El sistema endógeno de serotonina no participa en la abstinencia opiácea, aunque su inhibición por estimulación del receptor 5-HT1A incrementa la eficacia antidisfórica de la clonidina en ratas

El objetivo del estudio fue discernir el papel del sistema endógeno de serotonina en la abstinencia opiácea, tanto en su vertiente somática como emocional, así como su posible interacción con los efectos de la clonidina. Con tal fin, se empleó un protocolo basado en la lesión casi total de los principales centros serotoninérgicos del mesencéfalo, y también se bloqueó la actividad serotoninérgica mediante 8-hidroxi-dipropilaminotetralina (8-OHDPAT), agonista 5-HT1A. Los resultados indicaron que el sistema serotoninérgico no se encuentra involucrado en el síndrome somático de abstinencia y que la clonidina mantuvo su eficacia en el síndrome somático tras la depleción de serotonina. Los resultados también mostraron que el sistema de serotonina tampoco se encuentra involucrado en el síndrome emocional en la rata, evaluado mediante la aversión condicionada tras naloxona. Sin embargo, la eficacia antiaversiva de la clonidina se vio incrementada casi 10 veces tras la depleción casi completa de serotonina cerebral. Además, la inhibición farmacológica del sistema serotonérgico con 8-OHDPAT indujo efectos similares a la depleción serotoninérgica respecto a la eficacia antiaversiva de la clonidina. Por tanto, el uso combinado de compuestos agonistas del receptor 5- HT1A y clonidina podría ser eficaz para el tratamiento del síndrome de abstinencia opiáceo.The aim of the study was to discern the role of the endogenous serotonin system in opiate withdrawal, in both somatic and emotional aspects, along with its possible interaction with clonidine effects. To this end, a protocol based on near complete lesion of main serotonergic brain centers was carried out, and serotonin neurotransmission was also blocked by 8-hydroxy-dipropylaminotetraline (8-OHDPAT), 5- HT1A receptor agonist. The findings revealed that the serotonin system is not involved in somatic abstinence, and clonidine efficacy was not affected after serotonin depletion. The findings also revealed that the serotonin system is not involved in the emotional aspect of opiate abstinence, as measured through conditioned place aversion in rats. However, antiaversive clonidine efficacy was enhanced near 10 times following serotonin depletion. Moreover, 8-OHDPAT treatment induced similar effects on antiaversive clonidine efficacy to those found after serotonin depletion. Hence, the combined use of 5-HT1A receptor agonists and clonidine could be of value for treatment of opiate withdrawal syndrome

Prevalence and pharmacological factors associated with impulse-control disorder symptoms in patients with parkinson disease

BACKGROUND: Impulse-control disorders (ICDs) occur in patients with Parkinson disease (PD), especially in younger patients on dopamine therapies. OBJECTIVE: To assess the prevalence of ICD symptoms and its pharmacological correlations in a sample of French patients with PD and without PD (poststroke). METHODS: Outpatients with PD and without PD (poststroke) were screened for compulsive behaviors related to hypersexuality, compulsive shopping, pathological gambling, or compulsive eating by means of the Questionnaire for Impulse-Control Disorders-short version. Full medical history and Unified Parkinson's Disease Rating Scale scores were also recorded. Dose of dopamine agonists were converted to defined daily doses (DDDs), according to the World Health Organization Anatomical Therapeutic Chemical classification system classification system. RESULTS: Two hundred three patients with PD and 52 patients without PD were recruited (mean ± SD age, 67 ± 1 vs 69 ± 2, P= 0.4; males: 62% vs 55% P= 0.2). Symptoms of ICDs were reported by 0% of poststroke patients and 25% of the patients with PD (P < 0.001). Hypersexuality was reported by 10% of the patients with PD, compulsive shopping by 6%, pathological gambling by 3%, and compulsive eating by 14%. A logistic regression analysis found that age younger than 68 years (odds ratio [OR], 3.3; 95% confidence interval, 1.6-6.6) and exposure to dopamine agonists (OR, 20.3; 95% confidence interval, 2.7-65.0) or monoaminooxidase-B inhibitor (OR, 3.7; 95% confidence interval, 1.1-12.6) were significant factors associated with increased ICD frequency. Patients with ICD symptoms were exposed to higher dopamine doses than those without them (1.6 ± 0.1 vs 1.0 ± 0.1 daily-defined doses; P < 0.001). A dose-response pharmacodynamic model disclosed a significant nonlinear dose-response relationship between dopamine agonists and frequency of ICD symptoms (P < 0.01). CONCLUSIONS: Impulse-control disorder symptoms were more frequent in the patients with PD than in the poststroke patients with PD. Impulse-control disorder symptoms were related to younger age and exposure to monoaminooxidase-B inhibitors, and showed a nonlinear dose-response relationship with dopamine agonists.Fil: Perez Lloret, Santiago. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Inserm; FranciaFil: Rey, María Verónica. Inserm; FranciaFil: Fabre, Nelly. No especifíca;Fil: Ory, Fabienne. No especifíca;Fil: Spampinato, Umberto. No especifíca;Fil: Brefel Courbon, Christine. No especifíca;Fil: Montastruc, Jean Louis. No especifíca;Fil: Rascol, Olivier. Inserm; Franci

Short and long term outcome of bilateral pallidal stimulation in chorea-acanthocytosis

BACKGROUND: Chorea-acanthocytosis (ChAc) is a neuroacanthocytosis syndrome presenting with severe movement disorders poorly responsive to drug therapy. Case reports suggest that bilateral deep brain stimulation (DBS) of the ventro-postero-lateral internal globus pallidus (GPi) may benefit these patients. To explore this issue, the present multicentre (n=12) retrospective study collected the short and long term outcome of 15 patients who underwent DBS. METHODS: Data were collected in a standardized way 2-6 months preoperatively, 1-5 months (early) and 6 months or more (late) after surgery at the last follow-up visit (mean follow-up: 29.5 months). RESULTS: Motor severity, assessed by the Unified Huntington's Disease Rating Scale-Motor Score, UHDRS-MS), was significantly reduced at both early and late post-surgery time points (mean improvement 54.3% and 44.1%, respectively). Functional capacity (UHDRS-Functional Capacity Score) was also significantly improved at both post-surgery time points (mean 75.5% and 73.3%, respectively), whereas incapacity (UHDRS-Independence Score) improvement reached significance at early post-surgery only (mean 37.3%). Long term significant improvement of motor symptom severity (≥ 20 % from baseline) was observed in 61.5 % of the patients. Chorea and dystonia improved, whereas effects on dysarthria and swallowing were variable. Parkinsonism did not improve. Linear regression analysis showed that preoperative motor severity predicted motor improvement at both post-surgery time points. The most serious adverse event was device infection and cerebral abscess, and one patient died suddenly of unclear cause, 4 years after surgery. CONCLUSION: This study shows that bilateral DBS of the GPi effectively reduces the severity of drug-resistant hyperkinetic movement disorders such as present in ChAc

Outcomes from elective colorectal cancer surgery during the SARS-CoV-2 pandemic

This study aimed to describe the change in surgical practice and the impact of SARS-CoV-2 on mortality after surgical resection of colorectal cancer during the initial phases of the SARS-CoV-2 pandemic

Identification of genetic variants associated with Huntington's disease progression: a genome-wide association study

Background Huntington's disease is caused by a CAG repeat expansion in the huntingtin gene, HTT. Age at onset has been used as a quantitative phenotype in genetic analysis looking for Huntington's disease modifiers, but is hard to define and not always available. Therefore, we aimed to generate a novel measure of disease progression and to identify genetic markers associated with this progression measure. Methods We generated a progression score on the basis of principal component analysis of prospectively acquired longitudinal changes in motor, cognitive, and imaging measures in the 218 indivduals in the TRACK-HD cohort of Huntington's disease gene mutation carriers (data collected 2008–11). We generated a parallel progression score using data from 1773 previously genotyped participants from the European Huntington's Disease Network REGISTRY study of Huntington's disease mutation carriers (data collected 2003–13). We did a genome-wide association analyses in terms of progression for 216 TRACK-HD participants and 1773 REGISTRY participants, then a meta-analysis of these results was undertaken. Findings Longitudinal motor, cognitive, and imaging scores were correlated with each other in TRACK-HD participants, justifying use of a single, cross-domain measure of disease progression in both studies. The TRACK-HD and REGISTRY progression measures were correlated with each other (r=0·674), and with age at onset (TRACK-HD, r=0·315; REGISTRY, r=0·234). The meta-analysis of progression in TRACK-HD and REGISTRY gave a genome-wide significant signal (p=1·12 × 10−10) on chromosome 5 spanning three genes: MSH3, DHFR, and MTRNR2L2. The genes in this locus were associated with progression in TRACK-HD (MSH3 p=2·94 × 10−8 DHFR p=8·37 × 10−7 MTRNR2L2 p=2·15 × 10−9) and to a lesser extent in REGISTRY (MSH3 p=9·36 × 10−4 DHFR p=8·45 × 10−4 MTRNR2L2 p=1·20 × 10−3). The lead single nucleotide polymorphism (SNP) in TRACK-HD (rs557874766) was genome-wide significant in the meta-analysis (p=1·58 × 10−8), and encodes an aminoacid change (Pro67Ala) in MSH3. In TRACK-HD, each copy of the minor allele at this SNP was associated with a 0·4 units per year (95% CI 0·16–0·66) reduction in the rate of change of the Unified Huntington's Disease Rating Scale (UHDRS) Total Motor Score, and a reduction of 0·12 units per year (95% CI 0·06–0·18) in the rate of change of UHDRS Total Functional Capacity score. These associations remained significant after adjusting for age of onset. Interpretation The multidomain progression measure in TRACK-HD was associated with a functional variant that was genome-wide significant in our meta-analysis. The association in only 216 participants implies that the progression measure is a sensitive reflection of disease burden, that the effect size at this locus is large, or both. Knockout of Msh3 reduces somatic expansion in Huntington's disease mouse models, suggesting this mechanism as an area for future therapeutic investigation

Etude in vivo du contrôle inhibiteur tonique et phasique exercé par les récepteurs sérotoninergiques de type 5-HT2c sur l'activité des voies dopaminergiques nigrostriée et mésoaccumbale chez le rat

Ce travail, portant sur le récepteur sérotoninergique 2C (5-HT2c), a eu pour but d'approfondir la nature du contrôle tonique et phasique inhibiteur exercé par ce récepteur sur la libération de DA mesurée par microdyalyse intracérébrale dans le noyau accumbens (NAc) et le striatum chez le rat anestrhésié à l'halothane. A l'aide d'outils pharmacologiques appropriés (agoniste, agoniste inverse et antagoniste des récepteurs 5-HT2c), nous avons évalué 1) la participation de l'activité constitutive des récepteurs 5-HT2c in vivo 2) l'importance du niveau d'activité des neurones DA ascendants, et 3) l'existence de contrôles région-dépendants sur la voie DA mésolimbique. Dans les deux régions d'intérêt, l'effet excitateur de l'agoniste inverse 5 HT2c le SB 206553 sur la libération de DA est bloqué par l'antagoniste 5-HT2c le SB 242084 mais pas modifié par une réduction du tonus 5-HT central. Le SB 206553, sans effet sur la libération de DA induite par la clozapine, potentialise celle induite par l'halopéridol, alors que le SB 242084, sans effet sur l'halopéridol, bloque de façon dose-dépendante l'effet de la clozapine. Ces deux ligands 5-HT2c potentialisent la libération de DA évoquée par la cocaine alors que l'agoniste 5-HT2c le Ro 60-0175 ne la modifie pas, mais réduit celle induite par l'halopéridol. Enfin, l'application locale d'antagonistes 5-HT2c dans l'aire tegmentale ventrale (ATV) et le NAc bloque la diminution de la libération accumbale de DA induite par l'administration systémique du Ro 60-0175. Nos données montrent que 1) l'activité constitutive des récepteurs 5-HT2c participe au contrôle tonique inhibiteur exercé sur les neurones DA mésoaccumbaux et nigrostriés in vivo en conditions basales et activées ; 2) les récepteurs 5-HT2c modulent l'exocytose de DA de façon dépendante du degré d'activation des neurones DA ; 3) le contrôle inhibiteur de la voie DA mésolimbique implique, au moins en partie, les récepteurs 5-HT2c de l'ATV et du NAc. Ce travail ouvre des perspectives tant physiologiques que thérapeutiques quant au rôle des récepteurs 5-HT2c au sein des ganglions de la base.This study, concerning the serotonergic 2C (5-HT2c) receptor, was aimed to go deeper into the mechanisms of the tonic and phasic inhibitory control exerted by this receptor on DA release measured by intracerebral microdialysis in the halothane-anesthetized rat nucleus accumbens (NAc) and striatum. By using appropriate pharmacological tools (agonist, inverse agonist, antagonist of 5-HT2c receptors), we explored 1) the participation of the constitutive activity of 5-HT2c receptors in vivo 2) the relevance of the degree of activity of mesolimbic and nigrostriatal DA neurons, and 3) the existence of region-dependant controls of the mesolimbic DA pathway. In both brain regions, the excitatory effect of the 5-HT2c inverse agonist SB 206553 on DA release is blocked by the 5-HT2c antahonist SB 242084 but not modified by the reduction of the central 5-HT tone. SB 206553, without effect on clozapine-stimulated DA release, potentiates haloperidol-induced DA release, whereas SB 242084, without effect on haloperidol, dose-dependently blocks the DA effect of clozapine. Both 5-HT2c ligands potentiate cocaine-stimulated DA release while the 5-HT2c agonist Ro 60-0175 does not affect the DA effect of cocaine but reduces that of haloperidol. Finally, the local application of 5-HT2c antagonists in the ventral tegmental area (VTA) and the NAc blocks the inhibition of accumbal DA release induced by the systemic administration of Ro 60-0175. These findings show that 1) the constititive activity of 5-HT2c receptors participates in the tonic inhibitory control of mesoaccumbal and nigrostriatal DA neurons in vivo ; 2) 5-HT2c receptors modulate DA exocytosis in a manner that is dependent of the degree of activation of ascending DA neurons ; 3) the 5-HT2c-dependent inhibitory control of the mesolimbic DA pathway is mediated, at least in part, by 5-HT2c receptors located in the VTA and the NAc. This work brings up new physiological and therapeutical perspectivesconcerning the role of 5-HT2c receptors in the basal ganglia.BORDEAUX2-BU Santé (330632101) / SudocSudocFranceF

Serotonin 2B Receptor Interactions with Dopamine Network: Implications for Therapeutics in Schizophrenia

The serotonin 2B receptor (5-HT2BR) is the most recent addition to the 5-HT2R family. During the last decade, a growing number of studies have shown that the central 5-HT2BR participates in the control of serotonin (5-HT) and dopamine (DA) neuron activity and have underlined its potential for new therapeutic strategies for several neuropsychiatric disorders such as drug addiction, depression and schizophrenia. After reviewing the major advances in the identification and characterization of this receptor within the central nervous system, this chapter focuses on its functional role in the control of ascending DA pathway activity and on the mechanisms underlying this interaction, by covering electrophysiological, neurochemical and behavioral data mainly from in vivo studies in rats. Afterwards, the therapeutic relevance of 5-HT2BR antagonists for treating DA-dependent neuropsychiatric disorders is discussed by focusing on schizophrenia

Pharmacological and genetic interventions in serotonin (5-HT)(2C) receptors to alter drug abuse and dependence processes

The present review provides an overview on serotonin (5-hydroxytryptamine; 5-HT)(2C) receptors and their relationship to drug dependence. We have focused our discussion on the impact of 5-HT2C receptors on the effects of different classes of addictive drugs, illustrated by reference to data using pharmacological and genetic tools. The neurochemical mechanism of the interaction between 5-T-2C receptors, with focus on the mesocorticolimbic dopaminergic system, and drugs of abuse (using cocaine as an example) is discussed. Finally, we integrate recent nonclinical and clinical research and information with marketed products possessing 5-HT2C receptor binding affinities. Accordingly, available nonclinical data and some clinical observations targeting 5-T-2C receptors may offer innovative translational strategies for combating drug dependence. This article is part of a Special Issue entitled: Brain Integration. (C) 2012 Elsevier B.V. All rights reserved