Simultaneous versus solitary pharmacological manipulation of NMDA- and AMPA- receptors: effects of new drugs on contextual learning and its extinction

Both the attenuation of the NMDA-receptor mediated transmission via low affinity blockade mechanism, and the stimulation of AMPA receptor-mediated signaling were shown to result in beneficial neurobiological effects, such as an enhancement of memory and neurogenesis. We aimed to compare the effects of acute pharmacological manipulations of these mechanisms, exerted simultaneously or solely in mice, on learning of two mouse tasks with distinct predominant dependency on either glutamate receptor subtype. In a step-down avoidance task, memantine, low affinity NMDA receptor blocker (5 mg/kg), but not ampakine QQX (5 mg/kg) increased memory scores. In contrast, extinction of contextual fear conditioning was significantly enhanced by the latter, but not by the first drug. Among four new isothiourea derivates used at the doses 0.5-1 mg/kg, one compound that showed a maximal potency with respect to both glutamatergic mechanisms, as well as dimebon (1 mg/kg), had the most prominent memory enhancing effects. Thus, simultaneous low affinity blocade of the NMDA receptor and stimulation of AMPA-mediated transmission can result in eminent pro-cognitive activities. These data point to the importance of multi-target drug mechanism in the regulation of cognitive functions and suggest its potential for clinical implications

Dimebon enhances hippocampus-dependent learning in both appetitive and inhibitory memory tasks in mice

Dimebon, a compound recently proposed for a treatment of Alzheimer’s disorder was suggested to have memory enhancing properties in pre-clinical and clinical studies. We investigated whether dimebon at doses acutely (0.1 mg/kg and 0.5 mg/kg) or repeatedly (0.1 mg/kg) administered to mice via i.p. injections, increases memory scores respectively in an appetitive and an inhibitory learning task. Acute treatment with dimebon at the dose 0.1 mg/kg did not affect learning scores in either 3-month-old C57BL/6N or CD1 mice. Acute treatment with higher dose of dimebon (0.5mg/kg) was found to enhance inhibitory learning in 3- and 7-month-old mice as shown in the step-down avoidance paradigm in C57BL/6N mice. No effects on learning were seen in CD1 mice. In a model of appetitive learning, a spatial version of the Y-maze, repeated treatment with dimebon increased the rate of correct choices and decreased the latency of accessing a water reward after water deprivation. Repeated administration of dimebon also increased the duration of drinking behaviour during training/testing procedures although behaviours in others tests or water consumption were not altered. Acute treatment of water-deprived and non-water-deprived mice with dimebon also did not affect their water intake. Our data suggest that dimebon enhances hippocampus-dependent learning in both appetitive and inhibitory tasks in mice

Search for direct production of charginos and neutralinos in events with three leptons and missing transverse momentum in √s = 7 TeV pp collisions with the ATLAS detector

A search for the direct production of charginos and neutralinos in final states with three electrons or muons and missing transverse momentum is presented. The analysis is based on 4.7 fb−1 of proton–proton collision data delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in three signal regions that are either depleted or enriched in Z-boson decays. Upper limits at 95% confidence level are set in R-parity conserving phenomenological minimal supersymmetric models and in simplified models, significantly extending previous results