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Altres ajuts: acords transformatius de la UAB Altres ajuts: Swiss National Science Foundation (SNSF) [NCCR Synapsy grant: 51NF40-158776 and − 185897] Posttraumatic stress disorder (PTSD) is a highly disabling psychiatric condition that may arise after exposure to acute and severe trauma. It is a highly prevalent mental disorder worldwide, and the current treatment options for these patients remain limited due to low effectiveness. The time window right after traumatic events provides clinicians with a unique opportunity for preventive interventions against potential deleterious alterations in brain function that lead to PTSD. Some studies pointed out that PTSD patients present an abnormal function of the hypothalamic-pituitary-adrenal axis that may contribute to a vulnerability toward PTSD. Moreover, glucocorticoids have arisen as a promising option for preventing the disorder's development when administered in the aftermath of trauma. The present work compiles the recent findings of glucocorticoid administration for the prevention of a PTSD phenotype, from human studies to animal models of PTSD. Overall, glucocorticoid-based therapies for preventing PTSD demonstrated moderate evidence in terms of efficacy in both clinical and preclinical studies. Although clinical studies point out that glucocorticoids may not be effective for all patients' subpopulations, those with adequate traits might greatly benefit from them. Preclinical studies provide precise insight into the mechanisms mediating this preventive effect, showing glucocorticoid-based prevention to reduce long-lasting behavioral and neurobiological abnormalities caused by traumatic stress. However, further research is needed to delineate the precise mechanisms and the extent to which these interventions can translate into lower PTSD rates and morbidity.

Escitalopram is a selective serotonin reuptake inhibitor (SSRIs) antidepressant, drug that is currently used as first-line agents for the treatment of depression and it is also used in the treatment of other psychiatric disorders. The main goal of this study was to identify which brain areas are affected by escitalopram administration. This study was carried out on male Wistar rats that received escitalopram daily over 14 days and that were studied by 2-deoxy-2[18F]fluoro-D-glucose ([18F]FDG)-PET on the last day of treatment. Computed tomography (CT) images were acquired immediately before each PET scan and the main effects of drug administration were elucidated by Statistical Parametric Mapping. The results obtained indicated that repeated exposure to escitalopram increased metabolic activity in the retrosplenial and posterior cingulate cortices, while it decreased such activity in the ventral hippocampus, cerebellum, brainstem and midbrain regions, including the raphe nuclei and ventral tegmental area. Therefore, repeated exposure to escitalopram alters the activity of several brain areas closely related to the serotonergic system, and previously identified as key regions in the antidepressant effect induced by SSRIs. Furthermore, some of the changes found, such as the dampened metabolism in the ventral tegmental area, are similar to changes that have been described after treating with other fast-acting antidepressant approaches.

Despite decades of intense research, successful treatments for major depressive disorder (MDD) have still significant limitations. First-line treatments are drugs based on the classic monoamine the...

Inflammation and oxidative stress (IOS) are considered key pathophysiological elements in the development of mental disorders. Recent studies demonstrated that the antipsychotic risperidone elicits an antiinflammatory effect in the brain. We administered risperidone for 2-weeks at adolescence to assess its role in preventing brain-related IOS changes in the maternal immune stimulation (MIS) model at adulthood. We also investigated the development of volumetric and neurotrophic abnormalities in areas related to the HPA-axis. Poly I:C (MIS) or saline (Sal) were injected into pregnant Wistar rats on GD15. Male offspring received risperidone or vehicle daily from PND35-PND49. We studied 4 groups (8-15 animals/group): Sal-vehicle, MIS-vehicle, Sal-risperidone and MIS-risperidone. [18F]FDG-PET and MRI studies were performed at adulthood and analyzed using SPM12 software. IOS and neurotrophic markers were measured using WB and ELISA assays in brain tissue. Risperidone elicited a protective function of schizophrenia-related IOS deficits. In particular, risperidone elicited the following effects: reduced volume in the ventricles and the pituitary gland; reduced glucose metabolism in the cerebellum, periaqueductal gray matter, and parietal cortex; higher FDG uptake in the cingulate cortex, hippocampus, thalamus, and brainstem; reduced NFκB activity and iNOS expression; and increased enzymatic activity of CAT and SOD in some brain areas. Our study suggests that some schizophrenia-related IOS changes can be prevented in the MIS model. It also stresses the need to search for novel strategies based on anti-inflammatory compounds in risk populations at early stages in order to alter the course of the disease.

Accumulating evidence indicates that the antidepressant effects of ketamine are, in part, mediated by an increase in the AMPA receptor-mediated neurotransmission in depression related areas, such as the prefrontal cortex (PFC). Therefore, activity in PFC-projecting areas related to major depression, such as the dorsal raphe nucleus (DR), may also be modulated by ketamine. We used whole-cell patch-clamp recordings and western blot experiments to determine whether ketamine promotes acute and maintained alterations in glutamatergic transmission and mTOR pathway in the DR. Bath perfusion of ketamine, but not the NMDA receptor antagonist D-AP5, increased the frequency of AMPA receptor-mediated spontaneous EPSCs (sEPSCs) in DR neurons. However, ketamine did not affect evoked EPSCs or spontaneous inhibitory currents (sIPSCs). Pre-incubation of DR slices with the mTOR inhibitor PP242 decreased the frequency of sEPSCs and prevented the effect of ketamine. The results also show that while no electrophysiological effects were detected 24 h after ketamine administration, phosphorylation levels of mTOR were significantly increased in the DR. Nevertheless, expression levels of synaptic proteins were unaffected at that time. Altogether, the present data demonstrate that ketamine transiently increases spontaneous AMPA receptor-mediated neurotransmission in the DR.

Fear conditioning (FC) is a widely accepted tool for the assessment of learning and memory processes in rodents related to normal and dysregulated acquired fear. The study of sex differences in fear learning and memory is vast and currently increasing. Sex hormones have proven to be crucial for fear memory formation in males and females, and several methods have been developed to assess this hormonal state in rats and mice. Herein, we explain a routine FC and extinction protocol, together with the evaluation of sex hormonal state in male and female rodents. We explain three protocols for the evaluation of this hormonal state directly from blood samples extracted during the procedure or indirectly through histological verification of the estrous cycle for females or behavioral assessment of social hierarchies in males. Although females have typically been considered to present great variability in sex hormones, it is highlighted that sex hormone assessment in males is as variable as in females and equally important for fear memory formation. The readout of these protocols has had a great impact on different fields of fear learning and memory study and appears essential when studying FC. The proven interaction with drugs involved in the modulation of these processes makes sex hormone assessment during FC a valuable tool for the development of effective treatments for fear-related disorders in men and women. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Fear conditioning and fear extinction Basic Protocol 2: Blood collection for direct measurement of sex hormone levels in fear conditioning Basic Protocol 3: Indirect measurement of sex hormones in females during fear conditioning Basic Protocol 4: Assessment of dominance status in males before a fear conditioning protocol Support Protocol: Construction of a confrontation tube.

There is evidence that Deep Brain Stimulation (DBS) produces health benefits in patients even before initiating stimulation. Furthermore, DBS electrode insertion in rat infralimbic cortex (ILC) provokes antidepressant-like effects before stimulation, due to local inflammation and astrogliosis. Consequently, a significant effect of implanting electrodes is suspected. External fields, similar in magnitude to the brain’s endogenous fields, induce electric dipoles in conducting materials, in turn influencing neural cell growth through wireless effects. To elucidate if such dipoles influence depressive-like behavior, without external stimulation, the comparative effect of conducting and insulated electrodes along with the glial response is studied in unstressed rats. Naïve and implanted rats with electrically insulated or uninsulated steel electrodes were evaluated in the modified forced swimming test and expression of ILC-glial markers was assessed. An antidepressant-like effect was observed with conducting but not with insulated electrodes. Gliosis was detected in both groups, but astroglial reactivity was larger near uninsulated electrodes. Thus, induced dipoles and antidepressant-like effects were only observed with conducting implants. Such correlation suggests that dipoles induced in electrodes by endogenous fields in turn induce neuron stimulation in a feedback loop between electrodes and neural system. Further research of the effects of unwired conducting implants could open new approaches to regulating neuronal function, and possibly treat neurological disorders., This study was also supported by grants co-financed by the “Fondo Europeo de Desarrollo Regional” (FEDER)-UE “A way to build Europe” from the “Ministerio de Economía y Competitividad” (MINECO: RTI2018-099778-B-I00 (to E.B.), RTI2018-098269-B-I00 (to J.N.) and RTI2018-097753- B-I00 (to N.C.P.) and “Juan de la Cierva Formación” postdoctoral grant FJC2018-037958-I (to L.P.C.)) and PID2019-108562GB-I00 (to V.T.M); the “Consejería de Economía, Innovación, Ciencia y Empleo de la Junta de Andalucía” (CTS-510, to E.B.); the Severo Ochoa Program CEX2019-000917-S (to N.C.P.) and the “Centro de Investigación Biomédica en Red de Salud Mental-CIBERSAM” (CB/07/09/0033 and CB/07/09/0006).

Background An initial antidepressant effect when using deep brain stimulation (DBS) of the subcallosal area of the cingulate cortex (Cg25) to treat resistant depression that could be the result of electrode insertion has been described. We previously showed that electrode insertion into the infralimbic cortex (ILC; the Cg25 rodent correlate) provokes a temporally limited antidepressant-like effect that is counteracted by non-steroidal anti-inflammatory drugs, such as those routinely used for pain relief. Objective We characterized the effect of electrode insertion using functional neuroimaging and evaluated the impact of different analgesics on this effect. Methods The effect of electrode insertion into the ILC was evaluated by positron emission tomography. The effect of analgesics (ibuprofen, tramadol and morphine) on the behavioral effect induced by electrode insertion were evaluated through the forced swimming test and the novelty suppressed feeding test. Furthermore, glial fibrillary acidic protein (GFAP) and p11 expression were measured. Results Electrode implantation produces an antidepressant- and anxiolytic-like effect, a local decrease in glucose metabolism, and changes in several brain regions commonly related to depression and the antidepressant response. Ibuprofen counteracted the behavioral and molecular changes produced by electrode insertion (changes in GFAP and p11 protein expression). However, analgesics with no anti-inflammatory properties (e.g., tramadol) neither counteract the behavioral effects of electrode implantation nor the molecular mechanisms triggered. Conclusions Analgesics without anti-inflammatory properties may not limit the transient benefit produced by electrode insertion reducing the time required to achieve remission in depressive DBS patients.

Deep Brain Stimulation (DBS) was originally developed as a therapeutic approach to manage movement disorders, in particular Parkinson's Disease. However, DBS also seems to be an effective treatment against refractory depression when patients fail to respond satisfactorily to conventional therapies. Thus, DBS targeting specific brain areas can produce an antidepressant response that improves depressive symptomatology, these areas including the subcallosal cingulate region, nucleus accumbens, ventral capsule/ventral striatum, medial forebrain bundle, the inferior thalamic peduncle and lateral habenula. Although the efficacy and safety of this therapy has been demonstrated in some clinical trials and preclinical studies, the intrinsic mechanisms underlying its antidepressant effect remain poorly understood. This review aims to provide a comprehensive overview of DBS, focusing on the molecular and cellular changes reported after its use that could shed light on the mechanisms underpinning its antidepressant effect. Several potential mechanisms of action of DBS are considered, including monoaminergic and glutamatergic neurotransmission, neurotrophic and neuroinflammatory mechanisms, as well as potential effects on certain intracellular signaling pathways. Although future studies will be necessary to determine the key molecular events underlying the antidepressant effect of DBS, the findings presented provide an insight into some of its possible modes of action.

Deep brain stimulation (DBS) is a promising therapy to treat refractory major depressive disorder (MDD). Clinical trials have demonstrated the efficacy and safety of DBS when applied to different target areas, particularly the subgenual cingulate cortex, ventral capsule/ventral striatum, nucleus accumbens, and medial forebrain bundle. Despite a number of studies into this phenomenon, the mechanisms underlying the antidepressant effect of DBS remain poorly understood. The most relevant findings have come from preclinical assays, indicating that DBS activates the serotoninergic, catecholaminergic, and glutamatergic systems, promoting the expression of neurotrophic factors and facilitating synaptic plasticity. Thus, the antidepressant effect of DBS seems to be produced by multifactorial changes that induce widespread neuromodulation. Further studies will be necessary to discern the precise mechanism underlying the effects of DBS and to optimize the use of this technique to treat MDD.

Major depressive disorder is a severe, disabling disorder that affects around 4.7% of the population worldwide. Based on the monoaminergic hypothesis of depression, monoamine reuptake inhibitors have been developed as antidepressants and nowadays, they are used widely in clinical practice. However, these drugs have a limited efficacy and a slow onset of therapeutic action. Several strategies have been implemented to overcome these limitations, including switching to other drugs or introducing combined or augmentation therapies. In clinical practice, the most often used augmenting drugs are lithium, triiodothyronine, atypical antipsychotics, buspirone, and pindolol, although some others are in the pipeline. Moreover, multitarget antidepressants have been developed to improve efficacy. Despite the enormous effort exerted to improve these monoaminergic drugs, they still fail to produce a rapid and sustained antidepressant response in a substantial proportion of depressed patients. Recently, new compounds that target other neurotransmission system, such as the glutamatergic system, have become the focus of research into fast-acting antidepressant agents. These promising alternatives could represent a new pharmacological trend in the management of depression.

[Background] Deep Brain Stimulation (DBS) of the subgenual cingulate cortex (SCC) is a promising therapeutic alternative to treat resistant major depressive disorder. In preclinical studies, DBS of the ventromedial prefrontal cortex (vmPFC, the rodent SCC correlate) provokes an antidepressant-like effect, along with changes in noradrenaline levels at the site of stimulation. Hence, DBS appears to activate the noradrenergic-locus coeruleus (LC) system., [Objective/Hypothesis] The aim of this study was to evaluate the effect of vmPFC DBS on the electrical activity of noradrenergic LC neurons, cortical oscillations and coherence between both brain areas in male rats., [Methods] The antidepressant-like effect of vmPFC DBS was evaluated through the forced swimming test. Tonic and evoked activity of LC neurons, LC activity of alpha2-adrenoceptors, local field potentials from LC and electrocorticogram signals were studied after DBS by electrophysiological recordings in anaesthetized rats. The effect of DBS on tyrosine hydroxylase (TH), noradrenaline transporters (NAT), phosphorylation of the extracellular signal–regulated kinase (ERK) and corticotropin releasing factor (CRF) expression in the LC were measured by western blot assays., [Results] DBS induced an antidepressant-like effect increasing climbing behaviour in the FST that was accompanied by a robust increase of TH expression in the rat LC. The tonic and evoked activity of LC neurons was enhanced by DBS, which impaired alpha2-adrenoceptors activity. DBS also promoted an increase in slow LC oscillations, as well as a shift in LC-cortical coherence., [Conclusion] DBS of the vmPFC appears to affect the LC, producing changes that may underlie its antidepressant-like effects., This work was supported by grants from the “Ministerio de Economía y Competitividad” (MINECO) co-financed by “Fondo Europeo de Desarrollo Regional” FEDER “A way to build Europe” (SAF2015-68647-R; “Instituto de Salud Carlos III” (PI12/00915; PI16/00287)); the “Centro de Investigacion Biomedica en Red de Salud Mental-CIBERSAM” (Spain; G18, G02); the “Consejería de Economía, Innovacion, Ciencia y Empleo de la Junta de Andalucía ” (Spain; CTS-510 and CTS-7748); a 2015 NARSAD Young Investigator Grant from the Brain Behavior Research Foundation (NARSAD 23982); and a FPI fellowship (2011-145).

Major depressive disorder represents one of the most severe disabling disorders, affecting around 4.7% of the worldwide population. Many patients suffering this neuropsychiatric illness are treated successfully with various treatments, including antidepressant drugs and psychotherapy but also physical measures (electroconvulsive therapy, repetitive transcranial magnetic stimulation, vagal nerve stimulation). Despite the different treatment approaches available, unfortunately 30–40% of the patients fail to respond to most first-line treatments, and between 5 and 10% do not respond to conventional therapy at all. Thus, a considerable number of patients have a poor outcome and unfortunately fail to reach sustained remission. These data highlight the need to find new therapeutic approaches that especially focus on refractory patients. In this context, deep brain stimulation (DBS) emerges as an innovative physical treatment for refractory depressed patients. DBS has been successfully used for years in some neurological disorders such as Parkinson’s disease. Currently, in addition to its use in treating depression, DBS is also being tested in other psychiatric illness such as obsessive–compulsive disorder. Most studies on DBS have focused on efficiency and efficacy, or improvement in the technique, and a few were devoted to understanding the intrinsic mechanisms responsible. Understanding the molecular mechanisms of action of DBS is currently considered as crucial, not only in order to understand its efficacy but also to propose new antidepressant approaches. The aim of this chapter is to review the foundations, the efficacy, and the efficiency of DBS in depression, and to provide insight into the intrinsic mechanisms of action described until now. In addition, future developments will be discussed.

Although deep brain stimulation (DBS) has been used with success in treatment-resistant depression, little is known about its mechanism of action. We examined the antidepressant-like activity of short (1 h) DBS applied to the infralimbic prefrontal cortex in the forced swim test (FST) and the novelty-suppressed feeding test (NSFT). We also used in vivo microdialysis to evaluate the release of glutamate, γ-aminobutyric acid, serotonin, dopamine, and noradrenaline in the prefrontal cortex and c-Fos immunohistochemistry to determine the brain regions activated by DBS. One hour of DBS of the infralimbic prefrontal cortex has antidepressant-like effects in FST and NSFT, and increases prefrontal efflux of glutamate, which would activate AMPA receptors (AMPARs). This effect is specific of the infralimbic area since it is not observed after DBS of the prelimbic subregion. The activation of prefrontal AMPARs would result in a stimulation of prefrontal output to the brainstem, thus increasing serotonin, dopamine, and noradrenaline in the prefrontal cortex. Further, the activation of prefrontal AMPARs is necessary and sufficient condition for the antidepressant response of 1 h DBS., This work was supported by the Junta de Andalucía (CTS-510, CTS-7748 to E.B.) and by the Instituto de Salud Carlos III, Subdirección General de Evaluación y Fomento de la Investigación (FIS grants PI10-01103 and PI13-00038 to A.A. and PI12-00915 to E.B.) that were co-funded by the European Regional Development Fund (A way to build Europe). Funding from the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM, Intramural Project Grant P91G), and the Generalitat de Catalunya (2009SGR220) is also acknowledged. L.J.-S. was recipient of a predoctoral fellowship from the Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS).

Introduction : Clinical trials (CT) on triple therapy against HCV infection in HIV-infected patients including TVR plus pegylated interferon and ribavirin (PR) have reported considerably higher response rates than with PR alone. This study was aimed to evaluate the efficacy and safety of triple therapy including TVR in HIV/HCV-coinfected patients in real-life conditions. Material and Methods : HIV/HCV genotype 1 patients seen at four Hospitals in Madrid who received therapy including TVR plus PR for at least two weeks were included. The response was evaluated during treatment, and sustained viral response (SVR) was evaluated 12 and 24 weeks after the end of the treatment. Results : Fifty-eight patients have been included; 79% male, median age 48 y.o.; 38% were IL28B rs12979860 genotype CT or TT, 58.6% of patients presented cirrhosis and 24.1% presented fibrosis F3. Infection with genotype 1a was observed in 53.4% of patients. Median baseline HCV-RNA was 3,282,263 IU/mL (77.5% had >800,000 IU/mL). The most commonly used antiretroviral (ARV) drugs were tenofovir/emtricitabine [36 (62%) patients], etravirine [21 (36%) patients], abacavir/lamivudine [18 (31%) patients], boosted protease inhibitors [16 (27.5%) patients] and raltegravir [12 (20.6%) patients]. Of the 42 (72.4%) patients who had received previous HCV treatment, 13.7% were null responders, 25.8% were partial responders and 31% had relapsed. In an ITT approach, proportions of patients with undetectable HCV RNA were 67.8% (38/56) at TW4, 83.3% (40/48) at TW12, 80% (36/45) at TW24, 79.4% at TW36 (31/39) and 72% (26/36) at TW48. Fifteen (25.8%) patients discontinued HCV therapy [8 (13.8%) because they fulfilled stopping rules, 5 (8.6%) individuals due to adverse events and 2 (3.4%) were lost to follow-up]. Rash associated with TVR (grade 1) was observed in two cases (3.4%) and all the patients showed anaemia at some point of treatment. In an analysis by ITT in the 31 patients who had a 60 week follow-up after starting therapy, SVR-12 was observed in 21 (67.7%) patients. And in the analysis by ITT in 28 patients who had a 72 week follow-up after starting therapy, SVR-24 was observed in 17 (60.7%) patients. Conclusions : Response to triple therapy with TVR plus PR in HIV/HCV-patients under real-life conditions, and therefore, including a high proportion of difficult to treat patients, is similar to that found in CT. The safety profile of TVR-based therapy is also comparable to that shown in CT, with only a rate of discontinuation of 8.6% of individuals related to toxicity. (Published: 2 November 2014) Citation : De Los Santos I et al. Journal of the International AIDS Society 2014, 17(Suppl 3) :19633 http://www.jiasociety.org/index.php/jias/article/view/19633 | http://dx.doi.org/10.7448/IAS.17.4.19633