Loss of glycine receptors in the nucleus accumbens and ethanol reward in an Alzheimer´s Disease mouse model.

Alterations in cognitive and non-cognitive cerebral functions characterize Alzheimer's disease (AD). Cortical and hippocampal impairments related to extracellular accumulation of Aß in AD animal models have been extensively investigated. However, recent reports have also implicated intracellular Aß in limbic regions, such as the nucleus accumbens (nAc). Accumbal neurons express high levels of inhibitory glycine receptors (GlyRs) that are allosterically modulated by ethanol and have a role in controlling its intake. In the present study, we investigated how GlyRs in the 2xTg mice (AD model) affect nAc functions and ethanol intake behavior. Using transgenic and control aged-matched litter mates, we found that the GlyRα2 subunit was significantly decreased in AD mice (6-month-old). We also examined intracellular calcium dynamics using the fluorescent calcium protein reporter GCaMP in slice photometry. We also found that the calcium signal mediated by GlyRs, but not GABAAR, was also reduced in AD neurons. Additionally, ethanol potentiation was significantly decreased in accumbal neurons in the AD mice. Finally, we performed drinking in the dark (DID) experiments and found that 2xTg mice consumed less ethanol on the last day of DID, in agreement with a lower blood ethanol concentration. 2xTg mice also showed lower sucrose consumption, indicating that overall food reward was altered. In conclusion, the data support the role of GlyRs in nAc neuron excitability and a decreased glycinergic activity in the 2xTg mice that might lead to impairment in reward processing at an early stage of the disease.

Changes in ethanol effects in knock-in mice expressing ethanol insensitive alpha1 and alpha2 glycine receptor subunits.

AIMS: Glycine receptors (GlyRs) are potentiated by physiologically relevant concentrations of ethanol, and mutations in the intracellular loop of α1 and α2 subunits reduced the effect of the drug. Knock-in (KI) mice having these individual mutations revealed that α1 and α2 subunits played a role in ethanol-induced sedation and ethanol intake. In this study, we wanted to examine if the effects of stacking both mutations in a 2xKI mouse model (α1/α2) generated by a selective breeding strategy further impacted cellular and behavioral responses to ethanol. MAIN METHODS: We used electrophysiological recordings to examine ethanol's effect on GlyRs and evaluated ethanol-induced neuronal activation using c-Fos immunoreactivity and the genetically encoded calcium indicator GCaMP6s in the nucleus accumbens (nAc). We also examined ethanol-induced behavior using open field, loss of the righting response, and drinking in the dark (DID) paradigm. KEY FINDINGS: Ethanol did not potentiate GlyRs nor affect neuronal excitability in the nAc from 2xKI. Moreover, ethanol decreased the Ca2+ signal in WT mice, whereas there were no changes in the signal in 2xKI mice. Interestingly, there was an increase in c-Fos baseline in the 2xKI mice in the absence of ethanol. Behavioral assays showed that 2xKI mice recovered faster from a sedative dose of ethanol and had higher ethanol intake on the first test day of the DID test than WT mice. Interestingly, an open-field assay showed that 2xKI mice displayed less anxiety-like behavior than WT mice. SIGNIFICANCE: The results indicate that α1 and α2 subunits are biologically relevant targets for regulating sedative effects and ethanol consumption.

Molecular Pharmacology of Gelsemium Alkaloids on Inhibitory Receptors.

Indole alkaloids are the main bioactive molecules of the Gelsemium genus plants. Diverse reports have shown the beneficial actions of Gelsemium alkaloids on the pathological states of the central nervous system (CNS). Nevertheless, Gelsemium alkaloids are toxic for mammals. To date, the molecular targets underlying the biological actions of Gelsemium alkaloids at the CNS remain poorly defined. Functional studies have determined that gelsemine is a modulator of glycine receptors (GlyRs) and GABAA receptors (GABAARs), which are ligand-gated ion channels of the CNS. The molecular and physicochemical determinants involved in the interactions between Gelsemium alkaloids and these channels are still undefined. We used electrophysiological recordings and bioinformatic approaches to determine the pharmacological profile and the molecular interactions between koumine, gelsemine, gelsevirine, and humantenmine and these ion channels. GlyRs composed of α1 subunits were inhibited by koumine and gelsevirine (IC50 of 31.5 ± 1.7 and 40.6 ± 8.2 µM, respectively), while humantenmine did not display any detectable activity. The examination of GlyRs composed of α2 and α3 subunits showed similar results. Likewise, GABAARs were inhibited by koumine and were insensitive to humantenmine. Further assays with chimeric and mutated GlyRs showed that the extracellular domain and residues within the orthosteric site were critical for the alkaloid effects, while the pharmacophore modeling revealed the physicochemical features of the alkaloids for the functional modulation. Our study provides novel information about the molecular determinants and functional actions of four major Gelsemium indole alkaloids on inhibitory receptors, expanding our knowledge regarding the interaction of these types of compounds with protein targets of the CNS.

Molecular Docking Analysis at the Human α7-nAChR and Proliferative and Evoked-Calcium Changes in SH-SY5Y Cells by Imidacloprid and Acetamiprid Insecticides.

Acetamiprid (ACE) and Imidacloprid (IMI) are widely-used neonicotinoid insecticides (NNIs) with functional activity at human acetylcholine nicotinic receptors and, therefore, with putative toxic effects. The objective of this study was the evaluation of the interactions between NNIs and α7-nAChR, as this receptor keeps intracellular Ca2+ ([Ca2+]i) to an optimum for an adequate neuronal functioning. Possible interactions between NNIs and the cryo-EM structure of the human α-7 nAChR were identified by molecular docking. Additionally, NNI effects were analyzed in neuroblastoma SH-SY5Y cells, as they naturally express α-7 nAChRs. Functional studies included proliferative/cytotoxic effects (MTT test) in undifferentiated SH-SY-5Y cells and indirect measurements of [Ca2+]i transients in retinoic acid-differentiated SH-SY-5Y cells loaded with Fluo-4 AM. Docking analysis showed that the binding of IMI and ACE occurred at the same aromatic cage that the specific α-7 nAChR agonist EVP-6124. IMI showed a better docking strength than ACE. According to the MTT assays, low doses (10-50 µM) of IMI better than ACE stimulated neuroblastoma cell proliferation. At higher doses (250-500 µM), IMI also prevailed over ACE and dose-dependently triggered more abrupt fluorescence changes due to [Ca2+]i mobilization in differentiated SH-SY5Y neurons. Indeed, only IMI blunted nicotine-evoked intracellular fluorescence stimulation (i.e., nicotine cross-desensitization). Summarizing, IMI demonstrated a superior docking strength and more robust cellular responses compared to ACE, which were likely associated with a stronger activity at α-7nAChRs. Through the interaction with α-7nAChRs, IMI would demonstrate its high neurotoxic potential for humans. More research is needed for investigating the proliferative effects of IMI in neuroblastoma cells.

Efficacy of Early Intervention Programmes: Systematic Review and Meta-analysis / Eficacia de los programas de atención temprana: revisión sistemática y metaanálisis

Background: Early childhood intervention is a form of intervention aimed at children to overcome difficulties in different areas of their development after birth. There are multiple early intervention programmes, but only a few studies assess their efficacy using data. Objective: A systematic review and meta-analysis of early intervention programmes was carried out. Method: Inclusion criteria were considered to be empirical studies, with outcome data on children between 0 and 6 years of age with various developmental problems. The review was conducted in nine databases. Results: Of the total number of studies from 2000 to 2021 in English and Spanish, 40 studies were included that looked at the efficacy of the programmes. Of these, 19 used comparisons with a control group, and 13 used single-subject designs, as well as other designs. The programmes were very diverse, mostly based on behavioural procedures, and aimed at promoting the development of specific areas. The quality of the studies is medium-high. The meta-analysis included 18 studies with a mean effect size d = 0.45 (CI = 0.18, 0.67), with high sample heterogeneity and low study selection bias. Conclusions: Early childhood interventions have a medium and positive efficacy on the skills and abilities of children with developmental problems. The limitations of the reviewed studies are discussed, as well as the need for well-defined programmes, long-term measurements, and comparisons of different types of programmes among them. (AU)

Antecedentes: La atención temprana es una forma de intervención dirigida a niños y niñas para intentar superar las dificultades en distintas áreas de su desarrollo tras el nacimiento. Existen múltiples programas, pero pocos estudios comparando con datos su eficacia. Objetivo: Se ha realizado una revisión sistemática y un metaanálisis de los programas de atención temprana. Método: Como criterios de inclusión se consideró que fuesen estudios empíricos con resultados sobre niños con diversos problemas de desarrollo entre 0 y 6 años. La revisión se realizó con nueve bases de datos. Resultados: Del total de estudios desde 2000 a 2021 en español e inglés se incluyeron 40 estudios que permitían ver la eficacia de los programas. De ellos 19 utilizaron comparaciones frente a un grupo control y 13 con diseños de caso único, además de otros diseños. Los programas de atención temprana fueron muy diversos, en su mayoría basados en procedimientos conductuales y dirigidos a impulsar el desarrollo de áreas específicas. La calidad de los estudios es media-alta. En el metaanálisis se incluyeron 18 estudios con un tamaño del efecto medio, d = 0.45 (CI = 0.18, 0.67), con gran heterogeneidad de las muestras y poco sesgo en la selección de estudios. Conclusiones: Los programas de atención temprana presentan una eficacia media y positiva con respecto a las habilidades y capacidades de los niños y niñas con problemas de desarrollo. Se comentan las limitaciones de los estudios revisados y la necesidad utilizar programas bien definidos, mediciones a largo plazo y comparaciones de diversos tipos de programas entre sí. (AU)

Neurocytotoxicity of imidacloprid- and acetamiprid-based comercial insecticides over the differentiation of SH-SY5Y neuroblastoma cells.

Neonicotinoids are effective insecticides with specificity for invertebrate nicotinic acetylcholine receptors. Neonicotinoids are chemically stable and tend to remain in the environment for long so concerns about their neurotoxicity in humans do nothing but increase. Herein, we evaluated the chronic toxic effects of acetamiprid- and imidacloprid-based insecticides over the differentiation of human neuroblastoma SH-SY5Y cells, which were exposed to these insecticides at a concentration range similar to that applied to crop fields (0.01-0.5 mM). Both insecticides did not have acute cytotoxic effects in both non-differentiated and in staurosporine-differentiated SH-SY5Y cells cytotoxicity as measured by the MTT and vital-dye exclusion tests. However, after a chronic (7-day) treatment, only imidacloprid dose-dependently decreased the viability of SH-SY5Y cells (F(4,39) = 43.05, P < 0.001), largely when administered-during cell differentiation (F(4,39) = 51.86, P < 0.001). A well-defined dose-response curve was constructed for imidacloprid on day 4 (R2 = 0.945, EC50 = 0.14 mM). During differentiation, either imidacloprid or acetamiprid dose-dependently caused neurite branch retraction on day 3, likely because of oxidative stress, to the extent that cells turned into spheres without neurites after 7-day treatment. Despite their apparent safety, the neurodevelopmental vulnerability of SH-SY5Y neurons to the chronic exposure to imidacloprid and to a lesser extent to acetamiprid points to a neurotoxic risk for humans.

Aging in nucleus accumbens and its impact on alcohol use disorders.

Ethanol is one of the most widely consumed drugs in the world and prolonged excessive ethanol intake might lead to alcohol use disorders (AUDs), which are characterized by neuroadaptations in different brain regions, such as in the reward circuitry. In addition, the global population is aging, and it appears that they are increasing their ethanol consumption. Although research involving the effects of alcohol in aging subjects is limited, differential effects have been described. For example, studies in human subjects show that older adults perform worse in tests assessing working memory, attention, and cognition as compared to younger adults. Interestingly, in the field of the neurobiological basis of ethanol actions, there is a significant dichotomy between what we know about the effects of ethanol on neurochemical targets in young animals and how it might affect them in the aging brain. To be able to understand the distinct effects of ethanol in the aging brain, the following questions need to be answered: (1) How does physiological aging impact the function of an ethanol-relevant region (e.g., the nucleus accumbens)? and (2) How does ethanol affect these neurobiological systems in the aged brain? This review discusses the available data to try to understand how aging affects the nucleus accumbens (nAc) and its neurochemical response to alcohol. The data show that there is little information on the effects of ethanol in aged mice and rats, and that many studies had considered 2-3-month-old mice as adults, which needs to be reconsidered since more recent literature defines 6 months as young adults and >18 months as an older mouse. Considering the actual relevance of an aged worldwide population and that this segment is drinking more frequently, it appears at least reasonable to explore how ethanol affects the brain in adult and aged models.

Overexpression of wild type glycine alpha 1 subunit rescues ethanol sensitivity in accumbal receptors and reduces binge drinking in mice.

The nucleus accumbens (nAc) is a critical region in the brain reward system since it integrates abundant synaptic inputs contributing to the control of neuronal excitability in the circuit. The presence of inhibitory α1 glycine receptor (GlyRs) subunits, sensitive to ethanol, has been recently reported in accumbal neurons suggesting that they are protective against excessive binge consumption. In the present study, we used viral vectors (AAV) to overexpress mutant and WT α1 subunits in accumbal neurons in D1 Cre and α1 KI mice. Injection of a Cre-inducible AAV carrying an ethanol insensitive α1 subunit in D1 Cre neurons was unable to affect sensitivity to ethanol in GlyRs or affect ethanol drinking. On the other hand, using an AAV that transduced WT α1 GlyRs in GABAergic neurons in the nAc of high-ethanol consuming mice caused a reduction in ethanol intake as reflected by lowered drinking in the dark and reduced blood ethanol concentration. As expected, the AAV increased the glycine current density by 5-fold without changing the expression of GABAA receptors. Examination of the ethanol sensitivity in isolated accumbal neurons indicated that the GlyRs phenotype changed from an ethanol resistant to an ethanol sensitive type. These results support the conclusion that increased inhibition in the nAc can control excessive ethanol consumption and that selective targeting of GlyRs by pharmacotherapy might provide a mechanistic procedure to reduce ethanol binge.

Validación y propiedades psicométricas del “Cuestionario de valores de vida” (VLQ) para población española / Validation and psychometric properties of the "Life Values Questionnaire" (VLQ) for the Spanish population

El objetivo de este trabajo es presentar la adaptación española del “Cuestionario de valores de vida” (VLQ; Wilson et al., 2010), aportando datos sobre sus propiedades psicométricas. Se aplicó el cuestionario a 531 participantes de entre 18 y 70 años (M= 28,73), siendo el 70% mujeres universitarias. El análisis factorial exploratorio mostró tres factores principales: comunidad, cercanía y obligaciones, cuyos niveles de consistencia interna fueron de 0,70, 0,71 y 0,68, respectivamente, mientras que para la puntuación total fue de 0,71 que resultaron similares a los del original. En cuanto a la validez concurrente, el VLQ mostró correlaciones moderadas con el “Cuestionario de valores personales” (Schwartz, 1992) (r= 0,47) y con el “Cuestionario de instantánea vital” (Ruiz-García et al., 2021; Tsai et al., 2023) (r= 0,65). Se discute la utilidad del VLQ para evaluar y hacer seguimiento a los procesos clave involucrados en los cambios clínicos, así como para mejorar y evaluar los valores personales íntimamente relacionados con la calidad de vida, el sentido de la vida y el bienestar de la comunidad. (AU)

Enhancing students' well-being with a unified approach based on contextual behavioural science: A randomised experimental school-based intervention.

A new generation of interventions has begun to move towards principles of acceptance that deal with the context and function of psychological events. The aim of this paper is to analyse the effectiveness of a brief contextual behavioural intervention to improve the psychological well-being of secondary school students. This intervention represents a unified model with key processes based on contextual behavioural science, including Acceptance and Commitment Therapy (ACT) and Functional Analytic Psychotherapy (FAP). We conducted an intervention with 94 students (age range 17-19 years), randomly assigned to an experimental group (n = 50) or control group (n = 44). Participants took a pretest and post-test of distress, life satisfaction, psychological flexibility and mindfulness. The intervention consisted of three sessions of 1 h each. The results showed significant differences between the groups in distress and significant differences for the interaction (group × pre-post) in all the other variables. The intervention had greater benefits for girls than for boys. These results may provide a breakthrough, thus leading to a process of evidence-based therapies, which would be responsible for inducing psychological improvements in brief periods, in a population with an increasing risk of distress.

GKRP-dependent modulation of feeding behavior by tanycyte-released monocarboxylates.

Objectives: Glucokinase Regulatory Protein (GKRP) is the only known endogenous modulator of glucokinase (GK) localization and activity to date, and both proteins are localized in tanycytes, radial glia-like cells involved in metabolic and endocrine functions in the hypothalamus. However, the role of tanycytic GKRP and its impact on the regulation of feeding behavior has not been investigated. Here, we hypothesize that GKRP regulates feeding behavior by modulating tanycyte-neuron metabolic communication in the arcuate nucleus. Methods: We used primary cultures of tanycytes to evaluate the production of lactate and ß-hydroxybutyrate (ßHB). Similarly, we examined the electrophysiological responses to these metabolites in pro-opiomelanocortin (POMC) neurons in hypothalamic slices. To evaluate the role of GKRP in feeding behavior, we generated tanycyte-selective GKRP-overexpressing and GKRP-knock down mice (GKRPt-OE and GKRPt-KD respectively) using adenovirus-mediated transduction. Results: We demonstrated that lactate release induced by glucose uptake is favored in GKRP-KD tanycytes. Conversely, tanycytes overexpressing GKRP showed an increase in ßHB efflux induced by low glucose concentration. In line with these findings, the excitability of POMC neurons was enhanced by lactate and decreased in the presence of ßHB. In GKRPt-OE rats, we found an increase in post-fasting food avidity, whereas GKRPt-KD caused a significant decrease in feeding and body weight, which is reverted when MCT1 is silenced. Conclusion: Our study highlights the role of tanycytic GKRP in metabolic regulation and positions this regulator of GK as a therapeutic target for boosting satiety in patients with obesity problems.

Modulation of GABAA receptors and of GABAergic synapses by the natural alkaloid gelsemine.

The Gelsemium elegans plant preparations have shown beneficial activity against common diseases, including chronic pain and anxiety. Nevertheless, their clinical uses are limited by their toxicity. Gelsemine, one of the most abundant alkaloids in the Gelsemium plants, have replicated these therapeutic and toxic actions in experimental behavioral models. However, the molecular targets underlying these biological effects remain unclear. The behavioral activity profile of gelsemine suggests the involvement of GABAA receptors (GABAARs), which are the main biological targets of benzodiazepines (BDZs), a group of drugs with anxiolytic, hypnotic, and analgesic properties. Here, we aim to define the modulation of GABAARs by gelsemine, with a special focus on the subtypes involved in the BDZ actions. The gelsemine actions were determined by electrophysiological recordings of recombinant GABAARs expressed in HEK293 cells, and of native receptors in cortical neurons. Gelsemine inhibited the agonist-evoked currents of recombinant and native receptors. The functional inhibition was not associated with the BDZ binding site. We determined in addition that gelsemine diminished the frequency of GABAergic synaptic events, likely through a presynaptic modulation. Our findings establish gelsemine as a negative modulator of GABAARs and of GABAergic synaptic function. These pharmacological features discard direct anxiolytic or analgesic actions of gelsemine through GABAARs but support a role of GABAARs on the alkaloid induced toxicity. On the other hand, the presynaptic effects of the alkaloid provide an additional mechanism to explain their beneficial effects. Collectively, our results contribute novel information to improve understanding of gelsemine actions in the mammalian nervous system.

The Stimulatory Effects of Intracellular α-Synuclein on Synaptic Transmission Are Attenuated by 2-Octahydroisoquinolin-2(1H)-ylethanamine.

α-Synuclein (αSyn) species can be detected in synaptic boutons, where they play a crucial role in the pathogenesis of Parkinson's Disease (PD). However, the effects of intracellular αSyn species on synaptic transmission have not been thoroughly studied. Here, using patch-clamp recordings in hippocampal neurons, we report that αSyn oligomers (αSynO), intracellularly delivered through the patch electrode, produced a fast and potent effect on synaptic transmission, causing a substantial increase in the frequency, amplitude and transferred charge of spontaneous synaptic currents. We also found an increase in the frequency of miniature synaptic currents, suggesting an effect located at the presynaptic site of the synapsis. Furthermore, our in silico approximation using docking analysis and molecular dynamics simulations showed an interaction between a previously described small anti-amyloid beta (Aß) molecule, termed M30 (2-octahydroisoquinolin-2(1H)-ylethanamine), with a central hydrophobic region of αSyn. In line with this finding, our empirical data aimed to obtain oligomerization states with thioflavin T (ThT) and Western blot (WB) indicated that M30 interfered with αSyn aggregation and decreased the formation of higher-molecular-weight species. Furthermore, the effect of αSynO on synaptic physiology was also antagonized by M30, resulting in a decrease in the frequency, amplitude, and charge transferred of synaptic currents. Overall, the present results show an excitatory effect of intracellular αSyn low molecular-weight species, not previously described, that are able to affect synaptic transmission, and the potential of a small neuroactive molecule to interfere with the aggregation process and the synaptic effect of αSyn, suggesting that M30 could be a potential therapeutic strategy for synucleinopathies.

Modulatory Actions of the Glycine Receptor ß Subunit on the Positive Allosteric Modulation of Ethanol in α2 Containing Receptors.

Alpha1-containing glycine receptors (GlyRs) are major mediators of synaptic inhibition in the spinal cord and brain stem. Recent studies reported the presence of α2-containing GlyRs in other brain regions, such as nucleus accumbens and cerebral cortex. GlyR activation decreases neuronal excitability associated with sensorial information, motor control, and respiratory functions; all of which are significantly altered during ethanol intoxication. We evaluated the role of ß GlyR subunits and of two basic amino acid residues, K389 and R390, located in the large intracellular loop (IL) of the α2 GlyR subunit, which are important for binding and functional modulation by Gßγ, the dimer of the trimeric G protein conformation, using HEK-293 transfected cells combined with patch clamp electrophysiology. We demonstrate a new modulatory role of the ß subunit on ethanol sensitivity of α2 subunits. Specifically, we found a differential allosteric modulation in homomeric α2 GlyRs compared with the α2ß heteromeric conformation. Indeed, while α2 was insensitive, α2ß GlyRs were substantially potentiated by ethanol, GTP-γ-S, propofol, Zn2+ and trichloroethanol. Furthermore, a Gßγ scavenger (ct-GRK2) selectively attenuated the effects of ethanol on recombinant α2ß GlyRs. Mutations in an α2 GlyR co-expressed with the ß subunit (α2AAß) specifically blocked ethanol sensitivity, but not propofol potentiation. These results show a selective mechanism for low ethanol concentration effects on homomeric and heteromeric conformations of α2 GlyRs and provide a new mechanism for ethanol pharmacology, which is relevant to upper brain regions where α2 GlyRs are abundantly expressed.

Programa de intervención breve basado en las terapias contextuales para mejorar el bienestar psicológico en el entorno organizacional / Brief intervention programme based on contextual therapies to improve psychological well-being at the workplace

Introducción y objetivos: Este estudio examina la eficiencia y efectividad de un programa breve, basado en las dos terapias contextuales más representativa, para mejorar la salud general, y el bienestar laboral de los empleados/as de una cooperativa agrícola. La evaluación pretest se realizó con 25 empleados de la misma empresa, de los cuales 15 cumplieron con los criterios de inclusión; estableciendo como punto de corte puntuaciones moderadas de malestar psicológico. Los empleados recibieron una intervención basada en un programa breve con la combinación de la Terapia de Aceptación y Compromiso junto con la Psicoterapia Analítica-Funcional (FACT). Material y Métodos: Los participantes recibieron 3 sesiones, 2 individuales y 1 grupal. Se evaluaron con el Cuestionario de Salud General (GHQ-12); la Escala de Observación de Recompensa Ambiental (EROS); y la satisfacción laboral, que se evaluó con la subescala de bienestar laboral de la Escala de Bienestar Psicológico (EBP). Se utilizó un diseño intra-grupos con evaluación pre y post intervención. Resultados: Los participantes mejoraron en las variables analizadas, siendo estadísticamente significativos para las variables: GHQ-12 (W = -3.34, gl = 14, p = .001), EROS (W = -3.05, gl = 14, p = .002) y EBP (W = -3.08, gl = 14, p = .002). Conclusiones: Se discuten las implicaciones de la combinación de ambas aproximaciones que comparten las raíces filosóficas y analíticas basadas en el contextualismo funcional. Esta intervención se plantea como un modelo efectivo para producir cambios en la salud de los trabajadores/as en breves periodos de tiempo, de forma rápida y no invasiva para empleados y empresas.(AU)

Introduction and aims: This study examines the efficiency and effectiveness of a brief program based on the two most representative contextual therapies in order to improve the general health and well-being at the workplace with employees of an agricultural cooperative. The pre-test evaluation was carried out with 25 employees from the same company, of whom 15 met the inclusion criteria with moderate scores for psychological distress as the cut-off point. The employees received an intervention based on a brief program combining of Acceptance and Commitment Therapy and also Analytical-Functional Psychotherapy. Material and Methods: The employees received 3 sessions, 2 individual and 1 group session. They were assessed with the General Health Questionnaire (GHQ-12); the Environmental Reward Observation Scale (EROS); and job satisfaction, which was evaluated with the job well-being subscale of the Psychological Well-being Scale (EBP). An intra-group design with pre and post intervention assessment was used. Results: Participants improved statistically in the variables analyzed: GHQ-12 (W = -3.34, gl = 14, p = .001), EROS (W = -3.05, gl = 14, p = .002) and EBP (W = -3.08, gl = 14, p = .002). Conclusions: The implications of the combination of both approaches that share philosophical and analytical roots based on functional contextualism are discussed. This treatment is proposed as an effective model to produce changes in workers' health in short periods of time, in a fast and non-invasive way for employees and companies.(AU)

Contribution of GlyR α3 Subunits to the Sensitivity and Effect of Ethanol in the Nucleus Accumbens.

The glycine receptor (GlyR), a ligand-gated ion channel, is critical for inhibitory neurotransmission in brainstem, spinal cord, and in supraspinal regions. Recent data from several laboratories have shown that GlyRs are expressed in the brain reward circuitry and that α1 and α2 are the principal subunits expressed in the nucleus accumbens (nAc). In the present study, we studied the sensitivity to ethanol of homomeric and heteromeric α3 GlyR subunits in HEK293 cells and dissociated neurons from the nAc. Finally, we explored ethanol-related behaviors in a Glra3 knockout mouse (Glra3 -/-). Studies in HEK293 cells showed that while homomeric α3 GlyR subunits were insensitive to ethanol, heteromeric α3ß GlyR subunits showed higher sensitivity to ethanol. Additionally, using electrophysiological recordings in dissociated accumbal neurons, we found that the glycine current density increased in Glra3 -/- mice and the GlyRs were less affected by ethanol and picrotoxin. We also examined the effect of ethanol on sedation and drinking behavior in Glra3 -/- mice and found that the duration in the loss of righting reflex (LORR) was unchanged compared to wild-type (WT) mice. On the other hand, using the drinking in the dark (DID) paradigm, we found that Glra3 -/- mice have a larger ethanol consumption compared to WT mice, and that this was already high during the first days of exposure to ethanol. Our results support the conclusion that heteromeric α3ß, but not homomeric α3, GlyRs are potentiated by ethanol. Also, the increase in GlyR and GABA A R mediated current densities in accumbal neurons in the KO mice support the presence of compensatory changes to α3 knock out. The increase in ethanol drinking in the Glra3 -/- mice might be associated to the reduction in ß and compensatory changes in other subunits in the receptor arrangement.

Importance of the therapeutic relationship: efficacy of functional analytic psychotherapy with different problems / La importancia de la relación terapéutica: la eficacia de la psicoterapia analítica funcional en distintos problemas

Functional Analytical Psychotherapy (FAP) is a third generation and contextual therapy. It is based on therapeutic interaction, verbal and emotional client-therapist relationships. It also uses functional analysis of behaviour, and live on-going modification of clinical problem behaviours. The aim of this research was to study the efficacy of FAP with different types of psychological problems (anxiety, depression, obsession, sexual, personality, emotional control). An intra-group design (10 participants, 36 years old average) was used with pre-post and follow-up measurements. Different questionnaires have been used as common assessment tools for all clinical cases. The results showed a statistically significant change in all the standardised questionnaires, with a considerable size effect (d from -2.01 to -3.80) and maintained one year later. Also, as clinical change, the participants had improved in their daily lives. We conclude on the efficacy of FAP, focusing on the therapeutic relationship, regardless of diagnostic categories. (AU)

La Psicoterapia Analítica Funcional (FAP) es una terapia contextual y de tercera generación que se basa en la interacción terapéutica y las relaciones verbales y emocionales cliente-terapeuta. También utiliza el análisis funcional del comportamiento y la modificación en vivo de los comportamientos clínicos problemáticos. El objetivo de esta investigación es estudiar la eficacia de la FAP ante diferentes tipos de problemas psicológicos (ansiedad, depresión, obsesión, sexual, personalidad, control emocional). Se utilizó un diseño intragrupo (10 participantes, con un promedio de edad de 36 años) con mediciones previas, posteriores y de seguimiento. Se han utilizado diferentes cuestionarios como herramientas de evaluación comunes para todos los casos clínicos. Los resultados mostraron un cambio estadísticamente significativo en todos los cuestionarios estandarizados, con un efecto de tamaño considerable (d de -2.01 a -3.80) que se mantenía un año más tarde. Además, como cambio clínico, los participantes habían mejorado en su vida diaria. Concluimos sobre la eficacia de la FAP, centrándonos en la relación terapéutica, independientemente de las categorías diagnósticas. (AU)

Meta-analysis of the Efficacy and Effectiveness of Parent Child Interaction Therapy (PCIT) for Child Behaviour Problems.

BACKGROUND: Parent-Child Interaction Therapy (PCIT) is a well-established treatment for behavioural, hyperactivity and oppositional-defiant problems in children. Previous meta-analyses are scarce, and they have tended to mix problems and measures. OBJECTIVE: A meta-analysis study was conducted with all available studies on PCIT (1980 to 2020) to determine its specific efficacy and effectiveness for child behavioural problems. METHOD: Selection from databases collected a total of 100 studies. The inclusion criteria were to compare PCIT in children with behavioural problems between 2 and 12 years of age; comparing groups and using standardized instruments. RESULTS: PCIT exhibited a significant mean effect size ( d = -0.87 [95% CI: -1.10, -0.63] versus control and/or treatment-as-usual groups, but the effect size was smaller and not significant in follow-ups ( d = -0.23 [95% CI: -0.49, 0.04]). The within-group studies, comparing versions of PCIT, also demonstrated a significant effect size ( d = -0.26 (95% CI: -0.43, -0.08), and in pre-post comparisons this effect was greater ( d = -1.40 [95% CI: -1.69, -1.10]). CONCLUSIONS: PCIT is an effective intervention for treating child behaviour problems such as disruptive, hyperactive, negative, and externalizing problems. It is supported by 40 years of experimental and clinical studies, and also by this meta-analysis.

Synaptic dysregulation and hyperexcitability induced by intracellular amyloid beta oligomers.

Intracellular amyloid beta oligomer (iAßo) accumulation and neuronal hyperexcitability are two crucial events at early stages of Alzheimer's disease (AD). However, to date, no mechanism linking iAßo with an increase in neuronal excitability has been reported. Here, the effects of human AD brain-derived (h-iAßo) and synthetic (iAßo) peptides on synaptic currents and action potential firing were investigated in hippocampal neurons. Starting from 500 pM, iAßo rapidly increased the frequency of synaptic currents and higher concentrations potentiated the AMPA receptor-mediated current. Both effects were PKC-dependent. Parallel recordings of synaptic currents and nitric oxide (NO)-associated fluorescence showed that the increased frequency, related to pre-synaptic release, was dependent on a NO-mediated retrograde signaling. Moreover, increased synchronization in NO production was also observed in neurons neighboring those dialyzed with iAßo, indicating that iAßo can increase network excitability at a distance. Current-clamp recordings suggested that iAßo increased neuronal excitability via AMPA-driven synaptic activity without altering membrane intrinsic properties. These results strongly indicate that iAßo causes functional spreading of hyperexcitability through a synaptic-driven mechanism and offers an important neuropathological significance to intracellular species in the initial stages of AD, which include brain hyperexcitability and seizures.

Presence of ethanol-sensitive and ethanol-insensitive glycine receptors in the ventral tegmental area and prefrontal cortex in mice.

BACKGROUND AND PURPOSE: Glycine receptors composed of α1 and ß subunits are primarily found in the spinal cord and brainstem and are potentiated by ethanol (10-100 mM). However, much less is known about the presence, composition and ethanol sensitivity of these receptors in higher CNS regions. Here, we examined two regions of the brain reward system, the ventral tegmental area (VTA) and the prefrontal cortex (PFC), to determine their glycine receptor subunit composition and sensitivity to ethanol. EXPERIMENTAL APPROACH: We used Western blot, immunohistochemistry and electrophysiological techniques in three different models: wild-type C57BL/6, glycine receptor subunit α1 knock-in and glycine receptor subunit α2 knockout mice. KEY RESULTS: Similar levels of α and ß receptor subunits were detected in both brain regions, and electrophysiological recordings demonstrated the presence of glycine-activated currents in both areas. Sensitivity of glycine receptors to glycine was lower in the PFC compared with VTA. Picrotoxin only partly blocked the glycine-activated current in the PFC and VTA, indicating that both regions express heteromeric αß receptors. Glycine receptors in VTA neurons, but not in PFC neurons, were potentiated by ethanol. CONCLUSION AND IMPLICATIONS: Glycine receptors in VTA neurons from WT and α2 KO mice were potentiated by ethanol, but not in neurons from the α1 KI mice, supporting the conclusion that α1 glycine receptors are predominantly expressed in the VTA. By contrast, glycine receptors in PFC neurons were not potentiated in any of the mouse models studied, suggesting the presence of α2/α3/α4, rather than α1 glycine receptor subunits.