Rescuing prefrontal cAMP-CREB pathway reverses working memory deficits during withdrawal from prolonged alcohol exposure.

Both human and animal studies indicate that alcohol withdrawal following chronic alcohol consumption (CAC) impairs many of the cognitive functions which rely on the prefrontal cortex (PFC). A candidate signaling cascade contributing to memory deficits during alcohol withdrawal is the protein kinase A (PKA)/cAMP-responsive element binding (CREB) cascade, although the role of PKA/CREB cascade in behavioral and molecular changes during sustained withdrawal period remains largely unknown. We demonstrated that 1 week (1W) or 6 weeks (6W) withdrawal after 6-month CAC impairs working memory (WM) in a T-maze spontaneous alternation task and reduces phosphorylated CREB (pCREB) in the PFC but not the dorsal CA1 region (dCA1) of the hippocampus compared with CAC and water conditions. In contrast, both CAC-unimpaired and withdrawn-impaired mice exhibited decreased pCREB in dCA1 as well as reduced histone H4 acetylation in PFC and dCA1, compared with water controls. Next, we showed that enhancing CREB activity through rolipram administration prior to testing improved WM performance in withdrawn mice but impaired WM function in water mice. In addition, WM improvement correlates positively with increased pCREB level selectively in the PFC of withdrawn mice. Results further indicate that direct infusion of the PKA activator (Sp-cAMPS) into the PFC significantly improves or impairs, respectively, WM performance in withdrawn and water animals. In contrast, Sp-cAMPS had no effect on WM when infused into the dCA1. Collectively, these results provide strong support that dysregulation of PKA/CREB-dependent processes in prefrontal neurons is a critical molecular signature underlying cognitive decline during alcohol withdrawal.

Effects of positive modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors in a benzodiazepine-induced deficit of spatial discrimination in mice.

Imbalance between GABAergic and glutamatergic neurotransmission has been recently hypothesized to trigger memory decline related either to ageing or to Alzheimer's disease (AD). Thereby, benzodiazepine-induced anterograde amnesia has been construed as a model of hippocampal-related cognitive dysfunctions. Since spatial memory is altered both by ageing and by benzodiazepines such as alprazolam, we investigated the pharmacological sensitivity of alprazolam-induced deficit in a delayed spatial discrimination (SD) task, notably with positive allosteric modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors. We showed that alprazolam (0.1 mg/kg intraperitoneally) induced memory impairments as compared with vehicle-treated mice. The oral administration of modulators of AMPA receptors (IDRA-21: 10 mg/kg; S18986: 3 and 10 mg/kg) reversed the alprazolam-induced deficits. This study is first to show evidence that reference treatments of AD, such as memantine (a NMDA receptor antagonist) at 3 mg/kg per os (po) and donepezil (an acetylcholinesterase inhibitor) at 1 mg/kg po, also reversed the alprazolam-induced amnesia. Given such results, the SD task emerges as a valuable novel task to screen pro-cognitive compounds. Thus, we highlight the efficacy of modulators of AMPA-type glutamate receptors to counteract alprazolam-induced spatial deficits. These results could be viewed alongside the imbalance between excitation and inhibition observed during normal and pathological ageing.