Pasini A, Tortorella A, Gale K
Georgetown University, Department of Pharmacology, Washington, DC 20007, USA.
Brain Res. 1996 Jun 10;724(1):84-8. doi: 10.1016/0006-8993(96)00291-0.
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.
氟西汀是一种5-羟色胺（5-HT）再摄取抑制剂，有文献记载，当全身给药或局部注入黑质时，它在动物模型中对惊厥性癫痫发作具有保护作用。氟西汀的抗惊厥作用机制可能是由于内源性5-HT传递增强。为了在黑质内注射氟西汀的抗惊厥作用背景下评估这种可能性，我们在局灶性诱发复杂性部分性癫痫发作的大鼠模型中，研究了黑质中5-HT介导的传递对癫痫易感性的影响。除了氟西汀（3.5纳摩尔），我们还发现，直接作用的5-HT受体激动剂，1-[3-(三氟甲基)苯基]哌嗪（TFMPP）（10纳摩尔）、1-(3-氯苯基)哌嗪（间氯苯哌嗪，m-CPP）（7.4纳摩尔）、吉哌隆（70纳摩尔）和2-二丙基氨基-8-羟基-1,2,3,4-四氢萘氢溴酸盐（8-OH-DPAT）（10纳摩尔），当双侧微量注射到黑质时，可保护大鼠免受来自颞叶区（梨状皮质深吻侧的一个致痫部位）局灶性诱发的边缘性运动性癫痫发作。这表明黑质中的多种5-HT受体亚型可能参与癫痫发作的调节。与此一致的是，5-HT拮抗剂麦角林部分逆转了黑质内注射氟西汀的抗惊厥作用。通过对氯苯丙氨酸（PCPA）预处理耗尽内源性5-HT，完全阻止了黑质内注射氟西汀的抗惊厥作用，而不改变黑质内注射TFMPP的抗惊厥效果。这些发现支持了这样一种观点，即氟西汀在黑质中的抗惊厥作用是由于黑质内源性5-HT的突触作用增强，而这反过来又通过多种5-HT受体介导。因此，黑质内源性5-HT传递能够限制边缘环路中产生的癫痫活动的发展和传播。
