Abstracts

Rationale: Cerebral insults that constitute risk factors for the subsequent acquisition of mesial temporal lobe epilepsy (MTLE) are commonly associated with psychiatric disorders. Since selective serotonin reuptake inhibitor (SSRI) antidepressant drugs are generally prescribed to patients for the management of these psychiatric symptoms, it is essential to consider how these SSRIs might influence the epileptogenic processes which may take place following these cerebral insults. Evidence has demonstrated chronic SSRI treatment to facilitate epileptogenesis in rat models of MTLE, but the mechanism underlying this pro-epileptogenic outcome of SSRI treatment is yet to be identified. Since 5-HT2A receptor (2AR) signalling has been suggested to contribute to epileptogenesis, this study was designed to establish whether 2AR signalling is a mechanism by which SSRI treatment induces pro-epileptogenic consequences.  Methods: The effect of continuous fluoxetine treatment (10mg/kg/day for 28 days) versus vehicle treatment on amygdala kindling outcomes was examined in male homozygous 2AR-knockout mice and their littermate wildtype controls (n > 6/group). Seizure thresholds, kindling rates and seizure durations were compared between treatment groups in the wildtype mice and the 2AR-knockout mice. Results: Fluoxetine treatment appeared to accelerate kindling epileptogenesis in wildtype mice, in that fewer stimulations were required to induce Class V seizures in fluoxetine-treated mice compared with vehicle-treated controls. This effect approached statistical significance (p = 0.07). In the 2AR-knockout mice, fluoxetine treatment did not significantly accelerate kindling epileptogenesis when compared with their vehicle-treated controls (p = 0.21). No differences in seizure thresholds and seizure durations were observed between treatments in either wildtype mice or 2AR-knockout mice (p > 0.05).  Conclusions: We have replicated previous findings, in demonstrating that chronic treatment with fluoxetine – the prototypical SSRI – promotes epileptogenesis in mice. Our data suggests that this pro-epileptogenic consequence of chronic fluoxetine treatment is mediated by 2AR signalling. These preliminary findings emphasise the adverse consequences for epilepsy potentially associated with SSRI treatment and suggest a role for 2AR signalling in these adverse outcomes.  Funding: NHMRC Grant