Contributions of animal models of cognitive disorders to neuropsychopharmacology.

International audienceCognitive disorders and symptoms are key features of many mental and neurological diseases, with a large spectrum of impaired domains. Because of their possible evolution and detrimental functioning impact, they are a major pharmacological target for both symptomatic and disease-modifier drugs, while few cognitive enhancers have been marketed with an insufficient efficiency. It explains the need to model these cognitive disorders beyond the modelization of mental or neurological diseases themselves. According to the experimental strategy used to induce cognitive impairment, three categories of models have been identified: neurotransmission-driven models; pathophysiology-driven models; environment-driven models. These three categories of models reflect different levels of integration of endogenous and exogenous mechanisms underlying cognitive disorders in humans. Their comprehensive knowledge and illustration of their pharmacological modulation could help to propose a renewing strategy of drug development in central nervous system (CNS) field at a time when the academic and industrial invest seems to be declining despite the medical and social burden of brain diseases

Perturbations du contrôle traductionnel et troubles cognitifs dans un modèle expérimental de la maladie de Parkinson (études de neuroprotection)

POITIERS-BU Médecine pharmacie (861942103) / SudocSudocFranceF

Lack of direct involvement of a diazepam long-term treatment in the occurrence of irreversible cognitive impairment: a pre-clinical approach

AbstractSeveral observational studies have found a link between the long-term use of benzodiazepines and dementia, which remains controversial. Our study was designed to assess (i) whether the long-term use of benzodiazepines, at two different doses, has an irreversible effect on cognition, (ii) and whether there is an age-dependent effect. One hundred and five C57Bl/6 male mice were randomly assigned to the 15 mg/kg/day, the 30 mg/kg/day diazepam-supplemented pellets, or the control group. Each group comprised mice aged 6 or 12 months at the beginning of the experiments and treated for 16 weeks. Two sessions of behavioral assessment were conducted: after 8 weeks of treatment and after treatment completion following a 1-week wash-out period. The mid-treatment test battery included the elevated plus maze test, the Y maze spontaneous alternation test, and the open field test. The post-treatment battery was upgraded with three additional tests: the novel object recognition task, the Barnes maze test, and the touchscreen-based paired-associated learning task. At mid-treatment, working memory was impaired in the 15 mg/kg diazepam group compared to the control group (p = 0.005). No age effect was evidenced. The post-treatment assessment of cognitive functions (working memory, visual recognition memory, spatial reference learning and memory, and visuospatial memory) did not significantly differ between groups. Despite a cognitive impact during treatment, the lack of cognitive impairment after long-term treatment discontinuation suggests that benzodiazepines alone do not cause irreversible deleterious effects on cognitive functions and supports the interest of discontinuation in chronically treated patients

Modulation of lipid-induced ER stress by fatty acid shape.

IF : 5,709International audienceExposure of pancreatic β cells to long-chain saturated fatty acids (SFA) induces a so-called endoplasmic reticulum (ER) stress that can ultimately lead to cell death. This process is believed to participate in insulin deficiency associated with type 2 diabetes, via a decrease in β-cell mass. By contrast, some unsaturated fatty acid species appear less toxic to the cells and can even alleviate SFA-induced ER stress. In the present study, we took advantage of a simple yeast-based model, which brings together most of the trademarks of lipotoxicity in human cells, to screen fatty acids of various structures for their capacity to counter ER stress. Here we demonstrate that the tendency of a free fatty acid (FFA) to reduce SFA toxicity depends on a complex conjunction of parameters, including chain length, level of unsaturation, position of the double bonds and nature of the isomers (cis or trans). Interestingly, potent FFA act as building blocks for phospholipid synthesis and help to restore an optimal membrane organization, compatible with ER function and normal protein trafficking

Effects of acute ethanol and/or diazepam exposure on immediate and delayed hippocampal metabolite levels in rats anesthetized with isoflurane.

International audienceAlcohol and benzodiazepines are psychoactive substances frequently associated in voluntary drug intoxications that share common mechanisms of action, including facilitation of GABAergic transmission. This study aimed to assess the separate and combined effects of ethanol and diazepam acute exposure on hippocampal metabolite levels, as well as on delayed cognitive performance, in rats anesthetized with isoflurane. Adult male Wistar rats received one intraperitoneal injection containing either saline solution (“CTL” group, N = 15), a 5-mg/kg dose of diazepam (“DIA” group, N = 16), a 2-g/kg dose of ethanol (“EtOH” group, N = 18), or a 5-mg/kg dose of diazepam + a 2-g/kg dose of ethanol (“DIA + EtOH” group, N = 24). The levels of brain metabolites in the hippocampal region were assessed using in vivo magnetic resonance spectroscopy (MRS) before and after injection. Behavioral testing, including working memory and visual recognition memory assessment, was performed at week 3, while a new MRS acquisition was conducted 4 weeks after the injection. In the hour following acute exposure, a decrease in glutamate levels was found in the DIA + EtOH group only. Four weeks after injection, a decrease in GABA and glutamate levels and an increase in NAA levels were found in the EtOH group only. No significant between-group differences were found in the behavioral assessment. While the initial decrease in glutamate levels in the DIA + EtOH group suggests an early potentiation effect between ethanol and diazepam, the long-term modifications found only in the EtOH group suggest a possible downregulation of ethanol's effect by diazepam at 4 weeks

Donepezil increases contrast sensitivity for the detection of objects in scenes

We assessed the effects of donepezil, a drug that stimulates cholinergic transmission, and scopolamine, an antagonist of cholinergic transmission, on contrast sensitivity. 30 young male participants were tested under three treatment conditions: placebo, donepezil, and scopolamine in a random order. Pairs of photographs varying in contrast were displayed left and right of fixation for 50 ms. Participants were asked to locate the scene containing an animal. Accuracy was better under donepezil than under scopolamine, particularly for signals of high intensity (at higher levels of contrast). A control experiment showed that the lower performance under scopolamine did not result from the mydriasis induced by scopolamine. The results suggest that cholinergic stimulation, through donepezil, facilitates signal detection in agreement with studies on animals showing that the pharmacological activation of cholinergic receptors controls the gain in the relationship between the stimulus contrast (intensity of the visual input) and visual response. As Alzheimer disease is associated to depletion in acetylcholine, and there is evidence of deficits in contrast sensitivity in Alzheimer, it might be interesting to integrate such rapid and sensitive visual tasks in the biomarkers at early stage of drug development

Neurobehavioral and Cognitive Changes Induced by Sleep Deprivation in Healthy Volunteers

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Conclusive Article: Sorting the Good from the Bad: The Different Approaches to Predict Cognitive Properties of New Symptomatic Drug Candidates for Neurodegenerative Diseases in Early Development

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Conclusive Article: Sorting the Good from the Bad: The Different Approaches to Predict Cognitive Properties of New Symptomatic Drug Candidates for Neurodegenerative Diseases in Early Development

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Neurobehavioral and Cognitive Changes Induced by Hypoxia in Healthy Volunteers

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