Cannabidiol as a fast-acting antidepressant: identification of the molecular mechanisms implicated in its antidepressant effect

RESUMEN: La depresión mayor es una enfermedad mental común y severa. Dado que los tratamientos actuales poseen importantes limitaciones, es necesario encontrar otros fármacos más rápidos y eficaces. El cannabidiol, el principal componente no psicoactivo del Cannabis sativa, se postula como un posible candidato. En esta tesis, la infusión de cannabidiol en la corteza infralímbica produjo un efecto agudo de tipo antidepresivo en ratas, asociado a un incremento de marcadores de plasticidad sináptica en la corteza prefrontal. Dicho efecto no se observó tras 24 horas, pero se recuperó tras el bloqueo de los receptores 5-HT1A presinápticos, juntamente con la activación de ERK en la corteza prefrontal. En el modelo neuroinflamatorio inducido por lipopolisacárido, la pre-administración sistémica de cannabidiol produjo un efecto de tipo antidepresivo en ratones, en el cual la activación de los receptores 5-HT1A postsinápticos tuvo un papel clave. El efecto conductual se asoció a una disminución de la activación de las vías NF-ĸB y de la quinurenina en cerebro, de los niveles de interleucina-6 en cerebro y plasma, y a la modulación de los niveles de glutamato y GABA cerebrales.ABSTRACT: Major depression is a common and severe mental illness. Given that current antidepressant treatments have significant limitations, it is necessary to find other faster and more effective drugs. Cannabidiol, the main non-psychoactive component of Cannabis sativa, is being postulated as a possible candidate. In this thesis, cannabidiol infusion into the infralimbic cortex produced an acute antidepressant-like effect in rats, which was associated with an increase in synaptic plasticity markers in the prefrontal cortex. This effect was not observed after 24 hours, but it was recovered after blocking the presynaptic 5-HT1A receptors, together with the activation of ERK in the prefrontal cortex. In the lipopolysaccharide-induced neuroinflammatory model, the systemic pre-administration of cannabidiol produced an antidepressant-like effect in mice, in which the activation of postsynaptic 5-HT1A receptors played a key role. The behavioral effect was associated with a decrease in the activation of the NF-ĸB and kynurenine pathways in the brain and of interleukin-6 levels in the brain and plasma, and with the modulation of brain glutamate and GABA levels.Este trabajo ha sido financiado por: - Ministerio de Economía y Competitividad (SAF2015‐67457‐R MINECO/FEDER). - Ministerio de Ciencia, Innovación y Universidades (RTI2018‐097534‐B‐I00). - Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III

The endocannabinoid system in mental disorders: Evidence from human brain studies

Mental disorders have a high prevalence compared with many other health conditions and are the leading cause of disability worldwide. Several studies performed in the last years support the involvement of the endocannabinoid system in the etiopathogenesis of different mental disorders. The present review will summarize the latest information on the role of the endocannabinoid system in psychiatric disorders, specifically depression, anxiety, and schizophrenia. We will focus on the findings from human brain studies regarding alterations in endocannabinoid levels, cannabinoid receptors and endocannabinoid metabolizing enzymes in patients suffering mental disorders. Studies carried out in humans have consistently demonstrated that the endocannabinoid system is fundamental for emotional homeostasis and cognitive function. Thus, deregulation of the different elements that are part of the endocannabinoid system may contribute to the pathophysiology of several mental disorders. However, the results reported are controversial. In this sense, different alterations in gene and/or protein expression of CBI receptors have been shown depending on the technical approach used or the brain region studied. Despite the current discrepancies regarding cannabinoid receptors changes in depression and schizophrenia, present findings point to the endocannabinoid system as a pivotal neuromodulatory pathway relevant in the pathophysiology of mental disorders.This study was supported by the Spanish Ministry of Economy and Competitiveness (SAF2015-67457-R, MINECO/FEDER), the Plan Estatal de I+D+i 2013-2016, the Instituto de Salud Carlos III-Subdirección General de Evaluación y Fomento de la Investigación, Spanish Ministry of Economy, FEDER (PI13/01529) and the Basque Government (IT616/13). I I-L is a recipient of a Predoctoral Fellowship from the Basque Government. E F-Z is a recipient of a Predoctoral Fellowship from the University of Cantabria. CM is a recipient of a Postdoctoral Marie Skłodowska-Curie Individual Fellowship (H2020-MSCA-IF-2016, ID 747487)

Structural connectivity and subcellular changes after antidepressant doses of ketamine and Ro 25-6981 in the rat: an MRI and immuno-labeling study

Ketamine has rapid and robust antidepressant effects. However, unwanted psychotomimetic effects limit its widespread use. Hence, several studies examined whether GluN2B-subunit selective NMDA antagonists would exhibit a better therapeutic profile. Although preclinical work has revealed some of the mechanisms of action of ketamine at cellular and molecular levels, the impact on brain circuitry is poorly understood. Several neuroimaging studies have examined the functional changes in the brain induced by acute administration of ketamine and Ro 25-6981 (a GluN2B-subunit selective antagonist), but the changes in the microstructure of gray and white matter have received less attention. Here, the effects of ketamine and Ro 25-6981 on gray and white matter integrity in male Sprague-Dawley rats were determined using diffusion-weighted magnetic resonance imaging (DWI). In addition, DWI-based structural brain networks were estimated and connectivity metrics were computed at the regional level. Immunohistochemical analyses were also performed to determine whether changes in myelin basic protein (MBP) and neurofilament heavy-chain protein (NF200) may underlie connectivity changes. In general, ketamine and Ro 25-6981 showed some opposite structural alterations, but both compounds coincided only in increasing the fractional anisotropy in infralimbic prefrontal cortex and dorsal raphe nucleus. These changes were associated with increments of NF200 in deep layers of the infralimbic cortex (together with increased MBP) and the dorsal raphe nucleus. Our results suggest that the synthesis of NF200 and MBP may contribute to the formation of new dendritic spines and myelination, respectively. We also suggest that the increase of fractional anisotropy of the infralimbic and dorsal raphe nucleus areas could represent a biomarker of a rapid antidepressant response.Funding: Open Access funding provided thanks to the CRUE-CSIC agreement with Springer Nature. This work was supported by grants from the Instituto de Salud Carlos III, Subdirección General de Evaluación y Fomento de la Investigación (PI13/00038, PI16/00217 and PI19/00170 to A.A.) that were co-funded by the European Regional Development Fund (‘A way to build Europe’); Generalitat Valenciana, Conselleria d’ Educació, Investigació, Cultura i Esport (GV/2018/049 to A.B-S.); Ministerio de Ciencia, Innovación y Universidades (RTI2018-097534-B-I00 to F.P.-C.). Funding from the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III is also acknowledged

Cannabidiol antidepressant-like effect in the lipopolysaccharide model in mice: Modulation of inflammatory pathways

Major Depression is a severe psychiatric condition with a still poorly understood etiology. In the last years, evidence supporting the neuroinflammatory hypothesis of depression has increased. In the current clinical scenario, in which the available treatments for depression is far from optimal, there is an urgent need to develop fast-acting drugs with fewer side effects. In this regard, recent pieces of evidence suggest that cannabidiol (CBD), the major non-psychotropic component of Cannabis sativa with anti-inflammatory properties, appears as a drug with antidepressant properties. In this work, CBD 30 mg/kg was administered systemically to mice 30 min before lipopolysaccharide (LPS; 0.83 mg/kg) administration as a neuroinflammatory model, and behavioral tests for depressive-, anhedonic- and anxious-like behavior were performed. NF-?B, I?B? and PPAR? levels were analyzed by western blot in nuclear and cytosolic fractions of cortical samples. IL-6 and TNF? levels were determined in plasma and prefrontal cortex using ELISA and qPCR techniques, respectively. The precursor tryptophan (TRP), and its metabolites kynurenine (KYN) and serotonin (5-HT) were measured in hippocampus and cortex by HPLC. The ratios KYN/TRP and KYN/5-HT were used to estimate indoleamine 2,3-dioxygenase (IDO) activity and the balance of both metabolic pathways, respectively. CBD reduced the immobility time in the tail suspension test and increased sucrose preference in the LPS model, without affecting locomotion and central activity in the open-field test. CBD diminished cortical NF-?B activation, IL-6 levels in plasma and brain, and the increased KYN/TRP and KYN/5-HT ratios in hippocampus and cortex in the LPS model. Our results demonstrate that CBD produced antidepressant-like effects in the LPS neuroinflammatory model, associated to a reduction in the kynurenine pathway activation, IL-6 levels and NF-?B activation. As CBD stands out as a promising antidepressant drug, more research is needed to completely understand its mechanisms of action in depression linked to inflammation.FUNDING AND ACKNOWLEDGMENTS: This research was supported by the Ministerio de Economía y Competitividad (SAF2015-67457-R MINECO/FEDER), the Ministerio de Ciencia, Innovación y Universidades (RTI2018-097534-B-I00), the Instituto de Salud Carlos III (PI19/00170), and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM). E F-Z was supported by a predoctoral fellowship from the Universidad de Cantabria (Spain). We acknowledge the technical assistance of Annamaria Architravo and Deborah Vasturzo, and Dr Rebeca Vidal for her scientific advice

mTOR knockdown in the infralimbic cortex evokes a depressive-like state in mouse

Fast and sustained antidepressant effects of ketamine identified the mammalian target of rapamycin (mTOR) signaling pathway as the main modulator of its antidepressive effects. Thus, mTOR signaling has become integral for the preclinical evaluation of novel compounds to treat depression. However, causality between mTOR and depression has yet to be determined. To address this, we knocked down mTOR expression in mice using an acute intracerebral infusion of small interfering RNAs (siRNA) in the infralimbic (IL) or prelimbic (PrL) cortices of the medial prefrontal cortex (mPFC), and evaluated depressive- and anxious-like behaviors. mTOR knockdown in IL, but not PrL, cortex produced a robust depressive-like phenotype in mice, as assessed in the forced swimming test (FST) and the tail suspension test (TST). This phenotype was associated with significant reductions of mTOR mRNA and protein levels 48 h post-infusion. In parallel, decreased brain-derived neurotrophic factor (BDNF) expression was found bilaterally in both IL and PrL cortices along with a dysregulation of serotonin (5-HT) and glutamate (Glu) release in the dorsal raphe nucleus (DRN). Overall, our results demonstrate causality between mTOR expression in the IL cortex and depressive-like behaviors, but not in anxiety.Funding: This research was funded by grants of the Ministerio de Economía y Competitividad (SAF2011-25020 and SAF2015-67457-R MINECO); Ministerio de Ciencia, Innovación y Universidades (RTI2018-097534-B-I00); Ministerio de Ciencia e Innovación (PID2019-105136RB-100); and the European Regional Development Fund (ERDF), UE; Instituto de Salud Carlos III (PI19/00170), and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM)

The endocannabinoid system in mental disorders: Evidence from human brain studies

Mental disorders have a high prevalence compared with many other health conditions and are the leading cause of disability worldwide. Several studies performed in the last years support the involvement of the endocannabinoid system in the etiopathogenesis of different mental disorders. The present review will summarize the latest information on the role of the endocannabinoid system in psychiatric disorders, specifically depression, anxiety, and schizophrenia. We will focus on the findings from human brain studies regarding alterations in endocannabinoid levels, cannabinoid receptors and endocannabinoid metabolizing enzymes in patients suffering mental disorders. Studies carried out in humans have consistently demonstrated that the endocannabinoid system is fundamental for emotional homeostasis and cognitive function. Thus, deregulation of the different elements that are part of the endocannabinoid system may contribute to the pathophysiology of several mental disorders. However, the results reported are controversial. In this sense, different alterations in gene and/or protein expression of CB1 receptors have been shown depending on the technical approach used or the brain region studied. Despite the current discrepancies regarding cannabinoid receptors changes in depression and schizophrenia, present findings point to the endocannabinoid system as a pivotal neuromodulatory pathway relevant in the pathophysiology of mental disorders.This study was supported by the Spanish Ministry of Economy and Competitiveness (SAF2015-67457-R, MINECO/FEDER), the Plan Estatal de I+D+i 2013-2016, the Instituto de Salud Carlos III-Subdirección General de Evaluación y Fomento de la Investigación, Spanish Ministry of Economy, FEDER (PI13/01529) and the Basque Government (IT616/13). I I-L is a recipient of a Predoctoral Fellowship from the Basque Government. E F-Z is a recipient of a Predoctoral Fellowship from the University of Cantabria. CM is a recipient of a Postdoctoral Marie Skłodowska-Curie Individual Fellowship (H2020-MSCA-IF-2016, ID 747487)

Cannabidiol como antidepresivo rápido: ¿dónde y cómo actúa?

Resumen del trabajo presentado en el VI Laboratorio de ideas para jóvenes investigadores CIBERSAM, celebrado en San Fernando (Cádiz) del 31 de mayo al 01 de junio de 2018.El grupo de investigación del CIBERSAM que lidera el doctor Ángel Pazos en la Universidad de Cantabria, presenta unos resultados en los cuales muestra como el cannabidiol, componente no psicotomimético de la planta Cannabis sativa, produce un efecto de tipo antidepresivo de acción rápida en modelos animales. Este efecto se produce en parte actuando sobre la corteza frontal, área cerebral muy relevante en la depresión mayor. En esta región, el cannabidiol produce un incremento de marcadores de plasticidad sináptica. Esta mayor plasticidad sináptica, junto con una elevación en los niveles de algunos neurotransmisores como la serotonina y el glutamato, nos dan pistas sobre cuál es el mecanismo de acción de este compuesto que presenta potencialidad como fármaco antidepresivo

Antidepressant-like effect of cannabidiol in an animal model induced by lipopolysaccharide administration

Trabajo presentado en la 20ª Reunión Anual de la Sociedad Española de Investigación sobre Cannabinoides, celebrado en Barcelona del 21 al 23 de noviembre de 2019

Implicación de la metaloproteinasa-9 en la depresión y en el efecto antidepresivo

Trabajo presentado en el 8ª Laboratorio de Ideas. Impacto de la pandemia COVID-19, celebrado en modalidad virtual del 25 al 27 de mayo de 2021

Relevance of metalloproteinase-9 in depression: a study in transgenic animal models

Trabajo presentado en el 19th National Meeting of the Spanish Society of Neuroscience, celebrado en Lleida (España) del 03 al 05 de noviembre de 2021