ENHANCEMENT OF THE ANTICONVULSANT EFFECT OF FLUOXETINE FOLLOWING BLOCKADE OF 5-HT1A RECEPTORS

Serotonin reuptake inhibitors, such as fluoxetine, have been shown to exert anticonvulsant effects in several animal models of epilepsy. In view of recent studies showing that 5-HT1A receptor antagonists (somat odendritic autoreceptor antagonists) enhance the increase in extracell ular 5-hydroxytryptamine (5-HT, serotonin) produced by serotonin reupt ake inhibitors, it was of interest to determine if these antagonists a lso enhance the anticonvulsant effect of fluoxetine in Genetically Epi lepsy-Prone Rats (GEPRs). The 5-HT,, receptor antagonists(-)-pindolol and LY 206130 l-4-yloxy]-3-[cyclohexylamino]-2-propanol-maleate) were examined in the present study and both enhanced the anticonvulsant act ion of fluoxetine in severe seizure GEPRs (GEPR-9s). The latter effect of LY 206130 was found to be dose-and 5-HT-dependent. These findings provide further evidence that the increase in extracellular serotonin observed after administering fluoxetine in combination with a 5-HT,, r eceptor antagonist is physiologically important and that the anticonvu lsant effect of fluoxetine in the GEPR is mediated through an increase in extracellular 5-HT. (C) 1997 Elsevier Science B.V.