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.