Endogenous serotonin inhibits epileptiform activity in rat hippocampal CA1 neurons via 5-hydroxytryptamine1A receptor activation

doi:10.1016/S0306-4522(98)00106-7

Neuroscience

Volume 86, Issue 3, 8 June 1998, Pages 729-737

https://doi.org/10.1016/S0306-4522(98)00106-7 Get rights and content

Abstract

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 reuptake 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.

Section snippets

Experimental procedures

Male Sprague–Dawley rats (125–180 g) were decapitated and the brains rapidly removed from the skull. Coronal slices nominally 500 μm-thick were cut and the appropriate slices were placed in a beaker of artificial cerebrospinal fluid (ACSF). The ACSF was bubbled continuously with 95% O₂/5% CO₂ to maintain the pH at 7.3–7.5. The composition of the ACSF solution was (in mM): NaCl 117, KCl 4.7, CaCl₂ 2.5, MgCl₂ 1.2, NaHCO₃ 25, NaH₂PO₄ 1.2 and glucose 11.

The slices were kept at room temperature for at

Effect of serotonin on synaptic transmission

As shown in Fig. 1A, superfusion of 5-HT reversibly decreased the slope of fEPSP in a concentration-dependent manner. At concentrations of 10 and 30 μM, 5-HT suppressed the slope of fEPSP by an average of 24.5±3.6% and 53.5±1.9% (n=6, P<0.001), respectively.

5-HT_1A receptors on CA1 pyramidal neurons are coupled via a G protein to K⁺ channels which could be blocked by extracellular Ba²⁺ or internal Cs⁺.[1]Intracellular recordings were made using CsCl-filled microelectrodes and resting membrane

Discussion

The present study demonstrates that 5-HT can inhibit the picrotoxin-induced epileptiform activity in hippocampal CA1 neurons. This inhibition was mimicked by the selective 5-HT_1A agonist, 8-OH-DPAT and was blocked by the selective 5-HT_1A antagonist, NAN-190. In contrast, 5-HT_1B and 5-HT_1D agonists had no effect, and 5-HT still inhibited the epileptiform activity when the 5-HT₂ receptor was blocked by ketanserin. These results suggest that the inhibition of epileptiform activity by 5-HT is most

Conclusion

The data presented here demonstrate that fluoxetine is an effective antiepileptic agent in an in vitro experimental model of epilepsy. The parallel attenuation of the antiepileptic effects of fluoxetine and 5-HT by NAN-190 indicates that antiepileptic action of fluoxetine depends upon the enhancement of endogenous 5-HT transmission. This study suggests a role played by 5-HT as a modulator of convulsive seizures in the hippocampus.