Acetylcholine mediates the effects of fenfluramine on dentate granule cell excitability in the rat.

Reactivity of the hippocampal system to stimulation of its main afferent, the perforant path, was studied in the intact, anesthetized rat. Parentral administration of fenfluramine caused a marked elevation of population spike response to perforant path stimulation. An injection of atropine before, but not after fenfluramine, blocked the potentiating effect of fenfluramine. The atropine blockade was dose-dependent and not mimicked by the peripheral muscarinic receptor antagonist methyl atropine. This effect of fenfluramine was also prevented by an injection of the 5-HT receptor antagonist spiperone. The effect of fenfluramine was mimicked by the anticholinesterase physostigmine, which was not affected by spiperone pretreatment. It is proposed that release of 5-HT (5-hydroxytryptamine) by fenfluramine potentiates reactivity to afferent stimulation by interacting with cholinergic terminals in the hippocampus.