Abstract:The original aims of our study have been to investigate in sleep-deprived mice, the effects of modafinil administration on spatial working memory, in parallel with the evaluation of neural activity level, as compared to non sleep-deprived animals. For this purpose, an original sleepdeprivation apparatus was developed and validated with continuous electroencephalography recording. Memory performance was evaluated using spontaneous alternation in a T-maze, whereas the neural activity level was estimated by the quantification of the c-Fos protein in various cerebral zones. This study allowed altogether:First, to evidence that a diurnal 10-hr sleep deprivation period induced an impairment of spatial working memory.Second, to observe a decrease in c-Fos expression after sleep deprivation followed by a behavioural test, as compared to non sleep-deprived mice. This impairment in neural activity was evidenced in areas involved in wake-sleep cycle regulation (anterior hypothalamus and supraoptic nucleus), but also in memory (frontal cortex and hippocampus) and emotions (amygdala).Finally, to demonstrate that modafinil 64 mg/kg is able to restore on the one hand memory performance after a 10-hr sleep deprivation period, and on the other hand, the neural activity level in the very same brain areas where it was previously impaired by sleep deprivation and cognitive task.

This preclinical demonstration that S 24795 restored specific age-related memory deficits with as much efficacy as donepezil adds to recent literature in highlighting the potential interest of an alpha7 nAChR drug as a symptomatic AD therapeutic.

Overall, S 18986 emerges as having a beneficial impact on contextual memory processes in middle-aged mice.