Abstracts

RATIONALE: Enhancement of serotonin transmission by drugs such as fluoxetine has been found to exert an anticonvulsant action in several experimental seizure models. We are interested in identifying potential sites of action for this effect. In the present study, we examined the influence of intra-hippocampal fluoxetine on localized hippocampal seizures induced in vivo in physiologically normal adult rats. Localized seizure discharge (accompanied by wet dog shakes) was induced by focal application of the GABAA antagonist, bicuculline, or the GABAB agonist, baclofen, into dorsal hippocampus. METHODS: Experiments were conducted in awake, adult male Sprague-Dawley rats with bilateral intracerebral cannulae implanted in the dorsal hippocampus. Fluoxetine (7nmoles) or saline was infused bilaterally into the dorsal hippocampus fifteen minutes prior to infusion of the GABAA antagonist bicuculline (234pmoles) or the GABAB agonist baclofen (3.4 nmoles). RESULTS: Fluoxetine significantly increased the incidence and frequency of localized hippocampal seizure episodes induced by either bicuculline or baclofen but did not appear to decrease the threshold dose needed for inducing seizures. Fluoxetine did not evoke hippocampal seizure activity when given alone. CONCLUSIONS: Intra-hippocampal fluoxetine did not trigger hippocampal seizures when given alone, but consistently amplified the local seizure discharge triggered by a reduction in GABA inhibition. This amplification was observed with both postsynaptic (bicuculline) and presynaptic (baclofen) mechanisms of impairment of GABA transmission. These data suggest that serotonin may act to enhance focal hippocampal seizure discharge in vivo, possibly by inhibiting feedback control. Since we have previously found local hippocampal seizure discharge to elevate the threshold for generating limbic motor seizures from extra-hippocampal sites, the possibility that intra-hippocampal fluoxetine may augment this anticonvulsant mechanism will be explored.