P3‐412: INSULIN PROTECTS AGAINST BETA AMYLOID INDUCED HIPPOCAMPAL CELL DEATH

Background:The 5-HT6 receptor is primarily localized in the brain, in areas relevant for cognition. Combining a 5-HT6 receptor antagonist and an acetylcholinesterase inhibitor (AChEI) represents a promising new approach to the symptomatic treatment of Alzheimer’s disease. In a recent phase II trial, the selective 5-HT6 receptor antagonist Lu AE58054 improved cognition in patients with moderate Alzheimer’s disease on stable donepezil (AchEI) treatment. In rats, the increased power of oscillatory activity in deep brain regions has been linked to increased cognitive performance. In the present study, we investigated the ability of Lu AE58054 alone and in combinationwith donepezil tomodulate neuronal rhythms in themedial prefrontal cortex (mPFC).Methods: Cortical activity was recorded using intracranial mPFC electrodes in urethane anesthetized male Sprague Dawley rats. Electrical stimulation was applied to the brainstem reticular formation (0.3 ms square pulses delivered over 6 s at 250 Hz, repeated every 100 s). The power of oscillatory activity was compared between treatments to quantify the strength of the oscillation. Results: Intravenous (i.v.) injection of 2 mg/kg Lu AE58054 alone produced a transient increase in electricallyinduced gamma power. Furthermore, Lu AE58054 (2 mg/kg, i.v.) significantly potentiated the effect of donepezil (0.3 mg/kg i.v.) on brain-stem stimulation induced gamma oscillations. At 1 mg/kg i.v., Lu AE58054 alone did not increase gamma power in the mPFC, but did significantly potentiate the effect of donepezil (0.3 mg/kg i.v.). Conclusions: Lu AE58054 (2 mg/ kg, i.v.) increases gamma oscillations in the mPFC by electrical stimulation, such network activity believed to play a role in higher cognitive function. In addition, we demonstrated an add-on effect of Lu AE58054 (1 and 2 mg/kg i.v.) to donepezil (0.3 mg/kg i.v.). Such potentiation may contribute to the procognitive effects of Lu AE58054 in Alzheimer’s disease.