Solntseva_2014_Brain.Res.Bull_106C_56

Donepezil is a potent acetylcholinesterase inhibitor used for the treatment of Alzheimer's disease (AD). Additional therapeutically relevant target for donepezil is sigma1 receptor (Sig1-R). Beta-amyloid peptide (Abeta) is believed to contribute to the pathogenesis of AD. In our previous work (Kapai et al., 2012), we have shown that donepezil antagonizes the suppressive action of Abeta(1-42) on long-term potentiation (LTP) in rat hippocampal slices. The purpose of the present study was to determine whether Sig1-R is involved into the mechanisms of donepezil action. For this purpose, we have tested whether agonist of Sig1-R PRE-084 mimics, and antagonist of Sig1-R haloperidol abolishes the effect of donepezil. Population spikes (PSs) were recorded from the pyramidal layer of the CA1 region of rat hippocampal slices. Drugs were applied by addition to the perfusate starting 15min before and ending 5min after the tetanus. In the control group, the amplitude of PS 30min post-tetanus reached 153+/-10%. Abeta (200nM) markedly suppressed the LTP magnitude or even caused the suppression of baseline PS (82+/-8%, P<0.001). This suppression of LTP could be markedly prevented when 1muM donepezil was co-administered with Abeta (136+/-11%, P<0.05). Further, we co-administered three substances: Abeta, donepezil and 0.5muM haloperidol and have found that haloperidol antagonized the stimulating effect of donepezil on LTP (92+/-6%, P<0.05). Agonist of Sig1-R PRE-084 (0.1-10muM) enhanced control LTP and abolished the inhibitory effect of Abeta on LTP in a concentration-dependent manner. The amplitude of PS 30min post-tetanus reached 183+/-7% (P<0.01) for 10muM PRE-084. The results suggest that activation of Sig1-R is involved into the mechanisms of donepezil-induced rescue of hippocampal LTP impaired by Abeta.