Inhibition of G Protein-Activated Inwardly Rectifying K+ Channels by Different Classes of Antidepressants

Various antidepressants are commonly used for the treatment of depression and several other neuropsychiatric disorders. In addition to their primary effects on serotonergic or noradrenergic neurotransmitter systems, antidepressants have been shown to interact with several receptors and ion channels. However, the molecular mechanisms that underlie the effects of antidepressants have not yet been sufficiently clarified. G protein-activated inwardly rectifying K+ (GIRK, Kir3) channels play an important role in regulating neuronal excitability and heart rate, and GIRK channel modulation has been suggested to have therapeutic potential for several neuropsychiatric disorders and cardiac arrhythmias. In the present study, we investigated the effects of various classes of antidepressants on GIRK channels using the Xenopus oocyte expression assay. In oocytes injected with mRNA for GIRK1/GIRK2 or GIRK1/GIRK4 subunits, extracellular application of sertraline, duloxetine, and amoxapine effectively reduced GIRK currents, whereas nefazodone, venlafaxine, mianserin, and mirtazapine weakly inhibited GIRK currents even at toxic levels. The inhibitory effects were concentration-dependent, with various degrees of potency and effectiveness. Furthermore, the effects of sertraline were voltage-independent and time-independent during each voltage pulse, whereas the effects of duloxetine were voltage-dependent with weaker inhibition with negative membrane potentials and time-dependent with a gradual decrease in each voltage pulse. However, Kir2.1 channels were insensitive to all of the drugs. Moreover, the GIRK currents induced by ethanol were inhibited by sertraline but not by intracellularly applied sertraline. The present results suggest that GIRK channel inhibition may reveal a novel characteristic of the commonly used antidepressants, particularly sertraline, and contributes to some of the therapeutic effects and adverse effects

Éducation et formation a Madagascar : : vers une politique nouvelle pour la croissance économique et la réduction de la pauvreté

International audienceThe prospects for educational development are excellent in Madagascar, in light of the increasingly favorable, policy environment for the sector. Public spending for education, relative to the gross domestic product declined in the 90s, coinciding with a five-fold rise in the country's interest payment for external debt. As the debt service burden began to ease in the late 90s, public spending on education began to recover, and can be expected to grow. A key challenge however, is to transform the sector's public spending into educational outcomes that would make significant contributions to poverty reduction. The report identifies challenges at all levels of formal education, where a medium term goal is to achieve universal access to basic education, and of reasonable quality, while closely linking expansion of other levels, and types of education and training, to labor market demand. In primary education, challenges remain to raise educational enrollment rates and reduce grade repetition; including the rationalization of teacher allocation, and provision of learning materials. At the secondary level, policy issues should expand enrollment at a moderate pace, focusing on quality improvements. As for vocational and technical education, the provision of training should be rationalized, to reduce costs, aligning training to labor demand; similarly, for higher educatio

New Approaches for Funding Research and Innovation in Africa

It is without doubt that African countries’ individual and collective aspirations of economic development through research and innovation are in line with trends worldwide. Similarly, like elsewhere in different parts of the world, African countries have been exploring different approaches, institutional reforms, models and mechanisms towards more efficient and effective funding and financing of research and innovation. This commissioned paper derives from a study which used a combination of primary and secondary data sources to inform current debates and reviews on re-organization of research and innovation funding in Africa. The study specifically sought to identify and analyse “new approaches for funding research and innovation in Africa”. Study findings show that the importance of research and innovation is rated medium to high and is increasing in most of the African countries. This is demonstrated by practice, institutional and policy provisions for science, technology and innovation (STI), which have been instituted in the last few years. A number of dynamic new funding models have been developed, adopted and deployed in countries and sectors to deal with the realities of decreasing funding for research and innovation from traditional sources. These models, encompassing partnerships, co-funding and multi-disciplinary approaches, seek to ensure context-driven, efficient and effective utilisation of scarce resources. Challenges ranging from insufficient political will to lack of implementation plans and uncoordinated approaches to STI were said to be stalling the expansion and sustainable deployment of the new funding models

Central effects of acamprosate: Part 2. Acamprosate modifies the brain in-vivo proton magnetic resonance spectrum in healthy young male volunteers

Although acamprosate is a drug which is successfully used for therapy in maintaining alcohol abstinence following alcohol withdrawal in chronic alcoholism, little is understood about its mechanism of action in the central nervous system. Our objective was to assess the effects of acamprosate on the central nervous system in healthy subjects by dynamic proton magnetic resonance spectroscopy (MRS) measurements localized in brain tissue in vivo. Recordings were performed after intravenous administration of acamprosate or placebo to eight healthy male volunteers participating in a double-blind, randomized, cross-over, placebo-controlled study. The data were acquired using a spin-echo volume selective localized spectroscopy scheme on a 3-T whole body MRS system. Spectra obtained at baseline and at 20-min time intervals after the beginning of drug infusion were analyzed on the basis of five non-overlapping spectral integration regions. In the acamprosate-treated group, the median integral values in the regions for which N-acetylaspartate and glutamate are the main signal contributors showed decreases relative to placebo 20 min after the infusion began. Results suggest a central glutamatergic effect of acamprosate consistent with cerebral microdialysis glutamate measurements in vivo obtained from alcoholized rats treated with acamprosate (Part 1 of this study). This study is to our knowledge the first one describing a central effect of acamprosate in humans by MRS. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved

Central effects of acamprosate: part 1. Acamprosate blocks the glutamate increase in the nucleus accumbens microdialysate in ethanol withdrawn rats.

One of the known behavioral actions of acamprosate is to decrease hypermotility during alcohol withdrawal. However, the mechanism of this effect remains unclear. In this study, the concentrations of excitatory and inhibitory amino acids were assayed by the microdialysis technique with OPA/BME precolumn derivatization and electrochemical detection in the nucleus accumbens of male Wistar rats which were either alcoholized by ethanol inhalation or simultaneously alcoholized and treated orally by acamprosate (400 mg/kg/day) for 4 weeks. Without treatment, extracellular glutamate increased during the withdrawal phase, while other amino acids tested (aspartate, arginine, taurine, alanine and GABA) remained stable. In contrast, the alcoholized rats treated with acamprosate failed to present the increase in glutamate during ethanol withdrawal, while other amino acids tested also remained stable. The observed glutamate increase could be responsible for the hyperexcitability observed during episodes of ethanol withdrawal. These results suggest that acamprosate is able to reduce the ethanol withdrawal syndrome by reducing the concentration of glutamate in the nucleus accumbens