2011-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/642757摘要：在中樞神經系統中不同神經產生猝發性的動作電位稱之為「burst」，許多實驗顯示猝發性動作電位的產生可能代表大腦的某種特殊功能的發生，一般認為與增加神經傳遞物質的釋放有關；猝發性的動作電位也被認為在突觸可塑性及訊息處理上佔有很重要的地位，在海馬迴發生單一次猝發性的動作電位即可以造成長期突觸改變；另猝發性的動作電位也可能和癲癇的發生有關。在過去的實驗中，我們發現三類藥物在蝸牛神經元可以產生猝發性的動作電位，分別為(1) 中樞神經刺激藥物，例如 amphetamine (Chen and Tsai, 1997)、methamphetamine、3,4-methylenedioxymethamphetamine (MDMA, ecstasy) (Lin et al., 2010)、3,4-methylenedioxyamphetamine (MDA) (Chen and Tsai, 2007)；(2)局部麻醉藥物，例如 procaine (Lin and Tsai, 2005)、ropivacaine (Lin et al., 2007)；(3)治療阿茲海默藥物或是神經保護藥物，例如tacrine (Lin and Tsai, 2005)、memantine、paeonol (Chen et al., 2010)。這些藥物引起猝發性動作電位被證實和延遲整流型鉀離子電流的抑制效果有密切關係，此外實驗也顯示cyclic AMP-dependent protein kinase A (cAMP- PKA) 訊號傳遞途徑、 protein kinase C (PKC) 活性、phospholipase C (PLC) 活性，可以在蝸牛神經元上調控猝發性動作電位的產生。在初步實驗結果中，我們發現MDA和paeonol可以在新生大鼠的海馬迴的CA1神經元誘發猝發性動作電位，而且這些作用可能和TEA-sensitive 鉀電流有關。另外，memantine可以在蝸牛神經元上產生猝發性動作電位，文獻顯示memantine在大鼠的黑質緻密部神經元也會產生猝發性的動作電位 (Giustizieri et al., 2007)。本計畫目的在於探討：(1)這三類藥物在新生大鼠的海馬迴的CA1神經元或老鼠的黑質緻密部神經元是否都能產生誘發猝發性動作電位及其影響程度為何；(2) 測量這三類藥物在新生大鼠海馬迴的CA1神經元或老鼠黑質緻密部神經元對Na+電流、 Ca2+電流、fast-inactivating K+電流(IA)、Ca2+-activated K+電流(IK(Ca))、IKD 等電流改變的情況，了解猝發性動作電位產生的機制為何；(3) 確認PKA、PLC 、PKC等在訊號傳導路徑的角色為何。完成以上的實驗項目後可以幫助我們了解蝸牛神經元和哺乳動物神經元的關係，並協助我們利用電生理的技術了解上述藥物在哺乳動物身上作用的可能機制為何。<br> Abstract: Fast series of action potentials, typically referred to as “bursts,” are observed in various neuronal types in the central nervous system (Connors et al. 1982, Gray and McCormick 1996, Kandel and Spencer 1961, Llinas and Jahnsen 1982). Several lines of evidence indicate that bursts of firing have special importance in brain function. Bursts are reliably signaled because transmitter release is facilitated (Lisman, 1997). Besides, bursts appear to have a special role in synaptic plasticity and information processing. In the hippocampus, a single burst can produce long-term synaptic modifications (Huerta and Lisman, 1993, 1995). In addition, action potential bursts are associated with the cellular epileptic waveform (Jefferys, 1994, 1995).In our previous studies, we have found the following 3 categories of substances elicited action potential in the snail neurons of Achatina fulica. (1) CNS stimulants, such as amphetamine (Chen and Tsai, 1997), methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) (Lin et al., 2010) and 3,4-methylenedioxyamphetamine (MDA) (Chen and Tsai, 2007, Chen et al., 2006) . (2) Local anesthetics: procaine (Lin and Tsai, 2005), ropivacaine (Lin et al., 2007) (3) Anti-Alzheimer or neuroprotective drugs: tacrine (Lin and Tsai, 2005), memantine (unpublished data) and paeonol (one of the major components of Moutan cortex, the root bark of Paeonia suffruticosa Andrews, which has long been used for its antipyretic and anti-inflammatory effects in Traditional Chinese Medicine; it is also considered as a neuroprotective agen (Chen et al., 2010).The action potential bursts elicited by these substances are closely related to the inhibitory effects on the delayed rectifying K+ current (IKD). Further, cyclic AMP-dependent protein kinase A (cAMP- PKA) signaling pathway, protein kinase C (PKC) activity and phospholipase C (PLC) activity are able to modulate the action potential bursts in the snail neuron.In our preliminary studies, we have found that MDA and paeonol elicited action potential bursts in the hippocampal CA1 neurons of neonatal rats and these effects were related to a TEA-sensitive K+ currents. In literatures, memantine, which elicited action potential bursts in snail neurons, has been reported to elicited action potential bursts in substantia nigra pars compacta (SNc) neurons of rats.The aim of the proposed studies is to (1) test the effects of the 3 categories of substances on the action potential changes in mammalian hippocampal CA1 neurons and substantia nigra pars compacta (SNc) neurons, (2) test the effects of the 3 categories of substnaces on Na+ currents, Ca2+ currents, fast-inactivating K+ currents (IA), Ca2+-activated K+ currents (IK(Ca)), IKD and other ionic currents in mammalian hippocampal CA1 or substantia nigra pars compacta (SNc) neurons in order to understand the mechanism underlying the action potential bursts and (3) elucidate the role of PKA, PLC and PKC signaling pathway in above mentioned -induced changes in mammalian neurons.The completion of the study will help us understand the relationship between the results from snail neurons and mammalian neurons and help us understand how the above mentioned drugs affect electrophysiological behaviors on the mammalian neurons.動作電位蝸牛神經元MemantineAction PotentialSnail NeuronMemantine