The anticonvulsant action of fluoxetine in substantia nigra is dependent upon endogenous serotonin.

Fluoxetine, a serotonin (5-HT) reuptake inhibitor, has been documented to exert a protective action against convulsive seizures in animal models, when administered either systemically, or focally into substantia nigra. It is likely that the mechanism of anticonvulsant action of fluoxetine is due to an enhancement of endogenous 5-HT transmission. To evaluate this possibility in the context of the anticonvulsant action of intranigral fluoxetine, we examined the influence of 5-HT-mediated transmission in substantia nigra on seizure susceptibility in a rat model of focally evoked complex partial seizures. In addition to fluoxetine (3.5 nmol), we found that the directly acting 5-HT receptor agonists, 1-[3-(trifluoromethyl)phenyl]piperazine (TFMPP) (10 nmol), 1-(3-chlorophenyl)piperazine (m-CPP) (7.4 nmol), gepirone (70 nmol) and 2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide (8-OH-DPAT) (10 nmol), when microinjected bilaterally into substantia nigra, protected rats from limbic motor seizures evoked focally from area tempestas, an epileptogenic site in the deep rostral piriform cortex. This indicates that multiple 5-HT receptor subtypes in substantia nigra may contribute to seizure regulation. Consistent with this, the 5-HT antagonist, metergoline, partially reversed the anticonvulsant action of intranigral fluoxetine. Depletion of endogenous 5-HT, by pretreatment with parachlorophenylalanine (PCPA), completely prevented the anticonvulsant action of intranigral fluoxetine, without modifying the anticonvulsant effect of intranigral TFMPP. These findings support the proposal that the anticonvulsant action of fluoxetine in substantia nigra is due to an enhancement of the synaptic action of endogenous 5-HT in substantia nigra which in turn is mediated via multiple 5-HT receptors. Endogenous 5-HT transmission in substantia nigra is therefore capable of limiting the development and propagation of seizure activity generated in limbic circuits.