博士 / 國立成功大學 / 基礎醫學研究所 / 87 / Abstract
Serotonin (5-hydroxytryptamine, 5-HT) is an important neurotransmitter in the mammalian peripheral and central nervous systems. In the brain, most 5-HT-containing cells are located in the raphe nuclei which project to various brain regions including the hippocampus, amygdala, thalamus, prefrontal cortex and cerebellum. The hippocampal CA1 region is rich in 5-HT-containing terminals and expresses high density 5-HT1A receptors leads to a membrane hyperpolarization and inhibition of cell firing mediated via an increase in K+ conductance. Subsequently, various theories arose linking abnormalities of 5-HT function to the development of a number of psychiatric disorders, particularly schizophrenia and depression. Psychotherapeutic drugs are now available that are effective in depression, anxiety disorder and schizophrenia; some of these drugs have potent, and in some cases selective, effects on serotonin neurons in brain.
There has been increasing evidence showing that serotonergic neurotransmission modulated certain types of clinically as well as experimentally-induced seizures including systemically-administered pentylenetetrazole, neocortical and hippocampal kindling, and injections of bicuculline into the area tempestas. In genetically epilepsy-prone rats (GEPRs), an animal model of inherited generalized tonic-clonic epilepsy, the severity of audiogenic seizures was inversely related to brain 5-HT levels. Drugs which increased functional extracellular 5-HT decreased convulsion intensity whereas depletion of brain 5-HT by intracerebroventricular injection of 5,7-dihydroxytryptamine exacerbated audiogenic seizures. Furthermore, Statinick et al. recently reported that the 5-HT1A receptor sites were decreased in the hippocampus of GEPRS when compared to nonepileptic control rats.
In the present study, we tested the antiepileptic activity of 5-HT by using three different kinds of animal models, which includes in vitro picrotoxin induced model of epilepsy, kainate induce in vivo animal model and hypoxic ischemic animal model. We also addressed the questions of whether 5-HT1A receptor agonist 8-OH-DPAT or serotonin re-uptake blocker fluoxetine exerts antiepileptic actions and neuroprotection effects on kainate & hypoxic ischemic animal models.
The picrotoxin induce epiletiform in hippocampus can be reduced by administrated of either 5-HT1A receptor agonist or 5-HT re-uptake blocker, These results suggest that endogenous serotonin can provide an antiepileptic effect in hippocampus which in turn is mediated by 5-HT1A receptor. Endogenous serotonin transmission in the hippocampus is therefore capable of limiting the development and propagation of seizure activity.
Intraperitoneal injection of kainate resulted in repeated convulsive seizures with high mortality rate, severe cell death in hippocampal CA1 area and cause spatial memory deficit. The seizure severity and mortality rate was reduced by fluoxetine. Kainate induced cell death in hippocampus CA1 neurons was decreased by 8-OH-DPAT. It also attenuated the epileptiform activity and this effect was reversed by a selective 5-HT1A receptor antagonist NAN-190. Kainate treatment caused deficit in the performance of Morris water maze which could be rescued by fluoxetine. These results provide the first evidence that activation of 5-HT1A receptors protects hippocampus against kainate-induced neurotoxicity.
Neonatal hypoxia treatment resulted in increasing of spontaneous epiletiform activity, severe neural damage and deficient in formation of long-term potentiation in the hippocampus CA1 area. In addition, hypoxic rats were deficient in spatial memory, which may due to the deficient in ability of consolidation to transfer the short-term memory to long-term memory. The inhibition effect of serotonin changed in a time dependent manner, which reached its peak value at the 4 weeks after the hypoxia treatment and prolonged for more than 4 weeks. The hypoxia induced spontaneous epiletiform can be reduced by administration of serotonin or uptake blocker, fluoxetine. This inhibition effect is mediated by 5-HT1A or 5-HT2 receptor activation. Co-treatment of 5-HT1A receptor agonist in hypoxic animals can attenuate the hypoxic induced neural damage and spatial memory deficit. The hypoxic ischemic tolerance treatment can also exerts an protection effect on hypoxia induced neural damage and spatial memory deficit, it can be completely blocked by adenosine A1 receptor antagonist pretreatment. These results implicates that hypoxic ischemic treated in early infancy may have severe long-lasting consequences later in life and it can be eliminated by 5-HT1A receptor agonist in the early onset stage.
| Identifer | oai:union.ndltd.org:TW/087NCKU0325002 |
| Date | January 1999 |
| Creators | Lu, Kwok-Tung, 呂國棟 |
| Contributors | Po-Wu Gean,, 簡伯武 |
| Source Sets | National Digital Library of Theses and Dissertations in Taiwan |
| Language | zh-TW |
| Detected Language | English |
| Type | 學位論文 ; thesis |
| Format | 160 |
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