NMDA receptors (NMDAR) play an important role in neural plasticity including long-term potentiation and long-term depression, which are likely to explain their importance for learning and memory. Cognitive decline is a major problem facing an ageing human population, so much so that its reversal has become an important goal for scientific research and pharmaceutical development. Enhancement of NMDAR function is a core strategy toward this goal. In this review we indicate some of the major ways of potentiating NMDAR function by both direct and indirect modulation. There is good evidence that both positive and negative modulation can enhance function suggesting that a subtle approach correcting imbalances in particular clinical situations will be required. Excessive activation and the resultant deleterious effects will need to be carefully avoided. Finally we describe some novel positive allosteric modulators of NMDARs, with some subunit selectivity, and show initial evidence of their ability to affect NMDAR mediated events.

The history of ketamine and phencyclidine from their development as potential clinical anaesthetics through drugs of abuse and animal models of schizophrenia to potential rapidly acting antidepressants is reviewed. The discovery in 1983 of the NMDA receptor antagonist property of ketamine and phencyclidine was a key step to understanding their pharmacology, including their psychotomimetic effects in man. This review describes the historical context and the course of that discovery and its expansion into other hallucinatory drugs. The relevance of these findings to modern hypotheses of schizophrenia and the implications for drug discovery are reviewed. The findings of the rapidly acting antidepressant effects of ketamine in man are discussed in relation to other glutamatergic mechanisms. ACh receptors (muscarinic) GluN2BCannabinoid receptors GluN2C D2 receptor GluN2DMetabotrophic glutamate receptors Kainate receptors These Tables list key protein targets and ligands in this article which are hyperlinked to corresponding entries in http:// www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY (Pawson et al., 2014) and are permanently archived in the Concise Guide to PHARMACOLOGY 2013/14 ( a,b,c,d Alexander et al., 2013a. PreambleIn April 1981, Nabil Anis and David Lodge showed for the first time that ketamine was a selective antagonist of the NMDA subtype of glutamate receptor. Unlike the discovery of bicuculline as a GABA antagonist, reported by Graham Johnston in an earlier publication in this series of historical reviews (Johnston, 2013), the editors of Nature were not impressed, the finding 'not being of sufficient general interest'. Fortunately, the British Journal of Pharmacology took a different view and the resulting paper has now over 1000 citations . Both before and since this discovery, ketamine and its congener, phencyclidine, have captured the interest of clinicians, basic scientists and sections of the general public. This review will attempt to describe some of this history and bring the reader up to date with the latest twists of this fascinating story in the context of these drugs as NMDA receptor antagonists. Discovery of phencyclidine and ketamine: early observationsAbout 27 years earlier, phencyclidine had been synthesized by chemists at Parke Davis Company but not published for some 10 years (Maddox et al., 1965). Initial pharmacology, however, was described by Chen et al. (1959) who noted lack of sensation, hyperlocomotion, ataxia and catalepsy in rats and pigeons. They ascribed these to monoaminergic mechanisms and showed partial reversal by the neuroleptic chlorpromazine (Chen et al., 1959). At about the same time, Ed Domino commenced a fuller study of the neuropharmacology of phencyclidine (Domino, 1964). In rats, he described a 'drunken state' with increased locomotor activity leading to ataxia and catatonia at higher doses. Dogs also showed a similar state called 'canine delirium, although in monkeys a more satisfactory anaesthetic state was ...

International audienceThis paper explores the link between return migration and political outcomes in the origin country, using the case study of Mali. We use electoral and census data at the locality level to investigate the role of return migration on participation rates and electoral competitiveness. First, we run OLS and IV estimations for the 2009 municipal election, controlling for current emigration and using historical and distance variables as instruments for return migration and current emigration. Second, we build a panel dataset combining the 1998 and 2009 censuses and the electoral results for the municipal ballots of those two years to control for the potential time-invariant unobservable characteristics of the localities. We find a positive impact of the stock of return migrants on participation rates and on electoral competitiveness, which mainly stems from returnees from non-African countries. Finally, we show that the impact of returnees on turnout goes beyond their own participation, and that they affect more electoral outcomes in areas where non-migrants are poorly educated, which we interpret as evidence of a diffusion of political norms from returnees to non-migrants

Seizures are complex pathological network events characterized by excessive and hypersynchronized activity of neurons, including a highly diverse population of GABAergic interneurons. Although the primary function of inhibitory interneurons under normal conditions is to restrain excitation in the brain, this system appears to fail intermittently, allowing runaway excitation. Recent developments in optogenetics, combined with genetic tools and advanced electrophysiological and imaging techniques, allow us for the first time to assess the causal roles of identified cell-types in network dynamics. While these methods have greatly increased our understanding of cortical microcircuits in epilepsy, the roles played by individual GABAergic cell-types in controlling ictogenesis remain incompletely resolved. Indeed, the ability of interneurons to suppress epileptic discharges varies across different subtypes, and an accumulating body of evidence paradoxically implicates some interneuron subtypes in the initiation and maintenance of epileptiform activity. Here, we bring together findings from this growing field and discuss what can be inferred regarding the causal role of different GABAergic cell-types in seizures.