Long-term enhancements in antidepressant efficacy and neurogenesis: Effects of intranasal co-administration of neuropeptide Y 1 receptor (NPY1R) and galanin receptor 2 (GALR2) agonists in the ventral hippocampus.

This study evaluates the sustained antidepressant-like effects and neurogenic potential of a 3-day intranasal co-administration regimen of galanin receptor 2 (GALR2) agonist M1145 and neuropeptide Y Y1 receptor (NPY1R) agonist [Leu31, Pro34]NPY in the ventral hippocampus of adult rats, with outcomes analyzed 3 weeks post-treatment. Utilizing the forced swimming test (FST), we found that this co-administration significantly enhances antidepressant-like behaviors, an effect neutralized by the GALR2 antagonist M871, highlighting the synergistic potential of these neuropeptides in modulating mood-related behaviors. In situ proximity ligation assay (PLA) indicated a significant increase in GALR2/NPYY1R heteroreceptor complexes in the ventral hippocampal dentate gyrus, suggesting a molecular basis for the behavioral outcomes observed. Moreover, proliferating cell nuclear antigen (PCNA) immunolabeling revealed increased cell proliferation in the subgranular zone of the dentate gyrus, specifically in neuroblasts as evidenced by co-labeling with doublecortin (DCX), without affecting quiescent neural progenitors or astrocytes. The study also noted a significant uptick in the number of DCX-positive cells and alterations in dendritic morphology in the ventral hippocampus, indicative of enhanced neuronal differentiation and maturation. These morphological changes highlight the potential of these agonists to facilitate the functional integration of new neurons into existing neural circuits. By demonstrating the long-lasting effects of a brief, 3-day intranasal administration of GALR2 and NPY1R agonists, our findings contribute significantly to the understanding of neuropeptide-mediated neuroplasticity and herald novel therapeutic strategies for the treatment of depression and related mood disorders, emphasizing the therapeutic promise of targeting neurogenesis and neuronal maturation processes.

Enhanced neuronal survival and BDNF elevation via long-term co-activation of galanin 2 (GALR2) and neuropeptide Y1 receptors (NPY1R): potential therapeutic targets for major depressive disorder.

BACKGROUND: Major Depressive Disorder (MDD) is a prevalent and debilitating condition, necessitating novel therapeutic strategies due to the limited efficacy and adverse effects of current treatments. We explored how galanin receptor 2 (GALR2) and Neuropeptide Y1 Receptor (NPYY1R) agonists, working together, can boost brain cell growth and increase antidepressant-like effects in rats. This suggests new ways to treat Major Depressive Disorder (MDD). RESEARCH DESIGN AND METHODS: In a controlled laboratory setting, adult naive Sprague-Dawley rats were administered directly into the brain's ventricles, a method known as intracerebroventricular (ICV) administration, with GALR2 agonist (M1145), NPYY1R agonist, both, or in combination with a GALR2 antagonist (M871). Main outcome measures included long-term neuronal survival, differentiation, and behavioral. RESULTS: Co-administration of M1145 and NPYY1R agonist significantly enhanced neuronal survival and maturation in the ventral dentate gyrus, with a notable increase in Brain-Derived Neurotrophic Factor (BDNF) expression. This neurogenic effect was associated with an antidepressant-like effect, an outcome partially reversed by M871. CONCLUSIONS: GALR2 and NPYY1R agonists jointly promote hippocampal neurogenesis and exert antidepressant-like effects in rats without adverse outcomes, highlighting their therapeutic potential for MDD. The study's reliance on an animal model and intracerebroventricular delivery warrants further clinical exploration to confirm these promising results.

Potentiation of antidepressant effects: NPY1R agonist and ketamine synergy enhances TrkB signaling and neurogenesis in the ventral hippocampus.

BACKGROUND: Major Depressive Disorder (MDD) poses a significant challenge to global health, with current treatments often limited by efficacy and onset delays. This study explores the synergistic antidepressant-like effects of an NPY1R agonist and Ketamine, targeting their neurobiological interactions within the ventral hippocampus. RESEARCH DESIGN AND METHODS: Utilizing a preclinical model, this study administered Neuropeptide Y receptor 1 (NPY1R) agonist and Ketamine, both separately and in combination, through intracerebroventricular (icv) and intranasal (i.n.) routes. The Forced Swimming Test (FST) was employed to assess antidepressant-like activity, while in situ Proximity Ligation Assay and immunohistochemistry were used to examine NPY1R/TrkB heteroreceptor complexes and BDNF expression in the ventral dentate gyrus (DG), along with neurogenesis markers. RESULTS: The combined treatment significantly reduced immobility in the FST, indicative of enhanced antidepressant-like effects, correlated with increased formation of NPY1R/TrkB complex and brain-derived neurotrophic factor (BDNF) expression in the ventral DG. These molecular alterations were associated with increased neurogenesis. CONCLUSIONS: The coadministration of an NPY1R agonist and Ketamine in a rodent model demonstrated potentiated antidepressant responses through synergistic neurobiological pathways, including TrkB signaling and hippocampal neurogenesis. This indicates a novel therapeutic strategy for MDD, warranting further clinical investigation to fully understand its implications.

Decreased medial prefrontal cortex activity related to impaired novel object preference task performance following GALR2 and Y1R agonists intranasal infusion.

Different brain regions' interactions have been implicated in relevant neurological diseases, such as major depressive disorder (MDD), anxiety disorders, age-dependent cognitive decline, Alzheimer's disease (AD) and addiction. We aim to explore the role of the medial prefrontal cortex (mPFC) in the Neuropeptide Y (NPY) and Galanin (GAL) interaction since we have demonstrated specific NPY and GAL interactions in brain areas related to these brain diseases. We performed GALR2 and Y1R agonists intranasal infusion and analyzed the mPFC activation through c-Fos expression. To assess the associated cellular mechanism we studied the formation of Y1R-GALR2 heteroreceptor complexes with in situ proximity ligation assay (PLA) and the expression of the brain-derived neurotrophic factor (BDNF). Moreover, the functional outcome of the NPY and GAL interaction on the mPFC was evaluated in the novel object preference task. We demonstrated that the intranasal administration of both agonists decrease the medial prefrontal cortex activation as shown with the c-Fos expression. These effects were mediated by the decreased formation of Y1R-GALR2 heteroreceptor complexes without affecting the BDNF expression. The functional outcome of this interaction was related to an impaired performance on the novel object preference task. Our data may suggest the translational development of new heterobivalent agonist pharmacophores acting on Y1R-GALR2 heterocomplexes in the medial prefrontal cortex for the novel therapy on neurodegenerative and psychiatric diseases. DATA SHARING AND DATA ACCESSIBILITY: The data that support the findings of this study are openly available in Institutional repository of the University of Malaga (RIUMA) and from the corresponding author upon reasonable request.

GALR2 and Y1R agonists intranasal infusion enhanced adult ventral hippocampal neurogenesis and antidepressant-like effects involving BDNF actions.

Dysregulation of adult hippocampal neurogenesis is linked to major depressive disorder (MDD), with more than 300 million people diagnosed and worsened by the COVID-19 pandemic. Accumulating evidence for neuropeptide Y (NPY) and galanin (GAL) interaction was shown in various limbic system regions at molecular-, cellular-, and behavioral-specific levels. The purpose of the current work was to evaluate the proliferating role of GAL2 receptor (GALR2) and Y1R agonists interaction upon intranasal infusion in the ventral hippocampus. We studied their hippocampal proliferating actions using the proliferating cell nuclear antigen (PCNA) on neuroblasts or stem cells and the expression of the brain-derived neurothrophic factor (BDNF). Moreover, we studied the formation of Y1R-GALR2 heteroreceptor complexes and analyzed morphological changes in hippocampal neuronal cells. Finally, the functional outcome of the NPY and GAL interaction on the ventral hippocampus was evaluated in the forced swimming test. We demonstrated that the intranasal infusion of GALR2 and the Y1R agonists promotes neuroblasts proliferation in the dentate gyrus of the ventral hippocampus and the induction of the neurotrophic factor BDNF. These effects were mediated by the increased formation of Y1R-GALR2 heteroreceptor complexes, which may mediate the neurites outgrowth observed on neuronal hippocampal cells. Importantly, BDNF action was found necessary for the antidepressant-like effects after GALR2 and the Y1R agonists intranasal administration. Our data may suggest the translational development of new heterobivalent agonist pharmacophores acting on Y1R-GALR2 heterocomplexes in the ventral hippocampus for the novel therapy of MDD or depressive-affecting diseases.

Simbiosis y narcisisimo en la adolescencia. A propósito de un caso / Symbiosis and narcissism in adolescence. About a case / Simbiosi i narcisisme en l'adolescéncia. A propósit d'un cas

Las reflexiones que mostraremos a continuación parten de la experiencia asistencial con un caso asistido por los autores del artículo en co-terapia y de las conversaciones inter-sesión. Una gran parte de las reflexiones sobre el caso las hemos podido hacer a posteriori de la experiencia terapéutica. Nuestro objetivo principal es el cuidado y atención de los menores y sus familias. Escribir este artículo permite la elaboración mental del caso y la función de presentarlo es repensarlo para seguir velando por mejorar la asistencia a la salud mental infantil y juvenil desde nuestra institución

The reflections that we are going to show are based on our care experience in co-therapy and on conversations between sessions. A large part of the case reflections has been made after the therapeutic experience. Our main objective is the care and attention of minors and their families. Writing this article allows the mental elaboration of the case and presenting it aims at reconsidering and making our institution keep on improving the mental health assistance of children and youth

Les reflexions que mostrarem a continuació par­teixen de l'experiéncia assistencial amb un cas assistit pels autors en co-terápia i de les converses inter-sessió. Una gran part de les reflexions sobre el cas les hem pogut fer a posteriori de l’experiència terapèutica. El nostre objectiu principal és la cura i l'atenció dels menors i les seves famílies. Escriure l’article permet l'elaboració men­tal del cas i la funció de presentar-lo és repensar-lo per seguir vetllant per millorar l'assisténcia a la salut mental infantil i juvenil des de la nostra institució

Una experiencia grupal en pacientes con trastornos generalizados del desarrollo / A group experience with patients with pervasive developmental disorders / Una experiència grupal en pacients amb trastorns generalitzats del desenvolupament

Los trastornos generalizados del desarrollo presentan dificultades relacionales y de simbolización (Alcácer y Viloca, 2014), que se agravan con los cambios físicos de la pubertad. Nos planteamos un abordaje grupal centrado en la relación a través de una tarea que favorezca el proceso de simbolización. Observamos en los pacientes una mejoría en la capacidad de interesarse por el otro, una menor necesidad de contención con psicofármacos, un aumento de la capacidad de abstracción y una mayor simbolización. La hipótesis consiste en que la observación de imágenes y discusión sobre las mismas en grupo puede ser un elemento facilitador del trabajo del mundo interno y la relación entre los integrantes del grupo

Pervasive Developmental Disorders present relational and symbolic difficulties (Alcácer and Viloca, 2014), which are aggravated by the physical changes of puberty. We propose a relationship-centered group approach employing a task that favors the process of symbolization. We observed improvements in the patients in their capacity to be interested in others, a decreased need for containment with psychoactive drugs, an increase in the capacity for abstract thought and greater symbolization. The hypothesis is that the observation of images and discussion about them in a group might be an element that facilitates the work of the internal world and the relations between the members of the group

Els trastorns generalitzats del desenvolupament presenten dificultats relacionals I de simbolització (Alcácer I Viloca, 2014), que s'agreugen amb els canvis físics de la pubertat. Els plantegem un abordatge grupal centrat en la relació mitjançant una tasca que afavoreixi el procés de simbolització. Observem en els pacients una millora en la capacitat d'interessar-se per l'altre, una menor necessitat de contenció amb psicofàrmacs, un augment de la capacitat d'abstracció I una major simbolització. La hipòtesi consisteix en el fet que l'observació d'imatges I la discussió sobre aquestes en grup pot ser un element facilitador del treball del món intern I la relació entre els integrants del grup