Neural plasticity and proliferation in the generation of antidepressant effects: hippocampal implication

It is widely accepted that changes underlying depression and antidepressant-like effects involve not only alterations in the levels of neurotransmitters as monoamines and their receptors in the brain, but also structural and functional changes far beyond. During the last two decades, emerging theories are providing new explanations about the neurobiology of depression and the mechanism of action of antidepressant strategies based on cellular changes at the CNS level. The neurotrophic/plasticity hypothesis of depression, proposed more than a decade ago, is now supported by multiple basic and clinical studies focused on the role of intracellular-signalling cascades that govern neural proliferation and plasticity. Herein, we review the state-of-the-art of the changes in these signalling pathways which appear to underlie both depressive disorders and antidepressant actions. We will especially focus on the hippocampal cellularity and plasticity modulation by serotonin, trophic factors as brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor (VEGF) through intracellular signalling pathways-cAMP, Wnt/ β -catenin, and mTOR. Connecting the classic monoaminergic hypothesis with proliferation/neuroplasticity-related evidence is an appealing and comprehensive attempt for improving our knowledge about the neurobiological events leading to depression and associated to antidepressant therapies

Enhanced Stress Response in 5-HT1AR Overexpressing Mice: Altered HPA Function and Hippocampal Long-Term Potentiation

Postsynaptic 5-HT1A receptors (5-HT1AR) play an important role in anxiety and stress, although their contribution is still controversial. Previous studies report that mice overexpressing postsynaptic 5-HT1ARs show no changes in basal anxiety, though the influence of stress conditions has not been addressed yet. In this study, we used this animal model to evaluate the role of 5-HT1ARs in anxiety response after pre-exposure to an acute stressor. Under basal conditions, 5-HT1AR overexpressing animals presented high corticosterone levels and a lower mineralocorticoid/ glucocorticoid receptor ratio. After pre-exposure to a single stressor, they showed a high anxiety-like response, associated with a blunted increase in corticosterone levels and higher c-Fos activation in the prefrontal cortex. Moreover, these mice also presented a lack of downregulation of hippocampal long-term potentiation after stress exposure. Therefore, higher postsynaptic 5-HT1AR activation might predispose to a high anxious phenotype and an impaired stress coping behavior.Funding sources: This research was supported by Spanish Ministry of Economy and Competitiveness (SAF2011-25020 and SAF2015-67457-R), Instituto de Salud Carlos III (FIS Grant PI13-00038) co-funded by the European Regional Development Fund (‘A way to buildEurope’) and Centro de Investigacion Biomedica en Red de Salud Mental(CIBERSAM)

Cannabidiol potential for fast-antidepressant therapy: behavioural, neurochemical, molecular and cellular evidences. Implication of serotonergic and glutamatergic systems

RESUMEN: La depresión es la enfermedad psiquiátrica de mayor prevalencia en el mundo desarrollado y sin embargo, los tratamientos de los que disponemos en la actualidad presentan una eficacia terapéutica limitada, además de un fuerte retraso en la aparición de sus efectos. Puesto que la planta del Cannabis sativa ha sido utilizada desde la antigüedad con fines terapéuticos para la mejora del estado de ánimo, en la presente tesis doctoral se ha investigado el potencial del cannabidiol para la terapia antidepresiva en un modelo animal de depresión, así como el mecanismo de acción neurofarmacológico subyacente. Los hallazgos de este trabajo demuestran que la administración de cannabidiol da lugar a efectos antidepresivos de rápida instauración en el modelo de depresión de la bulbectomía olfatoria en ratón, a través de un mecanismo de acción dependiente del receptor 5-HT1A. Las acciones del cannabidiol incluyen la potenciación de la transmisión serotonérgica y glutamatérgica en la corteza prefrontal de los animales bulbectomizados, así como la reversión de las alteraciones propias del modelo en lo que se refiere a la funcionalidad de los receptores 5-HT1A y CB1, y a la expresión de marcadores proteicos asociados a neuroproliferación y neuroplasticidad. Los hallazgos de la presente tesis apoyan la eficacia del cannabidiol para el tratamiento de la depresión, que supondría una alternativa mejorada a los tratamientos antidepresivos utilizados actualmente en clínica, gracias a su rápida actuación y a su escasez de efectos adversos.ABSTRACT: Depression is the most prevalent psychiatric disorders of the developed world and however, current pharmacological treatments present a limited efficacy and a marked delay in the onset of action. As the plant of Cannabis sativa has been used for therapeutic purposes from ancient times to improve mood, in this doctoral thesis we have investigated the potential of cannabidiol for antidepressant therapy in an animal model of depression, as well as the neuropharmacological mechanism of action underlying. The findings of this work show that cannabidiol administration exerts antidepressant effects in a fast manner in the bulbectomy model of depression, through a 5-HT1A receptor-dependent mechanism of action. Cannabidiol actions entail serotonergic and glutamatergic enhancement in the prefrontal cortex of bulbectomized animals, and the reversal of the alterations of the bulbectomy model regarding 5-HT1A and CB1 receptors functionality, and the expression of protein markers associated to neuroprofliferation and neuroplasticity. The findings of this thesis support the efficacy of cannabidiol for the treatment of depression, what would represent an improved alternative to the current antidepressant treatments used in clinical practice, due to its quick actions and lack of adverse effects

2. Cannabidiol enhancement of serotonergic and glutamatergic signalling in a mouse model of depression induces fast and maintained antidepressant actions: implication of 5-HT1A receptors

Cannabidiol (CBD), the main non-psychotomimetic component of marihuana, exhibits anxiolytic-like properties in many behavioural tests, although its potential for treating major depression has been poorly explored. Moreover, the mechanism of action of CBD remains unclear. Herein, we have evaluated the effects of CBD following acute and chronic administration in the olfactory bulbectomy mouse model of depression (OBX), and investigated the underlying mechanism. For this purpose, we conducted behavioural (open field and sucrose preference tests) and neurochemical (microdialysis and autoradiography of 5-HT1A receptor functionality) studies following treatment with CBD. We also assayed the pharmacological antagonism of the effects of CBD to dissect out the mechanism of action. Our results demonstrate that CBD exerts fast and maintained antidepressant-like effects as evidenced by the reversal of the OBX-induced hyperactivity and anhedonia. In vivo microdialysis revealed that the administration of CBD significantly enhanced serotonin and glutamate levels in vmPFCx in a different manner depending on the emotional state and the duration of the treatment. The potentiating effect upon neurotransmitters levels occurring immediately after the first injection of CBD might underlie the fast antidepressant-like actions in OBX mice. Both antidepressant-like effect and enhanced cortical 5-HT/glutamate neurotransmission induced by CBD were prevented by 5-HT1A receptor blockade. Moreover, adaptive changes in pre- and post-synaptic 5-HT1A receptor functionality were also found after chronic CBD. In conclusion, our findings indicate that CBD could represent a novel fast antidepressant drug, via enhancing both serotonergic and glutamate cortical signalling through a 5-HT1A receptor-dependent mechanism.This research was supported by Spanish Ministry of Economy and Competitiveness (SAF2011-25020), Instituto de Salud Carlos III (FIS Grant PI13-00038) co-funded by the European Regional Development Fund (‘A way to build Europe’) and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM)