Comparison of the effects of the stereoisomers of fenfluramine on the acetylcholine content of rat striatum, hippocampus and nucleus accumbens

The (+)‐ and (‐)‐ isomeric forms of fenfluramine were compared for their effects on rat brain area acetylcholine (ACh) content. The drugs showed similar patterns in increasing ACh content in the accumbens and hippocampus and in being ineffective in the brainstem. The actions differed in the striatum where the (+)‐form markedly increased ACh content while the (‐)‐form produced no change. Both isomer‐induced increases in ACh in the accumbens were prevented when 5‐HT synthesis was blocked by p‐chlorophenylalanine, thus denoting 5‐hydroxytryptaminergic mediation of these effects. In striatum, the increase in ACh induced by (+)‐fenfluramine was summated with the increase in ACh induced by dopamine receptor stimulation with apomorphine and was not prevented by dopamine receptor blockade with pimozide. On the other hand, apomorphine's effect was blocked by (‐)‐fenfluramine while pimozide pretreatment unmasked an increase in ACh induced by (‐)‐fenfluramine. The results favour the notion that there is a population of cholinergic neurons intrinsic to the striatum which is under inhibitory 5‐HT regulation and independent of inhibitory dopamine regulation.