Role of Serotonin and Noradrenaline in the Rapid Antidepressant Action of Ketamine

Depression is a chronic and debilitating illness that interferes severely with many human behaviors, and is the leading cause of disability in the world. There is data suggesting that deficits in serotonin neurotransmission can contribute to the development of depression. Indeed, >90% of prescribed antidepressant drugs act by increasing serotonergic transmission at the synapse. However, this increase is offset by a negative feedback operating at the level of the cell body of the serotonin neurons in the raphe nuclei. In the present work, we demonstrate: first, the intracortical infusion of ketamine induced an antidepressant-like effect in the forced swim test, comparable to that produced by systemic ketamine; second, systemic and intracortical ketamine increased serotonin and noradrenaline efflux in the prefrontal cortex, but not in the dorsal raphe nucleus; third, systemic and intracortical administration of ketamine increased the efflux of glutamate in the prefrontal cortex and dorsal raphe nucleus; fourth, systemic ketamine did not alter the functionality of 5-HT1A receptors in the dorsal raphe nucleus. Taken together, these findings suggest that the antidepressant-like effects of ketamine are caused by the stimulation of the prefrontal projection to the dorsal raphe nucleus and locus coeruleus caused by an elevated glutamate in the medial prefrontal cortex, which would stimulate release of serotonin and noradrenaline in the same area. The impact of both monoamines in the antidepressant response to ketamine seems to have different time frames.Funding: This work was supported by the Instituto de Salud Carlos III, Subdirección General del Evaluación y Fomento de la Investigación (FIS Grants PI13-00038 and PI16-00217) that were cofunded by the European Regional Development Fund (“A way to build Europe”). Funding from the Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM) is also acknowledged. We also acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI)

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)

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)