Effects of Fluoxetine and TFMPP on Spontaneous Seizures in Rats with Pilocarpine‐induced Epilepsy

Abstract

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.

Long-term decrease in calbindin-D28K expression in the hippocampus of epileptic rats following pilocarpine-induced status epilepticus

“…However, the 1-and 2-year animals were monitored for two separate time periods and had a mean seizure frequency of 3.6 seizures per day. Although these seizure frequencies are only estimates of the actual seizure frequency over long time periods, they are comparable with the observations from other major laboratories using the pilocarpine model of AE: Pitkanen and co-workers have reported a frequency of 2.6 seizures per day (Goffin et al, 2007); Holmes and co-workers have reported 5.2 seizures per 42 h (Cha et al, 2004), and Dudek and coworkers have reported 6.9 seizures per day (Hernandez et al, 2002). Seizure durations are relatively short (35-50 s) in the pilocarpine model and animals have been shown to tolerate several brief seizures per day without significant behavioral effects (Goffin et al, 2007).…”

“…One animal demonstrated a cluster of high seizure frequencies and skewed the data to reflect a higher mean seizure frequency for this group. For long-term studies, animals were monitored two times at 12 and 24 months following SE and were found to have a mean seizure frequency of 0.9 ± 0.4 seizures per 6 h. The seizure frequencies observed in this study were comparable to those seen in other studies employing the pilocarpine model (Goffin et al, 2007;Hernandez et al, 2002;Cha et al, 2004;Wallace et al, 2003).…”

Chronic Stress Decreases the Number of Parvalbumin-Immunoreactive Interneurons in the Hippocampus: Prevention by Treatment with a Substance P Receptor (NK1) Antagonist

“…Experimental serotonin treatment hyperpolarizes both pyramidal and granule cells, with the effect possibly occurring directly on principal cells, or mediated by excitation of interneurons (Freund and Buzsaki, 1996). Accordingly, treatment with the SSRI fluoxetine can lead to a general inhibition of hippocampal network activity and, indeed, animal experiments suggest that SSRIs at therapeutic doses are able to decrease seizure susceptibility of the hippocampus (Wada et al, 1995;Hernandez et al, 2002). Thus, in our case, fluoxetine treatment may provide sufficient counterbalancing inhibition to the overexcited hippocampal circuitry, and thereby prevent the compensatory downregulation of parvalbumin to enhance GABA release.…”

Serotonin Depletion Does not Modify the Short-Term Brain Hypometabolism and Hippocampal Neurodegeneration Induced by the Lithium–Pilocarpine Model of Status Epilepticus in Rats

“…Thus, antidepressant drugs which increase the availability of monoamine neurotransmitters in the synaptic cleft have been associated both with proconvulsant and anticonvulsant effects (Jobe and Browning 2005;Hernandez et al 2002).…”