Fenfluramine (N-ethyl-α-methl-3-(trifluoromethyl)phenethylamine) is an anti-seizure medication (ASM) particularly effective in patients with
Dravet syndrome, a severe treatment-resistant epileptic
encephalopathy.
Fenfluramine acts not only as neuronal
serotonin (5-HT) releaser but also as a positive modulator of the
sigma-1 receptor (S1R). We here examined the modulatory activity of
Fenfluramine on the S1R-mediated anti-amnesic response in mice using combination analyses.
Fenfluramine and
Norfenfluramine, racemate and isomers, were combined with either the S1R agonist (PRE-084) or the S1R-acting neuro(active)
steroids,
pregnenolone sulfate (PREGS),
Dehydroepiandrosterone sulfate (DHEAS), or
progesterone. We report that
Fenfluramine racemate or (+)-
Fenfluramine, in the 0.1-1 mg/kg dose range, attenuated the
dizocilpine-induced learning deficits in spontaneous alternation and passive avoidance, and showed low-dose synergies in combination with
PRE-084. These effects were blocked by the S1R antagonist
NE-100.
Dehydroepiandrosterone sulfate or PREGS attenuated
dizocilpine-induced learning deficits in the 5-20 mg/kg dose range. Co-treatments at low dose between
steroids and
Fenfluramine or (+)-
Fenfluramine were synergistic.
Progesterone blocked
Fenfluramine effect. Finally,
Fenfluramine and (+)-
Fenfluramine effects were prevented by the
5-HT1A receptor antagonist
WAY-100635 or
5-HT2A antagonist RS-127445, but not by the 5-HT1B/1D antagonist
GR 127935 or the
5-HT2C antagonist SB 242084, confirming a 5-HT1A and
5-HT2A receptor involvement in the drug effect on memory. We therefore confirmed the positive modulation of
Fenfluramine racemate or dextroisomer on S1R and showed that, in physiological conditions, the drug potentiated the low dose effects of neuro(active)
steroids, endogenous S1R modulators. The latter are potent modulators of the excitatory/inhibitory balance in the brain, and their levels must be considered in the
antiepileptic action of
Fenfluramine.