Repeated diazepam administration reversed working memory impairments and glucocorticoid alterations in the prefrontal cortex after short but not long alcohol-withdrawal periods.

The study was designed to assess whether repeated administration of diazepam (Valium®, Roche)-a benzodiazepine exerting an agonist action on GABAA receptors-may alleviate both the short (1 week, 1W) and long-term (6 weeks, 6W) deleterious effects of alcohol withdrawal occurring after chronic alcohol consumption (6 months; 12% v/v) in C57/BL6 male mice. More pointedly, we first evidenced that 1W and 6W alcohol-withdrawn mice exhibited working memory deficits in a sequential alternation task, associated with sustained exaggerated corticosterone rise and decreased pCREB levels in the prefrontal cortex (PFC). In a subsequent experiment, diazepam was administered i.p. for 9 consecutive days (1 injection/day) during the alcohol withdrawal period at decreasing doses ranging from 1.0 mg/kg to 0.25 mg/kg. Diazepam was not detected in the blood of withdrawn mice at the time of memory testing, occurring 24 hours after the last diazepam injection. Repeated diazepam administration significantly improved alternation rates and normalized levels of glucocorticoids and pCREB activity in the PFC in 1W but not in 6W withdrawn mice. Thus, repeated diazepam administration during the alcohol-withdrawal period only transitorily canceled out the working memory impairments and glucocorticoid alterations in the PFC of alcohol-withdrawn animals.

Synergistic enhancing-memory effect of donepezil and S 47445, an AMPA positive allosteric modulator, in middle-aged and aged mice.

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.

Different implications of the dorsal and ventral hippocampus on contextual memory retrieval after stress.

This study assessed the relative contributions of dorsal (dHPC) and ventral (vHPC) hippocampus regions in mediating the rapid effects of an acute stress on contextual memory retrieval. Indeed, we previously showed that an acute stress (3 electric footschocks; 0.9 mA each) delivered 15 min before the 24 h-test inversed the memory retrieval pattern in a contextual discrimination task. Specifically, mice learned in a four-hole board two successive discriminations (D1 and D2) varying by the color and texture of the floor. Twenty-four hours later, nonstressed animals remembered accurately D1 but not D2 whereas stressed mice showed an opposite memory retrieval pattern, D2 being more accurately remembered than D1. We showed here that, at the time of memory testing in that task, stressed animals exhibited no significant changes neither in pCREB activity nor in the time-course evolution of corticosterone into the vHPC; in contrast, a significant decrease in pCREB activity and a significant increase in corticosterone were observed in the dHPC as compared to nonstressed mice. Moreover, local infusion of the anesthetic lidocaine into the vHPC 15 min before the onset of the stressor did not modify the memory retrieval pattern in nonstress and stress conditions whereas lidocaine infusion into the dHPC induced in nonstressed mice an memory retrieval pattern similar to that observed in stressed animals. The overall set of data shows that memory retrieval in nonstress condition involved primarily the dHPC and that the inversion of memory retrieval pattern after stress is linked to a dHPC but not vHPC dysfunction.

Role of corticosteroid binding globulin in the fast actions of glucocorticoids on the brain.

Corticosteroid binding globulin (CBG) is a glycoprotein synthesized in liver and secreted in the blood where it binds with a high affinity but low capacity glucocorticoid hormones, cortisol in humans and corticosterone in laboratory rodents. In mammals, 95% of circulating glucocorticoids are bound to either CBG (80%) or albumin (15%) and only the 5% free fraction is able to enter the brain. During stress, the concentration of glucocorticoids rises significantly and the free fraction increases even more because CBG becomes saturated. However, glucocorticoids unbound to CBG are cleared from the blood more quickly. Our studies on mice totally devoid of CBG (Cbg k.o.) showed that during stress these mutant mice display a lower rise of glucocorticoids than the wild-type controls associated with altered emotional reactivity. These data suggested that CBG played a role in the fast actions of glucocorticoids on behavior. Further analyses demonstrated that stress-induced memory retrieval impairment, an example of the fast action of glucocorticoids on the brain is abolished in the Cbg k.o. mice. This effect of stress on memory retrieval could be restored in the Cbg k.o. mice by infusing corticosterone directly in the hippocampus. The mechanisms explaining these effects involved an increased clearance but no difference in corticosterone production. Thus, CBG seems to have an important role in maintaining in blood a glucocorticoid pool that will be able to access the brain for the fast effects of glucocorticoids.