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Positive allosteric modulators of AMPA receptors (AMPA-PAMs) are described to facilitate cognitive processes in different memory-based models. Among them, S 47445 is a novel potent and selective AMPA-PAM. In order to assess its efficacy after repeated administration, S 47445 effect was evaluated in two aging-induced memory dysfunction tasks in old mice, one short-term working memory model evaluated in a radial maze task and one assessing contextual memory performance. S 47445 was shown to improve cognition in both models sensitive to aging. In fact, administration of S 47445 at 0.3 mg/kg (s.c.) reversed the age-induced deficits of the working memory model whatever the retention interval. Moreover, in the contextual task, S 47445 also reversed the age-induced deficit at all tested doses (from 0.03 to 0.3 mg/kg, p.o.). Since donepezil, an acetylcholinesterase inhibitor, induces only moderate symptomatic effects on memory in Alzheimer’s disease patients, an alternative strategy for treatment of cognitive symptoms could be to act simultaneously on both glutamatergic AMPA receptors and cholinergic pathways by combining pharmacological treatments. The present study further examined such effects by assessing combinations of S 47445 and donepezil given orally during 9 days in aged C57/Bl6J mice using contextual memory task (CSD) and the working memory model of serial alternation task (AT). Interestingly, a significant synergistic memory-enhancing effect was observed with the combination of donepezil at 0.1 mg/kg with S 47445 at 0.1 mg/kg p.o. in the CSD or with S 47445 at 0.1 and 0.3 mg/kg in AT in comparison to compounds given alone and without any pharmacokinetic interaction. Electronic supplementary material The online version of this article (10.1007/s00213-017-4792-5) contains supplementary material, which is available to authorized users.

Donepezil, an acetylcholinesterase inhibitor, induces only moderate symptomatic effects on memory in Alzheimer’s disease patients. An alternative strategy for treatment of cognitive symptoms could be to act simultaneously on both histaminergic and cholinergic pathways, to create a synergistic effect. To that aim, 14 month –old C57/Bl6 mice were administered per oesophagy during 9 consecutive days with Donepezil (at 0.1mg/kg and 0.3mg/kg) and S 38093 (at 0.1 mg/kg, 0.3 mg/kg and 1.0 mg/kg), a H3 histaminergic antagonist developed by Servier, alone or in combination and tested for memory in a contextual memory task that modelized the age-induced memory dysfunction. The present study shows that the combination of Donepezil and S 38093 induced a dose-dependent synergistic memory-enhancing effect in middle-aged mice with a statistically higher size of effect never obtained with compounds alone and without any pharmacokinetic interaction between both compounds. We demonstrated that the memory-enhancing effect of the S 38093 and Donepezil combination is mediated by its action on the septo-hippocampal circuitry, since it canceled out the reduction of CREB phosphorylation (pCREB) observed in these brain areas in vehicle-treated middle-aged animals. Overall, the effects of drug combinations on pCREB in the hippocampus indicate that the synergistic promnesiant effects of the combination on memory performance in middle-aged mice stem primarily from an enhancement of neural activity in the septo-hippocampal system.

The number of Americans older than 65 years old is projected to more than double in the next 40 years. Cognitive changes associated to aging can affect an adult's day-to-day functioning. Among these cognitive changes, reasoning, episodic memory, working memory, and processing speed decline gradually over time. Early memory changes include a decline in both working and episodic memory. The aim of the present study was to determine whether chronic (up to 75 days) daily administration of wild blueberry extract or a wild blueberry full spectrum powder would help prevent memory failure associated with aging in tasks involving various forms of memory. Both blueberry ingredients were used in a study comparing young mice (6 months old) to aged mice (18 months old). At this age, mice exhibit memory decline due to aging, which is exacerbated first by a loss in working and contextual (episodic-like) memory. Contextual memory (episodic-like memory) was evaluated using the contextual serial discrimination test. Working and spatial memory were evaluated using the Morris-Water maze test and the sequential alternation test. Statistical analysis was performed using an ANOVA with the Bonferroni post-hoc test. Supplementation with wild blueberry full spectrum powder and wild blueberry extract resulted in significant improvement of contextual memory, while untreated aged mice experienced a decline in such memory. Only the wild blueberry full spectrum powder significantly contributed to an improvement of spatial and working memory versus untreated aged mice. These improvements of cognitive performance may be related to brain oxidative status, acetylcholinesterase activity, neuroprotection, or attenuation of immunoreactivity.

Normal or pathological ageing is characterized by working-memory dysfunction paired with a marked reduction in several neurotransmitters activity. The development of therapeutic strategy centered on the glutamatergic system known to bear a critical role in cognitive functions, is therefore of major importance in the treatment of mild forms of AD or age-related memory dysfunctions.In Experiment 1, we investigated the effects of ageing on spatial working memory measured by sequential alternation (SA). Thus, the decay of alternation rates over a series of trials separated by varying intertrial temporal intervals (ITI, from 5 sec to 180 sec) was studied in mice of different age groups. In Experiment 2, we investigated the memory-enhancing potential of S 18986--a modulator of AMPA receptors--on age-related SA impairments, in comparison with memantine--an antagonist of NMDA receptors--.In Experiment 1, aged mice responded at chance with shorter ITI's and exhibited greater levels of interference in the SA task as compared to young adult mice. In Experiment 2, (1) S 18986 at 0.03 and 0.1 mg/kg reversed the memory deficit in aged mice but did not modify performance in young adult mice; (2) memantine at 10 mg/kg also increased SA rates in aged mice but did not improve performance in young adult mice.The SA task is a useful tool to reveal age-induced time-dependent working memory impairments. As compared to memantine, S 18986--a compound targeting AMPA receptors--contributes a valuable therapy in the treatment of age-related cognitive dysfunctions or mild forms of AD.

The organophosphorus compound soman produces long-lasting epileptic seizure activity which is associated to brain damage, more particularly in the hippocampus and the amygdala. The companion paper (see part 1 in the same journal issue) describes the neuropathology in the amygdala of soman-poisoned mice. The present paper examines the long-term effects of soman poisoning on emotional reactivity in mice, 30 or 90 days after intoxication using behavioral tasks involving amygdala function. The emotional behavior was estimated in animal tests of unconditioned fear (light/dark boxes, elevated plus-maze) and conditioned fear (auditory and contextual response). In the light/dark boxes and elevated plus-maze , mice intoxicated with soman (110 μg/kg, 1.2 LD50) showed an anxiety-like behavior profile at post-poisoning days 30 and 90. In conditioned fear, results showed that both auditory and contextual conditioned responses are increased on post-soman day 30 but no longer on post-soman day 90, evidencing behavioral recovery overtime. This latter behavioral result is in accordance with the delayed neuronal regeneration patterns described in the companion paper (part 1).

The number of Americans older than 65 years old is projected to more than double in the next 40 years. Cognitive changes associated to aging can affect adult's day-to-day functioning. Early memory ...

S 47445 is a novel positive allosteric modulator of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors (AMPA-PAM). S 47445 enhanced glutamate's action at AMPA receptors on human and rat receptors and was inactive at NMDA and kainate receptors. Potentiation did not differ among the different AMPA receptors subtypes (GluA1/2/4 flip and flop variants) (EC50 between 2.5-5.4 μM), except a higher EC50 value for GluA4 flop (0.7 μM) and a greater amount of potentiation on GluA1 flop. A low concentration of S 47445 (0.1 μM) decreased receptor response decay time of GluA1flop/GluA2flip AMPA receptors and increased the sensitivity to glutamate. Furthermore, S 47445 (0.1 and 0.3 μM) in presence of repetitive glutamate pulses induced a progressive potentiation of the glutamate-evoked currents from the second pulse of glutamate confirming a rapid-enhancing effect of S 47445 at low concentrations. The potentiating effect of S 47445 (1 μM) was concentration-dependently reversed by the selective AMPA receptor antagonist GYKI52466 demonstrating the selective modulatory effect of S 47445 on AMPA receptors. Using an AMPA-kainate chimera approach, it was confirmed that S 47445 binds to the common binding pocket of AMPA-PAMs. S 47445 did not demonstrate neurotoxic effect against glutamate-mediated excitotoxicity in vitro, in contrast significantly protected rat cortical neurons at 10 μM. S 47445 was shown to improve both episodic and spatial working memory in adult rodents at 0.3 mg/kg, as measured in the natural forgetting condition of object recognition and T-maze tasks. Finally, no deleterious effect on spontaneous locomotion and general behavior was observed up to 1000 mg/kg of S 47445 given acutely in rodents, neither occurrence of convulsion or tremors. Collectively, these results indicate that S 47445 is a potent and selective AMPA-PAM presenting procognitive and potential neuroprotective properties. This drug is currently evaluated in clinical phase 2 studies in Alzheimer's disease and in Major Depressive Disorder.

The effects of ibotenic acid lesions of either the mediodorsal thalamus (MD) or the mammillary bodies (MB) on the acquisition and retention of a reversal learning set in a T-maze were studied in mice. Both the MB and MD lesions disrupted performance in this task, but only MD lesions slowed down the rate of learning, MD-lesioned subjects requiring more trials than the other two groups to master the discrimination at the end of the learning phase. Surprisingly, increasing the intersession interval from 24 h to 10 days totally alleviated the deficit of MD-subjects and even improved their performance as compared to the last (8th day) session. The overall results of the study show that both MD and MB lesions do not induce important learning deficits nor anterograde amnesia in the reversal learning set task.

The aim of the present work was to investigate in mice the effects of a total 10-hr sleep deprivation on contextual (episodic-like) and spatial (reference) memory tasks. For that purpose, mice learned two consecutive discriminations (D1 and D2) in a 4-hole board involving either identical (Serial Spatial Discrimination, SSD) or distinct (Contextual Serial Discrimination, CSD) internal contextual cues. In a second step, we intended to assess the corrective effect of modafinil on memory impairments generated by sleep deprivation. Sleep deprivation was triggered through an alternative platform apparatus (water box), previously validated using EEG recording and spectral analysis. We showed that a 10-hr total sleep deprivation impaired the CSD task but not the SSD one. Moreover, the impairment of contextual memory in sleep-deprived animals was dose-dependently corrected by modafinil. Indeed, modafinil administered after the sleep deprivation period and 30 min before the test session restored a memory retrieval pattern identical to non sleep-deprived animals at the doses of 32 and 64 mg/kg, however not at 16 mg/kg. Results hereby evidence that the vigilance-enhancing drug modafinil is able to restore the contextual memory performance at a low dose as compared to other memory tasks, possibly by an enhancement of hippocampal activity known to be both involved in the processing of contextual information and impaired following our sleep deprivation procedure.

This study investigates the effects of lesioning the mamillary bodies (MB) or the dorsomedian nucleus (MD) of the thalamus on exploration of an elevated plus maze in mice. Exploration of 'open' and 'enclosed' arms of the maze has been used to evaluate anxiety in rodents. Normal rodents visit the enclosed arms more often than the open ones (innate agoraphobia). As operationally defined, the less the activity in the open arms, the more anxious is the subject. MB-lesioned mice entered the open alleys more often, and spent more time in them, than did controls, whereas the opposite was observed in MD-damaged subjects. It is suggested that, in mice given this task, MB lesions decrease anxiety and that MD lesions increase anxiety.

In the present study, we examined the effects of acamprosate for its ability to reduce handling induced convulsions (HICs) during alcohol withdrawal. Diazepam was used as a positive control. Swiss Webster male mice received three daily IP injections of alcohol (2.5 g/kg) or alcohol (2.5 g/kg) + methylpyrazole (4-MP) (9 mg/kg). (4-MP, being an alcohol dehydrogenase inhibitor slows down the breakdown of alcohol. 4-MP in combination with alcohol exhibits a dramatic increase in blood alcohol level compared to alcohol alone). Ten hours following the last alcohol injection, the mice were picked up by the tail and examined for their seizure susceptibility (HICs). Diazepam, a benzodiazepine known to reduce seizures during alcohol withdrawal, significantly reduced these HICs at doses of 0.25, 0.5 and 1mg/kg (p’s < 0.001). Acamprosate, an anti-relapse compound used clinically in newly abstinent alcoholics, also reduced these HICs at doses of 100, 200 and 300mg/kg (p’s < 0.05). This study supports the use of acamprosate during periods of alcohol withdrawal as well as during abstinence.

The organophosphorus compound soman produces long-lasting epileptic seizure activity which is associated to brain damage, more particularly in the hippocampus and the amygdala. The companion paper (see part 1 in the same journal issue) describes the neuropathology in the amygdala of soman-poisoned mice. The present paper examines the long-term effects of soman poisoning on emotional reactivity in mice, 30 or 90 days after intoxication using behavioral tasks involving amygdala function. The emotional behavior was estimated in animal tests of unconditioned fear (light/dark boxes, elevated plus-maze) and conditioned fear (auditory and contextual response). In the light/dark boxes and elevated plus-maze, mice intoxicated with soman (110 microg/kg, 1.2 LD(50)) showed an anxiety-like behavior profile at post-poisoning days 30 and 90. In conditioned fear, results showed that both auditory and contextual conditioned responses are increased on post-soman day 30 but no longer on post-soman day 90, evidencing behavioral recovery overtime. This latter behavioral result is in accordance with the delayed neuronal regeneration patterns described in the companion paper (part 1).

A large number of studies have investigated the effects of chronic ethanol administration (CEA) on performance in different types of learning and memory tasks in adult rodents. As a general rule, CEA has been reported to impair performance, although this depends both on the condition of administration (e.g. duration, presence or not of a withdrawn period) and on task demands (e.g. spatial versus non-spatial). Indeed, either no impairment or even a facilitation of performance have been reported following CEA. However, no study has directly addressed the issue as to whether the effect of CEA depends on the age of subjects. In this study, C57Bl/6 mice of two age ranges (i.e. 2-3- and 16-18-month-old) were given either a solution of ethanol (12% v/v) as their only source of fluid for 5 months (experimental groups) or were pair-fed with an isocaloric solution of dextri-maltose (control groups). Then, they were submitted to a place discrimination task in an 8-arm radial maze. Additionally, mice were tested for long-term retention following a 21-day interval. Confirming our previous findings, the results showed that, with respect to adults (7-8-month-old at the time of testing), aged mice (21-23-month-old) of the control group displayed impaired relational memory but not procedural memory performance. Further they exhibited a higher level of forgetting than adults over the 21-day interval. In the same paradigm, CEA resulted in an overall attenuation of both type of deficit in aged subjects without altering their procedural memory. Furthermore these ethanol-consuming aged mice displayed significantly less levels of forgetting than their age-matched controls. Conversely, in the adult group, CEA resulted in an overall, although, somewhat less selective impairment of relational memory with respect to procedural memory but had no effect on long-term forgetting. While confirming the deleterious effect of CEA on learning and memory processes in adults, our present findings provide evidence that CEA can selectively ameliorate certain cognitive deficits normally associated with ageing.

Neurogranin (Ng) is a Ca(2+)-sensitive calmodulin-binding neuron-specific protein that has been implicated in the regulation of numerous post-synaptic signalling pathways. Here, we investigate the effects of 5 months low level ethanol consumption (approximately 20% of total calories intake) on Ng mRNA expression in the brain of adult (approximately 7-8 months) and aged (approximately 21-22 months) mice using in situ hybridization histochemistry. Results showed that ageing was accompanied by a decrease in amounts of mRNA coding for Ng, especially in the hippocampus (approximately 25% of adults) known to play a critical role in higher cognitive functions. Chronic ethanol consumption restored this decline up to pre-senescent (adult) levels without altering Ng mRNA levels in adult mice. On the basis of recent data indicating a central role for Ng in the regulation of hippocampal synaptic plasticity and spatial learning, our results suggest that moderate ethanol consumption might have a beneficial influence on cognitive deterioration during senescence. Such a possibility is in fact congruent with recent follow-up studies conducted in elderly people.