ROLE OF HIPPOCAMPAL SEROTONERGIC NEURONS IN ISCHEMIC NEURONAL DEATH

To clarify the serotonergic mechanisms involved in the protection agai nst ischemic neuronal damage, ZD-211 (citalopram HBr), a serotonin (5- hydroxytryptamine; 5-HT) re-uptake inhibitor, or buspirone, a 5-HT1A a gonist, was locally administered into the hippocampus of gerbils. Addi tionally, to clarify the role of the 5-HT nervous system in the hippoc ampus during ischemic neuronal damage, animals were subjected to the l ocal administration of 5,7-dihydroxytryptamine (5,7-DHT), a 5-HT neuro toxin, before ischemia challenge. Gerbils received intrahippocampal ad ministration of ZD-211 (200 nmol/animal) or buspirone (20 mnol/animal) before 5-min ischemia, 5,7-DHT was intrahippocampally administered 7 days before a 2-min non-lethal ischemia challenge. In vehicle-treated animals subjected to 5 min of ischemia, almost all hippocampal CA1 pyr amidal neurons were lost. The treatment with ZD-211 or buspirone showe d a significant protective effect, and the number of neurons was signi ficantly increased compared to vehicle-treated animals. Pretreatment w ith NAN-190, a 5-HT1A antagonist, completely abolished the protective effect of ZD-211 or buspirone. In the 5,7-DHT-treated animals, the num ber of neurons was significantly reduced following 2 min of ischemia c ompared to vehicle-treated animals in which this period of ischemia is non-lethal. Thus, intrahippocampal treatment with ZD-211 or buspirone can protect neuronal damage following transient ischemia in gerbils. These effects of ZD-211 and buspirone were mediated through the 5-HT1A receptor in the hippocampus. Furthermore, the destruction of the 5-HT nervous system in the hippocampus aggravated ischemic neuronal damage . Therefore, this study showed that the enhanced activity of the 5-HT nervous system in the hippocampus may protect against neuronal damage following cerebral ischemia.