No description available.

安非他命與古柯鹼皆屬心理興奮性藥物(psychostimulants)，在藥理上有很多功能相似的機制，而且兩種藥物濫用成癮的問題一直是臨床及基礎研究所關心的問題。就動物行為模式而言，安非他命與古柯鹼具有影響包括反射性及制約學習性的行為表現的效果。若針對藥物的酬賞性做探討時，制約性場地偏好行為模式的相關研究益發受到重視，本研究實驗一先針對此作業之操弄時間及環境變項做一探討，再研究安非他命與古柯鹼之作用機制。過去的研究發現，週邊注射安非他命或古柯鹼與某環境刺激配對能引發制約性引發場地偏好的傾向，但兩藥的行為現象卻對藥理的操弄呈不一致的結果，隱含兩藥背後的神經機制可能也不同。其中阿控博核是一個值得再驗證的區域。阿控博核被認為是動機系統與運動系統的介面。此部位因其解剖及生化功能的異質性，故實驗二針對其次分區進行中樞藥物注射，於是直接將安非他命(10，15μg)與古柯鹼(50，100μg)分別注射於阿控博核之次級區。結果發現安非他命直接注入阿控博核核區或古柯鹼注入阿控博核殼區可表現顯著的場地偏好效果。基於阿控博核所含有的麩胺酸神經末梢源自內側前額葉皮質，實驗三則發現安非他命或古柯鹼注入內側前額葉皮質可引發制約性場地偏好行為。實驗四將麩胺酸專屬受體抑制劑與安非他命共同注入核區或與古柯鹼共同注入殼區，結果發現不論NMDA或non-NMDA受體抑制劑均減抑了安非他命與古柯鹼注入阿控博核不同區所引發之制約性場地偏好的效果。最後實驗五利用內側前額葉遭破壞的受試，發現古柯鹼注入阿控博核殼區所引發之制約性場地偏好的效果受損，但不影響安非他命注入阿控博核核區所引發之制約性場地偏好的效果。綜觀上述結果顯示安非他命與古柯鹼的酬賞特質所引發行為的神經機制可能不同，腦中之內側前額葉皮質及阿控博核對兩藥的行為效果有不同的涉入。 / The function of the nucleus accumbens (NACC) has been suggestedto play an important role of the rewarding effects of psychostimulants.It is hypothesized that the neural substrates for amphetamine and cocaineto produce behavioral effects can be different. As conducted in Experiment 1, a conditioned place preference (CPP) task with procedures for amphetamine microinjection was established from the manipulation of conditioning environment. In considering the heterogeneity of NACC, Experiments 2 investigated the potentiality of the CPP effects after local infusion of amphetamine (10, 15 μg/site) or cocaine (50, 100 μg/site) into the core and shell subareas of NACC. Amphetamine microinjection into the NACC core significantly produced CPP, whereas such effect only appeared under treatment of the high dose of cocaine into the shell area. Lack of the CPP effects for amphetamine or cocaine infused into the boundary areas of the core and shell regions was seen in Experiment 2 (part B). In Experiment 3, the involvement of the medial prefrontal cortex (mPFC) was challenged for amphetamine and cocaine on the CPP task. Both doses of cocaine and the low dose of amphetamine locally infused in mPFC significantly produced CPP. In Experiment 4, glutamatergic NMDA receptor antagonist APV (0.5, 1 μg/site) and non-NMDA receptor antagonist CNQX (1 μg/site) significantly attenuated the CPP effects of amphetamine infused into the NACC core. This antagonism was also true for the cocaine-induced CPP in the NACC shell. These results implied that the other cortical areas can modulate such CPP effects, in particular the mPFC. In Eperiment 5, lesion of mPFC significantly inhibited the cocaine-induced CPP in the shell area but not for the amphetamine-induced CPP in the core area. Taken together, the NACC is an important neural substrate for mediating the rewarding effects for amphetamine and cocaine on the CPP task, and such effects can be dissociated as drugs locally infused into core and shell areas. Glutamatergic projections originating mPFC may provide some motivational information to the NACC. The mPFC may distinctly be involved in the motive circuit of cocaine- or amphetamine-induced CPP in the NACC. These results highlight that different processes are involved in the acquisition of CPP for microinjection of amphetamine or cocaine into the NACC subareas.

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.

甲基安非他命是一種被廣泛濫用的非法神經興奮劑，而且使用之後常伴隨著精神疾病的發生，動物研究也顯示，施打甲基安非他命所引起的神經毒性不僅會造成多巴胺神經元及血清素神經元的損傷，也引起認知功能和社交行為的缺失，同時對於產生迷幻作用的5-HT2A受體作用劑的行為反應增強。N,N,N-trimethylglycine (TMG)和N,N-dimethylglycine (DMG)是甘胺酸的甲基化衍生物，由於這兩種藥物具有治療神經系統疾病的潛力，因此本研究的目的為評估TMG及DMG是否可以預防或改善小鼠在甲基安非他命的暴露下所導致的行為缺失包括新位置辨識測試，新物體辨識測試，社交行為互動測試以及使用5-HT2A受體作用劑DOI 誘導小鼠頭部抽搐(head twitch )的行為。實驗方式為腹腔注射給予雄性ICR小鼠甲基安非他命，一天注射四劑（4 × 5mg/kg），每劑間隔兩小時。實驗一，小鼠在暴露甲基安非他命，先確認行為改變後，給予腹腔注射TMG及DMG (10或30 mg/kg)連續七天，評估TMG及DMG的治療效果。實驗二在施打每劑甲基安非他命30分鐘前給予TMG及DMG (100 mg/kg)，七天後進行行為評估，實驗三，評估TMG及DMG個別及混合劑量的治療效果，小鼠給予甲基安非他命之後，先確認行為改變，再給予腹腔注射TMG及DMG (20、5+5或是10+10 mg/kg) 連續七天，七天後進行行為測試。實驗四，檢測TMG及DMG的治療效果是否藉由活化NMDA受體glycine binding site，小鼠給予甲基安非他命七天之後，腹腔注射TMG及DMG (20 mg/kg)並在給予TMG及DMG前30分鐘給予glycine binding site 拮抗劑7-chlorokynurenic acid (7-CK) (1 mg/kg)，連續給藥七天，七天後進行行為評估。實驗結果發現連續給予七天TMG及DMG在個別劑量及混合劑量中都能夠恢復甲基安非他命所造成的認知功能缺損，社交退縮和降低由DOI 誘導小鼠頭部抽搐行為表現，以及在紋狀體中酪氨酸羥化酶的蛋白質表達減少情況。而前給予7-CK則阻斷TMG及DMG對甲基安非他命所造成的認知功能缺損，社交退縮的改善作用，但是對TMG及DMG對DOI 誘導小鼠頭部抽搐的行為的改善作用影響較小，顯示TMG及DMG可能都是經由活化NMDA 受體的glycine binding site改善甲基安非他命所造成的認知功能缺損，社交退縮，這些發現表示，TMG及DMG具有治療甲基安非他命成癮者所造成的精神分裂等異常症狀的潛力。 / Methamphetamine (METH) is a widely abused illicit psychostimulant. METH use is commonly associated with psychosis. A neurotoxic regimen of METH, which damages the dopaminergic and serotonergic neurons, causes cognitive dysfunction, social interaction deficits, and supersensitivity to hallucinogen in mice. N,N,N-trimethylglycine (TMG) and N,N-dimethylglycine (DMG) are methyl derivatives of amino acid glycine and naturally occur as intermediate metabolites in choline-to-glycine metabolism. Growing evidence shows that both compounds have potential to treat some neurological disorders. The aim of this study was to examine the protective and therapeutic effects of TMG and DMG on METH-induced behavioral aberrations. The novel location recognition test (NLRT), the novel objective recognition test (NORT), the social interaction and the hallucinogenic 2, 5-dimethoxy-4-iodoamphetamine (DOI)-induced head twitch response were evaluated. Male ICR mice received one day drug treatment with four injections of METH (4 × 5 mg/kg, i.p.) or saline at 2h interval. First, TMG or DMG (10 or 30 mg/kg, i.p.) were separately administered once daily for seven consecutive days after the behavioral impairment was confirmed in METH-treated mice. Seven days after final injection of TMG and DMG, the behavioral tests were monitored. Secondly, the preveting effects of TMG and DMG were examined by TMG and DMG (100 mg/kg, i.p.) pretreatment, 30 min prior to each dose of METH. Third, the lower dose (20 mg/kg) and combined effects of TMG and DMG (5+5 or 10+10 mg/kg i.p.) were evaluated. Fourth, in order to determine if the improving effects of TMG and DMG are mediated by NMDA receptor glycine binding site, the glycine binding site antagonist 7-CK (1 mg/kg, i.p.) was administered 30 min prior to each dose of TMG and DMG (20 mg/kg, i.p.), TMG and DMG dose-dependently improved, but not prevented the METH-induced cognition deficits, social withdrawal and hypersensitivity to hallucinogen with additional effect. Pretreatment of 7-CK, reversed the improving effects of TMG and DMG on behavioral deficits after METH exposure, yet had minor effect on hypersensitivity to hallucinogen. These results demonstrate that TMG and DMG might activate the glycine binding site of NMDA receptor to improve METH-induced cognition deficits and social withdrawal. TMG and DMG may be the novel therapeutic agents for psychiatric disorders related to METH abuse.

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.

本研究以心理興奮性藥物(psychosimulants)引發之行為致敏化作為探討環境與藥物的配對學習如何影響個體長期使用藥物後對藥物的反應。首先於實驗一建立安非他命引發自發活動致敏化基本模式，以及不同的重複注射情境下致敏化的表現，結果顯示經由本實驗操弄注射情境的程序可有效引發在測試箱、飼養籠，和第三處的安非他命致敏化表現，並且致敏化自發活動表現量在測試箱組顯著高於飼養籠組和第三處組。實驗二對致敏化形成歷程中可能與安非他命配對的刺激進行消除，以釐清致敏化形成歷程中連結學習的要素，結果顯示消除程序沒有降低致敏化活動量的效果。實驗三使用中樞注射麩胺酸受體拮抗劑NBQX於依核以影響致敏化的連結學習歷程，結果顯示該操弄可阻斷在飼養籠重複注射安非他命引發的行為致敏化。測試箱組經過該操弄後其致敏化活動量顯著降低但仍有顯著的致敏化活動量表現。實驗四分別破壞前額葉皮質兩處次級區塊以瞭解其在致敏化連結學習歷程中扮演的角色，結果顯示破壞背側前額葉皮質只阻斷在飼養籠注射安非他命所引起的行為致敏化，破壞腹側前額葉皮質只阻斷測試箱組行為致敏化。綜合上述研究結果顯示安非他命引發致敏化的形成深受藥物配對的環境影響而可區分環境相依與環境獨立之行為致敏化，環境相依行為致敏化的行為機制可由場合建立的觀點加以解釋。在依核內之麩胺酸傳導和前額葉皮質次級區塊之功能在兩種行為致敏化上的差異可以反應環境相依和環境獨立行為致敏化的潛在神經機制可能有所不同。 / The present study investigated the neurobehavioral mechanisms of d-amphetamine (AMP) induced behavioral sensitization, with the aim to elucidate the role of associative learning between the context and drug. Experiment 1 compared the sensitization effects of repeated (AMP) conducted in three different contexts by the measurement of locomotion activity. The results showed that behavioral sensitization of locomotion was significantly induced AMP repeatedly injected in each of the contexts. However, the magnitudes of behavioral sensitization were different among those three conditions. The highest degree of sensitized locomotion was observed in the group with repeated AMP conducted in the test box in comparing to the other two groups with drug administration in the home cage and a third place, Experiment 2 was designed to examine the effects of extinction on the injection procedure and the contextual cue on the behavioral sensitization of AMP induced in the test box, the home cage, and a third place. The resu lts clearly indicate all three types of locomotion sensitization were resistant to the manipulation of extinction. Experiment 3 tested the effects of NBQX, a glutamatergic AMPA receptor antagonist, infused into the nucleus accumbens on the establishment of behavioral sensitization of AMP induced in the test box and the home cage. This intra-accumbens NBQX treatment significantly suppressed the formation of behavioral sensitization of AMP induced in the home cage, but not in the test box. Experiment 4 investigated the lesion effects of medial prefrontal cortex (mPFC) on the establishment of behavioral sensitization of AMP induced in the test box and the home cage. Two subareas of the mPFC, dorsal and ventral parts, were lesioned by ibotenic acid. The findings indicated a double dissociation existing in the mPFC subareas for the behavioral sensitization of AMP induced in different contexts. The lesion of ventral mPFC inhibited the formation of behavioral sensitization of AMP induced in the test box, whereas the lesion of dorsal mPFC attenuated the AMP sensitization induced at the home cage. Together, these data suggest that the association of the repeated drug effects pairing to the context is critical for the development of behavioral sensitization. Such sensitization can further be differentiated into the context-depentdent and context-independent forms based on the uniqueness of contextual cue in the environment where drug is administered. Different neural substrates are involved in the establishment of behavioral sensitization of AMP.