Summary: Purpose: Fluoxetine is a selective serotonin [5-hydroxytryptamine (5-HT)] reuptake inhibitor (SSRI) commonly used to treat depression. Some uncontrolled clinical studies have reported that SSRIs increase seizures, but animal experiments with evoked-seizure models have suggested that SSRIs at therapeutic doses decrease seizure susceptibility. We tested the hypothesis that fluoxetine and trifluoromethylphenylpiperazine (TFMPP, a nonselective 5-HT–receptor agonist) reduce the frequency of spontaneous motor seizures in pilocarpine-treated rats.
Methods: Fluoxetine (20 mg/kg) and TFMPP (5 mg/kg) were administered to rats with pilocarpine-induced epilepsy. Phenobarbital (PB; 10 mg/kg) was a positive control, and saline (i.e., 0.5 ml) controlled for the injection protocol. Each rat received each treatment (intraperitoneally) once per day for 5 consecutive days with 1 week between treatments. Rats were continuously video-monitored for the last 72 h of each treatment.
Results: When compared with saline over the entire 72-h observation period, PB and fluoxetine treatment, but not TFMPP, reduced the spontaneous-seizure rate. Plots of magnitude of the drug effect as a function of seizure frequency after saline treatment revealed larger drug effects for fluoxetine and PB in the rats with the highest control seizure rate. When the data from the five rats with the highest seizure frequency in saline were analyzed for the first 6 h after treatment, TFMPP also significantly reduced seizure frequency.
Conclusions: Animal models with spontaneous seizures can be used to screen potential antiepileptic drugs, and fluoxetine and TFMPP reduce spontaneous seizures in the pilocarpine model of temporal lobe epilepsy.