Repeated Treatment With Alpha 7 Nicotinic Acetylcholine Receptor Ligands Enhances Cognitive Processes And Stimulates Erk1/2 And Arc Genes In Rats

The alpha 7 nicotinic acetylcholine receptor (alpha 7 nAChR) is a potential target for the treatment of cognitive decline in patients with schizophrenia, Alzheimer's disease, and attention-deficit/hyperactivity disorder.Here we examined the promnesic activity of the alpha 7 nAChR agonist (A582941), the type I (CCMI), and the type II (PNU120596) positive allosteric modulators (PAMs) in rats following single and repeated (once daily for seven days) treatment. To determine the neuronal mechanisms underlying the procognitive activity of the tested compounds, levels of the extracellular signal-regulated kinases (Erk1/2) and the activity-regulated cytoskeletonassociated protein (Arc) mRNAs were assessed in the frontal cortical and hippocampal brain regions.Using the novel object recognition test, we demonstrate that the lower doses of A582941 (0.1 mg/kg), CCMI (1 mg/kg), and PNU120596 (0.3 mg/kg) improved recognition memory after repeated but not single administration, suggesting a cumulative effect of repeated dosing. In contrast, the higher doses of A582941 (0.3 mg/kg), CCMI (3 mg/kg) and PNU120596 (1 mg/kg) demonstrated promnesic efficacy following both single and repeated administration. Subsequent in situ hybridization revealed that repeated treatment with A582941 and CCMI, but not PNU120596 enhanced mRNA expression of the Erk1/2 and Arc in the frontal cortex and hippocampus.Present data suggest that both the alpha 7 nAChR agonist and PAMs exhibit procognitive effects after single and repeated administration. The increased level of the Erk1/2 and Arc genes is likely to be at least partially involved in this effect.