Selective Serotonin Reuptake Inhibitor Antidepressant Treatment Discontinuation Syndrome: A Review of the Clinical Evidence and the Possible Mechanisms Involved

Besides demonstrated efficacy, selective serotonin reuptake inhibitors (SSRIs) hold other advantages over earlier antidepressants such as greater tolerability and a wider range of clinical applications. However, there is a growing body of clinical evidence which suggests that SSRIs could, in some cases, be associated with a withdrawal reaction upon cessation of regular use. In addition to sensory and gastrointestinal-related symptoms, the somatic symptoms of the SSRI discontinuation syndrome include dizziness, lethargy, and sleep disturbances. Psychological symptoms have also been documented, usually developing within 1–7 days following SSRI discontinuation. The characteristics of the discontinuation syndrome have been linked to the half-life of a given SSRI, with a greater number of reports emerging from paroxetine compared to other SSRIs. However, many aspects of the neurobiology of the SSRI discontinuation syndrome (or SSRI withdrawal syndrome) remain unresolved. Following a comprehensive overview of the clinical evidence, we will discuss the underlying pathophysiology of the SSRI discontinuation syndrome and comment on the use of animal models to better understand this condition

Short-Term Environmental Stimulation Spatiotemporally Modulates Specific Serotonin Receptor Gene Expression and Behavioral Pharmacology in a Sexually Dimorphic Manner in Huntington’s Disease Transgenic Mice

Huntington’s disease (HD) is a neurodegenerative disorder caused by a tandem repeat mutation encoding an expanded polyglutamine tract in the huntingtin protein, which leads to cognitive, psychiatric and motor dysfunction. Exposure to environmental enrichment (EE), which enhances levels of cognitive stimulation and physical activity, has therapeutic effects on cognitive, affective and motor function of transgenic HD mice. The present study investigated gene expression changes and behavioral pharmacology in male and female R6/1 transgenic HD mice at an early time-point in HD progression associated with onset of cognitive and affective abnormalities, following EE and exercise (wheel running) interventions. We have demonstrated changes in expression levels of the serotonin (5-HT) receptor Htr1a, Htr1b, Htr2a and Htr2c genes (encoding the 5-HT1A, 5-HT1B, 5-HT2A and 5-HT2C receptors, respectively) in HD brains at 8 weeks of age, using quantitative real-time PCR. In contrast, expression of the serotonin transporter (SerT, also known as 5-HTT or Slc6a4) was not altered in these brains. Furthermore, we identified region-specific, sex-specific and environmentally regulated (comparing EE, exercise and standard housing conditions) impacts on gene expression of particular 5-HT receptors, as well as SerT. For example, SerT gene expression was upregulated by exercise (wheel running from 6 to 8 weeks of age) in the hippocampus. Interestingly, when EE was introduced from 6 to 8 weeks of age, Htr2a gene expression was upregulated in the cortex, striatum and hippocampus of male mice. EE also rescued the functional activity of 5-HT2 receptors as observed in the head-twitch test, reflecting sexually dimorphic effects of environmental stimulation. These findings demonstrate that disruption of the serotonergic system occurs early in HD pathogenesis and, together with previous findings, show that the timing and duration of environmental interventions are critical in terms of their ability to modify gene expression. This study is the first to show that EE is able to selectively enhance both gene expression of a neurotransmitter receptor and the functional consequences on behavioral pharmacology, and links this molecular modulation to the therapeutic effects of environmental stimulation in this neurodegenerative disease

Sexually Dimorphic Serotonergic Dysfunction in a Mouse Model of Huntington's Disease and Depression

Depression is the most common psychiatric disorder in Huntington's disease (HD) patients. In the general population, women are more prone to develop depression and such susceptibility might be related to serotonergic dysregulation. There is yet to be a study of sexual dimorphism in the development and presentation of depression in HD patients. We investigated whether 8-week-old male and female R6/1 transgenic HD mice display depressive-like endophenotypes associated with serotonergic impairments. We also studied the behavioral effects of acute treatment with sertraline. We found that only female HD mice exhibited a decreased preference for saccharin as well as impaired emotionality-related behaviors when assessed on the novelty-suppressed feeding test (NSFT) and the forced-swimming test (FST). The exaggerated immobility time displayed by female HD in the FST was reduced by acute administration of sertraline. We also report an increased response to the 5-HT1A receptor agonist 8-OH-DPAT in inducing hypothermia and a decreased 5-HT2A receptor function in HD animals. While tissue levels of serotonin were reduced in both male and female HD mice, we found that serotonin concentration and hydroxylase-2 (TPH2) mRNA levels were higher in the hippocampus of males compared to female animals. Finally, the antidepressant-like effects of sertraline in the FST were blunted in male HD animals. This study reveals sex-specific depressive-related behaviors during an early stage of HD prior to any cognitive and motor deficits. Our data suggest a crucial role for disrupted serotonin signaling in mediating the sexually dimorphic depression-like phenotype in HD mice

Mécanismes sérotoninergiques sous-tendant les effets de la MDMA ("ecstasy") chez la souris

Nous avons évalué les effets renforçants de la MDMA via une procédure d auto-administration couplée à la technique de microdialyse. Les modifications qui suivent un traitement avec la MDMA ont également été étudiées. Nous montrons que les souris 5-HTT-/- ne s auto-administrent pas la MDMA contrairement à leurs congénères sauvages. Les données obtenues par microdialyse montrent que les effets renforçants de la MDMA sont liés à l induction de la libération de sérotonine par cette drogue. Nous démontrons l existence d une hypersensibilité de l autorécepteur 5-HT1A chez des souris sauvages 28 jours après MDMA, ainsi qu une baisse des taux tissulaires de sérotonine. Ce traitement à la MDMA provoque une baisse de la prolifération cellulaire. Utilisant le test de la nage forcée, nous mettons en évidence un allongement du temps d immobilité chez les souris traitées par la MDMA. Ces modifications qui révèlent une action dépressiogène de la MDMA, ne sont pas observées chez les souris 5-HTT-/-.PARIS-BIUP (751062107) / SudocSudocFranceF

Effets de la MDMA ( ECSTASY ) sur le système sérotoninergique de la souris (comparaison avec la fluoxétine )

Bien que la fluoxétine (ISRS) et l'ecstasy ((+-3,4)-méthylènedioxyméthamphétamine ou MDMA) présentent une certaine homologie structurale, ces deux molécules exercent des effets à long terme opposés. Alors qu'un traitement chronique avec la fluoxétine induit des effets antidépresseurs, au contraire, la MDMA a des effets dépressiogènes. De nombreuses données suggèrent qu'une désensibilisation fonctionnelle des autorécepteurs 5-HT1A dans le noyau du raphé dorsal (NRD) serait en partie responsable des effets antidépresseurs de la fluoxétine. Aussi, par une approche multidisciplinaire nous nous sommes attachés à étudier les effets aigus in vitro de la MDMA au nivau du NRD chez la souris et à comparer les effets à long terme de la MDMA et de la fluoxétine sur la fonctionnalité des autorecepteurs 5-HT1A. Nos résultats suggèrent que le 5-HTT est la cible principale de la MDMA dans son action sur la libération de la 5-HT. Par ailleurs, nos données confirment la désensibilisation des autorécepteurs 5-HT1A après un traitement chronique de la fluoxétine. Il apparaît, au contraire, que la MDMA, à long terme, induit une hypersensibilité de ces mêmes récepteurs.CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocSudocFranceF

Préparation ét évaluation biologique de nanosphères et de nanaocapsules à base de copolymères polyester/polyéthylène-glycol chargées en antioestrogène

L 'hormonothérapie des cancers oestrogéno-dépendants chez les femmes ménopausées restait majoritairement basée sur l'utilisation du Tamoxifène. Récemment, un anti-oestrogène (RU 58668) " pur" a été identifié comme capable de lever la résistance au Tamoxifène. Afin de limiter ses effets secondaires et obtenir une accumulation tumorale, nous avons formulé plusieurs préparations galéniques à base de copolymères biodégradables. Après encapsulation du RU 58668 et du Tamoxifène au sein de nanosphères ou nanocapsules a contenu huileux, les tailles obtenues mesurées par microscopie électroniques après cryofracture, restent toujours compatibles avec une extravasation qui se vérifie in vivo. Le couplage de chaînes de PEG à la surface des formulations diminue l'adsorption des opsonines, un prérequis nécessaire à la prolongation du temps de circulation plasmatique. ln vitro, des expériences utilisant des lignées cellulaires de cancer du sein humain ont montré que l' encapsulation des anti-oestrogènes retardait et prolongeait leurs activités anti-prolifératives. ln vivo, la pegylation des formulations prolonge l'activité anti-utérotrophique des anti-oestrogènes et induit une régression tumorale sur des xénogreffes à cellules de cancers du sein humain oestrogéno-sensibles (MCF-7) ou insensibles (MCF-7/Ras).Ces résultats suggèrent que l'encapsulation d'un anti-oestrogène au sein de nanoparticules constitue un système de " drug delivery " prometteurStealth nanoparticles made of polyester-PEG copolymer, nanospheres or nanocapsules with an oily core were loaded with the mixed antiestrogen 40H- Tamoxifen or the "pure" antiestrogen RU 58668. The nanoparticle size (120 to 250 nm) is compatible with a capacity to cross through the discontinous tumoral endothelium. Pegylation of aIl nanoparticles allows them to resist to the opsonization process and macrophage capture, leading to an increase of blood circulation time. Nanoparticles are characterized in vitro by a prolonged and delayed inhibition of estrogen-induced reporter gene expression in MELN cells. ln vivo, a prolonged antiuterotrophic activity of encapsulated antiestrogen occurs. ln human breast cancer MCF- 7 cells xenografts as weIl as the estradiol insensitive MCF -7/Ras cells tumors, antiestrogen loaded nanoparticles inhibit tumor growth progression. Altogether these data suggest that incorpration of an antiestrogen into long circulating systems enhance its antitumoral activity and may constitute a promising delivery system for breast cancer treatmentCHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

New frontiers in the neuropsychopharmacology of mental illness

In recent years, mental illnesses have become recognized as a huge emotional and financial burden to the individual, their relatives and society at large. Stress-related and mood disorders as well as psychoactive substance abuse are among the disorders associated with most disability in high income countries. Suicide, which is often attributed to some underlying mental disorders, is a leading cause of death among teenagers and young adults. At the same time, mental disorders pose some of the toughest challenges in neuroscience research. There are many different categories of mental disorder as defined and classified by the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) and the International Statistical Classification of Diseases 10th Revision (ICD-10). Despite the ongoing improvements of those widely used manuals, the validity and reliability of their diagnoses remain a constant debate. However, it has now become accepted by the scientific community that mental disorders can arise from multiple sources. In that regard, both clinical and animal studies looking at gene-environment interactions have helped to better understand the mechanisms involved in the pathophysiology as well as the discovery of treatments for mental disorders. This Research Topic aims to cover recent progress in research studying how genetic make-up and environmental factors (such as stress paradigm or pharmacological treatment) can contribute to the development of mental disorders such as anxiety, depression, and schizophrenia. This Research Topic also seeks to highlight studies looking at affective-like disorders following the intake of drugs of abuse. We also welcome all research articles, review papers, brief communications, and commentary on topics related to the broad field of Neuropsychopharmacology

How the enriched get richer? Experience-dependent modulation of microRNAs and the therapeutic effects of environmental enrichment

Environmental enrichment and physical exercise have many well-established health benefits. Although these environmental manipulations are known to delay symptom onset and progression in a variety of neurological and psychiatric conditions, the mechanisms underlying these effects remain poorly understood. A notable candidate molecular mechanism is that of microRNA, a family of small noncoding RNAs that are important regulators of gene expression. Research investigating the many diverse roles of microRNAs has greatly expanded over the past decade, with several promising preclinical and clinical studies highlighting the role of dysregulated microRNA expression (in the brain, blood and other peripheral systems) in understanding the aetiology of disease. Altered microRNA levels have also been described following environmental interventions such as exercise and environmental enrichment in non-clinical populations and wild-type animals, as well as in some brain disorders and associated preclinical models. Recent studies exploring the effects of stimulating environments on microRNA levels in the brain have revealed an array of changes that are likely to have important downstream effects on gene expression, and thus may regulate a variety of cellular processes. Here we review literature that explores the differential expression of microRNAs in rodents following environmental enrichment and exercise, in both healthy control animals and preclinical models of relevance to neurological and psychiatric disorders.</p

Effect of enhanced voluntary physical exercise on brain levels of monoamines in Huntington disease mice

Using the R6/1 mouse model of Huntington disease (HD), we have recently shown that voluntary physical activity was able to correct the depressive-like behaviours exhibited by the HD animals at a pre-motor symptomatic stage of the disease. Using the high performance liquid chromatography system, we have now evaluated the effect of exercise on monoamine metabolism in HD mice. We found that serotonin and its metabolite as well as dopamine and noradrenaline were reduced across several brain regions in female R6/1 animals. Our data also suggest that some of these neurochemical deficits were modulated by physical activity, in a genotype-region dependent manner. These newly identified changes could account for some of the behavioural effects of exercise previously reported in HD mice

Life-long hippocampal neurogenesis: environmental, pharmacological and neurochemical modulations.

International audienceIt is now well documented that active neurogenesis does exist throughout the life span in the brain of various species including human. Two discrete brain regions contain progenitor cells that are capable of differentiating into neurons or glia, the subventricular zone and the dentate gyrus of the hippocampal formation. Recent studies have shown that neurogenesis can be modulated by a variety of factors, including stress and neurohormones, growth factors, neurotransmitters, drugs of abuse, and also strokes and traumatic brain injuries. In particular, the hippocampal neurogenesis may play a role in neuroadaptation associated with pathologies, such as cognitive disorders and depression. The increased neurogenesis at sites of injury may represent an attempt by the central nervous system to regenerate after damage. We herein review the most significant data on hippocampal neurogenesis in brain under various pathological conditions, with a special attention to mood disorders including depression and addiction