本研究藉著側中膈、腹中膈及二者聯合的破壞，對大白鼠活動及觸覺驚嚇反應的影響 ，來探討側中膈及腹中膈，在中膈破壞後的過度反應性現象中，所扮演的角色。 結果發現，側中膈破壞組的刻板行為和活動時間增加，而活動距離則與控制組無異。 由此顯示，側中膈破壞組常作多而短的移動，而此反應持續性高，與以前研究結果相 符。 不論是側中膈、腹中膈或二者聯合的破壞，對大白鼠在開放式場地的中央區域之活動 量均顯著減少，尤其是腹中膈破壞組效果更大。此項結果顯示中膈破壞對壓力反應的 減小的確有影響。而在開放式場地行為的活動和探索行為指標－鑽洞及前腿站立寺， 中膈此二部位的破壞，均使之減少，但差異未達顯著。 在驚嚇反應－時間過程中，側中膈破壞組的反應增強，有習慣化傾向。而在測、腹中 膈聯合破壞的反應強度，出現倒U 的傾向。由此可知，先前文獻研究發現之分歧，可 能是由於實驗解剖位置及測量時間過程不同所致。

兒茶酚胺類神經傳遞系統被認為與包括記憶學習等行為功能有很重要的關連，在記憶多元化理論的假設下，該神經系統與其它者對於特定記憶學習行為應有再確認之必要。過去對於空間性記憶的研究，其相關支持證據所依據之實驗操弄泰半集中在海馬迴系統上。但仍有部份研究指出大腦中的其他區域可能同樣與一般記憶的運作有密切的關連。特別是兒茶酚胺系統所在之紋狀總體組織部位（包括尾狀核與阿控博核），vP A僅與感覺接受、運動反應及增強作用等機制有關外，同時可能也扮演影響記憶表現的重要因子。本研究使用慾求性的八角迷津為工具，藉其地點學習與反應學習這兩種不同的迷津作業，及利用兒茶酚胺類的藥物或神經毒素，探討相關的記憶習得與記憶保持歷程所造成的影響。實驗的操弄包括：(1) 迷津作業之地點學習與反應學習以探討這兩種記憶之行為機制。(2) 記憶習得與記憶保持階段以瞭解這兩種迷津作業所引發記憶之全部歷程。(3) 中樞（阿控博核或尾狀核）神經毒素之破壞以及周邊藥物注射以確認兒茶酚胺類藥物對於記憶之神經藥理機制。本研究分為兩大實驗進行，實驗一以地點學習為主，實驗二以反應學習為主。實驗結果可以簡單歸納如下：(1) 兩 種學習作業的記憶策略有不同的習得歷程及需要不同的處理訊息。(2) 在迷津學習前用神經毒素 6-OHDA 破壞尾狀核或阿控博核，皆會影響地點記憶的習得，但對於反應記憶的習得，則需要同時破壞尾狀核及阿控博核才有類似的干擾效果。(3) 相對於神經毒素 6-OHDA的干擾效果，DSP-4皆不影響地點學習與反應學習的習得歷程。(4) 在記憶保持階段中，周邊注射兒茶酚胺類藥物 d-amphetamine、haloperidol 與 propranolol均會干擾地點記憶的提取，但卻不影響反應記憶的提取表現。(5) 於地點記憶與反應記憶習得後，給予尾狀核加阿控博核的雙側 6-OHDA 注射均不影響這兩種記憶的提取表現。實驗結果顯示兒茶酚胺類神經傳導系統對於記憶功能具有明顯的影響，其中紋狀體扮演了相當重要的角色。相對於不影響記憶提取之歷程，紋狀體的破壞對記憶習得歷程有阻滯之效果，其內部之尾狀核與阿控博核分別依不同之迷津作業具有相異之效果，且多巴胺系統較正腎上腺素系統明顯的參與了影響效果，這些結果顯示兒茶酚胺類神經傳導系統與記憶表現有密切的關連。 / Catecholamine (CA) neurotransmission systems are critically involved in the control of many behavioral functions including learning and memory. The role of CA in mediating learning and memory is recently focused on the basis of multiple memory hypothesis. In addition to the previous finding of spatial memory relevant to the hippocampal areas, the striatum containing the caudate nucleus and the nucleus of accumbens is thought to be important for executing the learning and memory function. By the use of radial arm maze (RAM), the present study examined the effects of CA related neurotoxins and drugs on the acquisition and retention stages of both place and response tasks. Two major parts of experiments were designed to reveal the neurobehavioral mechanisms for the place and response tasks of RAM. Food-deprivated rats were trained to enter the arms baited with chocolate in the eight-arm maze. Specific four arms were baited for each rat in the place task, while randomly selected four arms each cued with a piece of sand paper on the arm entrance were baited for the rat in the response task.The results can be summarized as followings. (1) Differen behavioral processes were shown in performing the place and response tasks. (2) The acquisition deficits were significantly produced by 6-hydroxydopamine (6-OHDA) lesion on either caudate or accumbens for the place task, whereas the acquisition of response task was only impaired by 6-OHDA lesions of both caudate and accumbens together. (3) In contrast to 6-OHDA, adrenergic neurotoxin DSP-4 did not significantly affect subjects to acquire either task. (4) During the retention stage, the performance of place task was significantly disrupted by d-amphetamine, haloperidol, or propranolol. However, this was not the case for the retrieval of response task. (5) Once acquired, neither place nor response task performamce could be influenced by 6-OHDA simultaneously administered on the caudate and accumbens areas.Taken together, these data collected from RAM support the idea that the striatal CA is essential for the leraning and memory. Shift of the CA neurotransmission function induced by either 6-OHDA lesions or relevant drugs can disrupt the RAM behavior, which impairment to be detectable is depended on the learning task itself as well as the time of a specific task being leraned.

「風險決策」行為非常普遍的存在於吾人之日常生活中，而選項所帶來的風險和獎勵是吾人進行決策時的重要考量因素。風險選擇的適當與否，對於個體的生存扮演著相當重要的角色。在以往的文獻中，對於決策的行為歷程已有所關注及探討，但對於風險選擇行為的神經生理機制迄今未明。本研究藉由大白鼠於T字迷津中，選擇確定之低酬賞或高不確定性之高酬賞的行為表現，進行風險選擇行為的探討。本研究中以兩項主要實驗，探討風險選擇行為之神經行為機制。實驗1a中，確定之低酬賞端固定呈現1顆食物粒，而高不確定性之高酬賞端則同時操弄酬賞物機率(50%、25%及12.5%)以及酬賞物的量(2、4及8顆)，以系統性地檢驗期望值(0.5、1和2)於此風險選擇行為中扮演的角色。行為結果顯示當風險較低時，大白鼠會選擇高不確定性之高酬賞端；而風險較高時，則轉為選擇確定之低酬賞端。實驗1b中，系統性地施打不同劑量之安非他命，探討多巴胺系統在此風險選擇行為中之機制。實驗結果顯示施打安非他命後，大白鼠表現出相對地追求風險之行為，亦即選擇高不確定之高酬賞端之比例顯著高於控制組。實驗2中，藉由毀除大腦特定部位(依核、背外側之紋狀體、眶前額皮質、內側之前額皮質)，檢驗風險選擇行為之神經基礎。毀除後之結果顯示，僅有依核受到毀除之大白鼠表現出相對地趨避風險之選擇行為。綜合以上結果，本研究建立之風險選擇行為與多巴胺有關，而依核在此行為歷程中扮演重要的調節角色。 / Many decisions people make every day involve uncertainty where both risks and rewards associated with each option need to be considered. Behavioral performance associated to risk-based choice appears wildly over the lifespan, and the fitness of risky choice behavior plays an important role in individual survival. Despite a growing body of research has focused to investigate the neurobiology of decision making, little is known about the neurobehavioral mechanisms of risky choice behavior. Based on a pilot work, this study used a T-maze to study decision under a probability-based risk in the rat. The subject was assessed on making choice to obtain either a large reward associated with risk of non-reward “empty” or a small reward ensured for every entry. Two experiments were conducted in this project to investigate neurobehavioral mechanisms of probabilistic risky choice behavior. In Experiment 1a, probabilistic risky choice behavior was systemically assessed under three expected values (0.5, 1.0, and 2.0) by manipulating the probabilities of reward presence (50%, 25%, and 12.5%) and the reward magnitude (2, 4, or 8 pellets) in the probabilistic high reward (PHR) arm. Behavioral data showed that the subject chose the probabilistic high reward in a lower risk condition but would shift to the choice of certain low reward (CLR) as the risk is increased. In Experiment 1b, the dose effects of amphetamine on this probabilistic risky choice task was tested to verify whether the dopaminergic mechanism was involved. Amphetamine, presumably activating brain dopamine systems, produced a relatively risk-seeking effect on the present behavioral task. In Experiment 2, the excitoneurotoxic lesion was conducted in the nucleus accumbens, the dorsolateral striatum, the orbitofrontal cortex, and the medial prefrontal cortex to examine the neural substrates for this probabilistic risky choice behavior. The results showed that the lesion of the nucleus accumbens significantly produced a relatively risk-averse effect on the present behavioral task, as compared to the lesions made on the other three brain areas. In conclusion, the probabilistic risky choice behavior established in the present study is dopamine dependent. And, the nucleus accumbens plays a major role of mediating this behavioral processing.

制約場地偏好行為為研究藥物成癮的常用模式之一，對於其行為表現及再復發的神經機制，多巴胺系統佔有舉足輕重的地位。而大腦神經滋養因子(BDNF)與多巴胺系統密切相關，影響其神經元可塑性。故本研究以BDNF來作為目標分子，進行一系列的實驗探討制約場地偏好的神經機制。實驗一A以不同劑量安非他命建立制約場地偏好行為，並分析其BDNF mRNA的表現量。實驗結果顯示1 mg/kg安非他命能夠引發制約場地偏好行為，但是對於內側前額葉、紋狀體、依核、背側海馬迴、杏仁核等五個區塊的BDNF mRNA無顯著的影響效果。實驗一B再次確認實驗一A的結果，顯示俱有安非他命引發制約場地偏好行為的受試，其大腦五個區塊BDNF mRNA沒有顯著的變化。實驗二探測制約場地偏好行為再復發對於相同的五個區塊BDNF mRNA變化。結果發現0.75 mg/kg安非他命能誘發制約場地偏好再復發行為，並且能引發內側前額葉中BDNF mRNA的增加，但對其餘四個區塊則無明顯的影響效果。實驗三以單次注射安非他命探討對於BDNF mRNA是否有立即性的影響，結果顯示五個區塊皆無明顯的變化。實驗四以安非他命引發的行為致敏化反應為行為模式，偵測BDNF mRNA的表現情形。結果發現藥物制約配對組與單次注射安非他命組在活動量上無顯著的差異，顯示出無行為致敏化反應的發生。檢驗五個區塊BDNF mRNA的表現，亦沒有發現明顯的改變。綜合以上的實驗結果，本研究得到安非他命制約場地偏好再復發行為，會伴隨內側前額葉BDNF mRNA的增加。而單獨的安非他命引發制約場地偏好行為，並不會改變BDNF mRNA。這些結果顯示BDNF參與在較複雜的制約學習行為歷程，而不是在單獨的藥物注射或與環境配對的制約過程。 / Conditioned place preference (CPP) is widely used as an experimental behavioral model in the study of drug addiction and reward learning. Brain dopamine systems play an important role to drive the CPP performance and its relapse. Brain-derived neurotrophic factor (BDNF) is closely related to dopamine system that can promote neuron plasticity involved in certain types of behavior. Taking BDNF as the target molecule, this project conducted a series of experiments to delve into the neural mechanism of CPP. Different doses of amphetamine on the CPP behavior were assessed in Experiment 1A, and BDNF mRNA was tested after CPP test. The results show that 1 mg/kg amphetamine significantly induced CPP, but no significant effect on BDNF mRNA in any of five brain areas tested, including medial prefrontal cortex, striatum, nucleus accumbens, dorsal hippocampus and amygdala. The results of Experiment 1A was further confirmed by Experiment 1B, indicating no significant change on BDNF mRNA in five brain areas of rats with significant amphetamine-induced CPP. Experiment 2 examined the effects of CPP relapse and tested BDNF mRNA in the aforementioned five brain areas. The results show that 0.75 mg/kg amphetamine significantly induced CPP relapse and also increased BDNF mRNA level in medial prefrontal cortex. Such an increase of BDNF mRNA was not observed in any other four areas. Single acute injection of amphetamine was administered in Experiment 3 to delve into the possible immediate drug effect on BDNF mRNA. Its results show no significant change on five brain areas following this acute drug treatment. Experiment 4 used amphetamine-induced behavioral sensitization as a behavioral mode to determine the expression of BDNF mRNA. The results show no significant difference both for amphetamine-paired group and acute amphetamine group on locomotion, that indicated no behavioral sensitization formed in this test. There was no significant difference in the expression of BDNF mRNA in five brain areas. These results indicate that amphetamine-induced CPP relapse, but not CPP performance itself, is accompanied by the increase of BDNF mRNA level in medial prefrontal cortex. These findings indicate that BDNF is involved in place conditioning formed by psychostimulant drug when it is reinstated after extinction, rather than by a solitary drug injection or a relatively simple conditioning process by pairing drug with the environmental context.

本研究藉由測量制約場地偏好行為及制約活動量兩種制約反應，透過制約期及後測期對藥物配對刺激之操弄，探討制約刺激與酬賞性藥物配對之歷程及其相關之神經機制。本文所使用的為低劑量(1.5 mg/kg)之安非他命，採腹腔注射方式給藥。實驗一探討後測日呈現不同的藥物配對刺激組合對兩種制約反應之影響效果，實驗結果發現受試只對與藥物配對過的兩個以上元素刺激同時出現才能引發受試表現制約場地偏好，且受試對複合刺激的活動量皆顯著高於對單一元素刺激的活動量。實驗二在制約期分別將視覺刺激與觸覺刺激與藥物配對，後測期於藥物配對箱單獨呈現視覺刺激或兩者所組成的複合刺激，測量受試兩種制約反應。實驗結果發現視覺刺激與複合刺激皆能引發制約場地偏好，受試對複合刺激的活動量亦高於對視覺刺激的活動量。實驗三則是於制約前分別破壞受試之杏仁核、背側海馬或腹側海馬，並進行實驗二之制約實驗程序。結果發現破壞杏仁核顯著的減抑單一元素刺激所引發之制約場地偏好，但不影響複合刺激引發之制約場地偏好。破壞背側海馬及腹側海馬減抑複合刺激引發之制約場地偏好。但在制約活動量表現方面，這三個腦組織均未獲得較一致性的結果。總而言之，本研究得到制約刺激之連結強度確實可以透過制約場地偏好及制約活動量反映出差異，且結果支持Rescorla-Wagner元素理論對制約刺激與非制約刺激配對歷程之假設。由破壞杏仁核及海馬對受試表現制約場地偏好造成不等程度之影響，可見杏仁核與海馬所參與以藥物配對的制約之行為功能不同。 關鍵字：心理藥物學，安非他命，制約場地偏好，制約活動，元素理論，整體理論，大白鼠 / By measuring of conditioned place preference (CPP) and conditioned locomotion, the present study manipulated various patterns of environment by composing three different contextual stimuli in the test chamber during different stages of conditioning to investigate behavioral processing and neural mechanisms underlying the association of conditioned stimulus and psychoactive drug. A relatively low dose of amphetamine (1.5 mg/kg) administered via intraperitoneal route was conducted as drug treatment throughout the study. In Experiment 1, the effects of CPP and conditioned locomotion were evaluated as different patterns of contextual stimuli composed in the test chamber presented during post-conditioning stage. The results showed CPP was significantly induced in the environment with context stimuli composed by at least two elements. And, the magnitude of conditioned locomotion induced by compound stimulus was higher than that induced by a single elemental stimulus. In Experiment 2, the effects of CPP and conditioned locomotion induced by a two-element compound stimulus were evaluated in the subjects received the drug pairing with both of each element stimulus in separate during the conditioning stage. The CPP was reliable induced by that compound stimulus. Although such CPP effect could also induced by an elemental stimulus specifically regarding to visual modality, it was not true for the other elemental stimulus manipulated on tactual modality. In Experiment 3, behavioral effects tested on the procedures of Experiment 2 were re-evaluated in the subjects received neurotoxic lesions in the amygdala, the dorsal hippocampus, or the ventral hippocampus before conditioning. While amygdaloid lesion significantly attenuated the CPP induced by elemental stimulus, such lesion did not inhibit the CPP induced by the compound stimulus. Lesions on those two hippocampal subareas disrupted the formation of CPP induced by compound stimulus. Regarding the conditioned locomotion, in contrast to what found on CPP, lesion treatment did not produce reliable effect induced by compound stimulus or elemental stimulus. In conclusion, the present findings on two conditioned responses measured support the assumption of Rescorla-Wagner Model on elemental theory. The lesion data indicate that amygdala and hippocampus are differentially involved in conditioned responses induced by psychoactive drug. Key words: psychopharmacology, amphetamine, conditioned place preference, conditioned locomotion, elemental theory, configural theory, rat.

本研究以神經毒素ibotenic acid破壞不同尾核區域以及鋰鹽去價值程序為操弄變項，觀測此兩種實驗操弄對於大鼠之迷津行為之影響，進而探討標誌系統之行為內涵及神經機制。實驗所採用的作業為線索學習作業以及自我中心作業，分別代表標誌系統下的線索導引策略及體位導向策略。實驗一及實驗二在於檢驗尾核功能缺損對於大鼠迷津行為之影響，從探測嘗試發現大鼠在線索學習的行為表現需依賴砂紙線索的導引，而在自我中心作業之行為則不以環境刺激為依據（實驗一A、二A），顯示大鼠在各迷津作業的行為符合標誌系統的運作原則。神經機制之操弄結果顯示在記憶習得階段，尾核破壞之受試在線索學習作業上的表現並沒有顯著變差，尾核功能缺損並未導致學習的延宕或阻斷，其進步的速度仍與控制組相同（實驗一B）。相較於線索學習作業，尾核破壞之受試在自我中心作業上的表現則明顯變差，幾乎沒有進步的趨勢（實驗二B）。而在記憶保持階段，不管是線索學習作業或自我中心作業之表現皆會因尾核破壞而顯著變差（實驗一C、二C）。實驗三及實驗四則利用鋰鹽去價值程序降低食餌之誘因價值，觀測大鼠行為有無相對應改變。結果發現去價值程序的操弄只會影響到大鼠在自我中心作業的行為表現（實驗四），而不影響其在線索學習作業之行為（實驗三）。由此可知，兩種迷津作業所形成的記憶表徵是不同的，自我中心學習歷程會將增強物表徵在聯結單位中，而線索學習之習得歷程則不會。綜合上述實驗結果，標誌系統下確實有兩個不同空間行為機制，一個為線索導引策略，另一個為體位導向策略，雖皆受到尾核的調節，但調節的程度是不同的。不管是記憶習得或保持階段，尾核在體位導向策略的運作中皆扮演重要的角色，而在線索導引策略只參與了記憶保持歷程的運作。另外，兩個空間行為機制在學習內涵上也不盡相同，以線索導引策略為依據之空間行為會形成刺激反應(S-R)的聯結型態，而以體位導向策略為依據之空間行為則會形成反應及增強物(R-S*)聯結。 / This study investigated the neurobehavioral mechanisms of taxon system of spatial memory through manipulating lesions of subareas in the caudate nucleus by ibotenic acid and lithium chloride (LiCl)-induced reward devaluation. With respect to behavioral measurement in an eight-arm radial maze, a cue learning task and an egocentric task were used for testing the guidance and orientation hypotheses of taxon system, respectively. Data from probing procedures showed that the performance of rats in the cue learning task was impaired when the cue was removed, but the performance in the egocentric task was not affected by changing the context (Experiments 1A and 2A). These results indicate that behavior reactions in two tasks are corresponding to those two operational principles of taxon system. In terms of the acquisition, deficits were significantly produced by the lesion of the dorsomedial caudate on egocentric task, while the ibotenate lesions did not affect cue learning task (Experiments 1B and 2B). For retention test, the performances in both cue learning and egocentric tasks were impaired by dorsomedial caudate lesion, no such impairment was observed from dorsolateral and posterolateral caudate lesions (Experiments 1C and 2C). In the third and fourth experiments, LiCl devaluation procedure was employed to lower the reward value of the bait in the maze. This manipulation significantly impaired the performance of egocentric task but not that of the cue learning task. These results indicate that the memory representations in the two tasks used in the present study are different. The memory representation in the egocentric task contains the reinforcer, whereas that in the cue learning task is not necessarily relevant to the reinforcer. In conclusion, the guidance and orientation hypotheses can be differentiated as behavioral mechanisms existing in the taxon system of spatial memory. Although the caudate nucleus is critically important for the operation of both hypotheses, the degrees of this brain site to get involved are different. The caudate nucleus participates in the acquisition and retention of orientation hypothesis, but only in the retention of guidance hypothesis. In addition, behavioral performance of the spatial memory using guidance hypothesis is based on forming the association of stimulus and response (S-R), while that using orientation hypothesis is based on forming the association of response and reinforcer (R-S*).