(Sourbron J et al. 2017). Fenfluramine (FA) is known to affect serotonin (5-HT) levels in the brain, but there are several different 5-HT receptor subtypes that may be involved in FA’s mechanism of action. This study explored the anti-epileptic mechanisms of FA in SCN1Lab-mutant zebrafish by selectively targeting each of the receptors believed to be involved in the anti-seizure action of FA with compounds known to inhibit or stimulate the receptors, and examining whether the different compounds diminished the anti-epileptic effects of FA. The hypothesis was that if the compound interfered with FA’s anti-epileptic effects, then that particular receptor was likely involved in FA’s mechanism of action.
Zebrafish larvae were treated with FA and several compounds that agonize (stimulate) and antagonize (inhibit) different 5-HT and sigma receptors. Three tests were performed: movement (seizure-like activity), brain activity (similar to EEG recordings), and post-experimental measurement of neurotransmitters in the heads of the zebrafish larvae. Compounds known to affect receptor subtypes 5-HT1D, 5-HT2A, 5-HT2C, Beta 2, Sigma 1, and Sigma 2 were studied. If significant change in epileptiform activity was found for a compound, the authors then studied how the zebrafish larvae responded to treatment with both the compound and FA, the compound alone, and FA alone.
The authors found that antagonists (inhibitors) of 5-HT1D and 5-HT2C receptor subtypes were able to counteract FA’s inhibition of seizures and brain epileptiform activity, suggesting that FA’s mechanism of action may involve agonizing (stimulating) 5-HT1D and 5-HT2C receptors. Conversely, a 5-HT2A antagonist (ketanserin) was not able to counteract FA’s effect. In additon, the Sigma 1 agonist was unable to counteract the anti-epileptiform activity of FA in the movement test but did counteract the effects in brain recordings, suggesting this receptor’s involvement in FA’s action. The concentration of some neurotransmitters (dopamine and noradrenaline) changed after FA treatment, but GABA and glutamate levels did not.