the Creative Commons Attribution-NonCommercial-No Derivative Works 3.0 Unported License.-- et al. ; Current antidepressants, which inhibit the serotonin transporter (SERT), display limited efficacy and slow onset of action. Here, we show that partial reduction of SERT expression by small interference RNA (SERT-siRNA) decreased immobility in the tail suspension test, displaying an antidepressant potential. Moreover, short-term SERT-siRNA treatment modified mouse brain variables considered to be key markers of antidepressant action: reduced expression and function of 5-HT(1A)-autoreceptors, elevated extracellular serotonin in forebrain and increased neurogenesis and expression of plasticity-related genes (BDNF, VEGF, Arc) in hippocampus. Remarkably, these effects occurred much earlier and were of greater magnitude than those evoked by long-term fluoxetine treatment. These findings highlight the critical role of SERT in serotonergic function and show that the reduction of SERT expression regulates serotonergic neurotransmission more potently than pharmacological blockade of SERT. The use of siRNA-targeting genes in serotonin neurons (SERT, 5-HT(1A)-autoreceptor) may be a novel therapeutic strategy to develop fast-acting antidepressants. ; This research was supported by grants from Spanish Ministry of Science and Innovation-CDTI, with the participation of the DENDRIA Consortium; from Instituto de Salud Carlos III PI10/00290 and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM, P91C). Structural funds of the European Union, through the National Applied Research Projects (R+D+I 2008/11) and from the Catalan Government (grant 2009SGR220) are also acknowledged. ; Peer Reviewed

A Ferrés-Coy et al. ; Major depression brings about a heavy socio-economic burden worldwide due to its high prevalence and the low efficacy of antidepressant drugs, mostly inhibiting the serotonin transporter (SERT). As a result, similar to 80% of patients show recurrent or chronic depression, resulting in a poor quality of life and increased suicide risk. RNA interference (RNAi) strategies have been preliminarily used to evoke antidepressant-like responses in experimental animals. However, the main limitation for the medical use of RNAi is the extreme difficulty to deliver oligonucleotides to selected neurons/systems in the mammalian brain. Here we show that the intranasal administration of a sertraline-conjugated small interfering RNA (C-SERT-siRNA) silenced SERT expression/function and evoked fast antidepressant-like responses in mice. After crossing the permeable olfactory epithelium, the sertraline-conjugated-siRNA was internalized and transported to serotonin cell bodies by deep Rab-7-associated endomembrane vesicles. Seven-day C-SERT-siRNA evoked similar or more marked responses than 28-day fluoxetine treatment. Hence, C-SERT-siRNA (i) downregulated 5-HT1A-autoreceptors and facilitated forebrain serotonin neurotransmission, (ii) accelerated the proliferation of neuronal precursors and (iii) increased hippocampal complexity and plasticity. Further, short-term C-SERT-siRNA reversed depressive -like behaviors in corticosterone-treated mice. The present results show the feasibility of evoking antidepressant -like responses by selectively targeting neuronal populations with appropriate siRNA strategies, opening a way for further translational studies. ; This work was supported by grants from CDTI—Spanish Ministry of Science and Innovation—DENDRIA contribution, 'nLife all rights reserved' (to AB and FA); Instituto de Salud Carlos III PI10/00290 and PI13/01390 (to AB), PI/10/0123 (to JCL) and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM); NARSAD Independent Investigator Grant from the Brain & Behavior Research Foundation Grant 20003 (to AB); Ministry of Economy and Competitiveness SAF2012-35183 (to FA) and SAF2011-25020 (to AP); and Generalitat de Catalunya, Secretaria d'Universitat i Recerca del Departament d'Economia i Coneixement (SGR2014) Catalan Government Grant 2009SGR220 (to FA). Some of these grants are co-financed by the European Regional Development Fund 'A way to build Europe'. AF-C is a recipient of a fellowship from Spanish Ministry of Education, Culture and Sport. ; Peer Reviewed