Endogenous serotonin inhibits epileptiform activity in rat hippocampal CA1 neurons via 5-hydroxytryptamine(1A) receptor activation

The modulatory effects of endogenous serotonin on the synaptic transmission and epileptiform activity were studied in the rat hippocampus with the use of extracellular and intracellular recording techniques. Field excitatory postsynaptic potential was reversibly depressed by serotonin in a concentration-dependent manner. Intracellular recordings revealed that serotonin-mediated synaptic depression was unaffected by extracellular Ba²⁺ or intracellular application of Cs⁺ while the postsynaptic hyperpolarizing effect was completely blocked. Epileptiform activity induced by picrotoxin (50 μM), a GABA(A) receptor antagonist, was also dose-dependently suppressed by serotonin. The antiepileptic effect was mimicked by 5- hydroxytryptamine(1A) agonist and was blocked by 5-hydroxytryptamine(1A) antagonists. 5-Hydroxytryptamine₂ antagonist had no effect on the modulation. Similarly, fluoxetine, a selective serotonin re-uptake blocker, potently inhibited the epileptiform activity and this effect was blocked by 5-hydroxytryptamine(1A) receptor antagonist. Depletion of endogenous serotonin by pretreating the slices with p-chloroamphetamine completely prevented the antiepileptic action of fluoxetine, without modifying the action of serotonin in the same cells. These results suggest that the antiepileptic action of fluoxetine is due to an enhancement of endogenous serotonin which in turn is mediated by 5-hydroxytryptamine(1A) receptor. Endogenous serotonin transmission in the hippocampus is therefore capable of limiting the development and propagation of seizure activity.