Reversal by flunarizine of the decrease in hippocampal acetylcholine release in pentylenetetrazole-kindled rats

Abstract

The aim of our study was to evaluate the effect of the non-selective calcium antagonist flunarizine on hippocampal acetylcholine (ACh) release with the microdialysis technique in freely moving rats after long-term concomitant administration of pentylenetetrazole (PTZ) in comparison with rats treated long-term with PTZ (kindled animals). The basal extracellular concentration of ACh in the hippocampus of rats treated with PTZ alone was significantly reduced relative to that of vehicle-treated rats (2.04 ± 0.2 vs 3.94 ± 0.3 pmol per 20-min sample; P < 0.01). Administration of flunarizine (7.5 mg/kg i.p.) before each PTZ injection prevented this decrease in basal ACh output (3.75 ± 0.4 pmol per 20-min sample). On the contrary, the expression of PTZ-induced kindling was not prevented by administration of flunarizine. The specific antagonistic effect of flunarizine on the kindling-induced decrease in hippocampal ACh release is shared by the selective antagonist of the L-type calcium channel, nifedipine, but not by the dopamine D 2 antagonist, (−)-sulpiride, suggesting that the decrease in Ca 2+ overload by a blockade of the L-type calcium channel may be responsible for the protective action on cholinergic neurons exerted by flunarizine. These data also suggest a potential therapeutic role for flunarizine in counteracting impairment of hippocampal cholinergic activity.