在臨床上，許多疾病或藥物的使用會讓病患產生癢覺，而癢覺症狀的產生讓病患的日常生活品質下降，令人苦惱不已。因此，研究能夠抑制癢覺症狀的新藥物，是目前迫切需要的。臨床的研究發現，脊髓腔內注射類鴉片mu受體致效劑同時產生止痛與引發癢覺的功能。動物實驗也證明中樞給予類鴉片mu受體致效劑能引發搔癢的行為反應，而類鴉片kappa受體致效劑則可以降低類鴉片mu受體致效劑所引發的搔癢反應而不會干擾其止痛效果。本研究的目的，在於檢視類鴉片mu和kappa受體對於大白鼠的痛覺與癢覺的調控能力。藉由建立bombesin引發搔癢反應的動物行為模式，用以檢測實驗性藥物其抑制癢覺反應的功效，來比較類鴉片kappa受體致效劑、類鴉片mu受體拮抗劑以及組織胺受體拮抗劑對於bombesin所引發之搔癢反應的抑制效果。此外，並測試各類藥物在其引發癢覺或抑制癢覺時是否改變痛覺閾閥。最後，再透過側腦室給予類鴉片kappa受體拮抗劑來確認中樞神經系統裡類鴉片kappa受體在抗搔癢行為上的角色。研究結果得知兩項主要結論：（一）大白鼠的中樞類鴉片mu受體雖能抑制痛覺，但對於癢覺的傳遞或引發搔癢反應的功能有限。（二）不同類型的類鴉片kappa受體致效劑在無法抑制痛覺的低劑量範圍裡，都有抑制搔癢反應的效果。而且拮抗劑的使用，確認了中樞類鴉片kappa受體在抑制癢覺功能上的角色。相對於類鴉片mu受體拮抗劑及組織胺受體拮抗劑兩者都無法減緩bombesin所引發的搔癢反應，類鴉片kappa受體致效劑具有抑制不同根源的癢覺症狀的廣泛性。這些動物研究的發現有待進一步的臨床研究來確認類鴉片kappa受體致效劑作為新一代止癢藥物的潛在療效。 / Itch/pruritus is a symptom derived from several diseases or drug use that afflicts a large population of humans. It is important to study and develop novel drugs as antipruritics. Clinical studies have shown that intrathecal administration of mu opioid receptor agonists simultaneously produces analgesia and itch. Animal studies have also shown that centrally administered mu opioids can elicit itch/scratching responses and that kappa opioid receptor agonists can attenuate intrathecal morphine-induced scratching without interfering with antinociception. The aim of this study was to investigate the roles of mu and kappa opioid receptors in modulating pain and itch sensation in rats. Experiments were conducted to establish bombesin-induced scratching as an itch model to evaluate the antiscratching effectiveness of various drugs. A thermal nociceptive assay was used to examine whether drugs eliciting or inhibiting scratching can change rat’s nociceptive threshold. In addition, antagonist experiments were conducted to verify the receptor mechanism underlying the antiscratching effects of kappa opioids. Findings from a series of experiments suggest that central mu opioid receptors in rats have limited functions in expressing scratching responses. More importantly, kappa opioid receptor agonists, but not an opioid receptor antagonist or a histamine receptor antagonist, can attenuate bombesin-induced scratching. The antiscratching effects of kappa opioids occur at low and non-antinociceptive doses and such effects can be reversed by a kappa opioid receptor antagonist. These findings warrant additional clinical studies to document effectiveness of kappa opioid receptor agonists as antipruritics in a broader context.

本研究探討舔飲蔗糖液之成本利益情境中，多巴胺受體拮抗劑對舔飲行為配置的影響，以釐清阻斷多巴胺使行為受損的條件與所代表之意義。實驗設計為「高位置高濃度糖液＋低位置低濃度糖液」雙管情境中的舔飲行為，實驗一確立高、低位置分別代表高、低成本後，實驗二至實驗七調整糖液濃度、裝盛容器與舔飲經驗，發現唯有「高位置籠外水管20％糖液＋低位置伸入式水瓶15％糖液」且增加單獨對低瓶的舔飲經驗，方能建立多巴胺受體拮抗劑的「此降彼升」動物模式。實驗八確認「此降彼升」的三要件為低位置是（1）低成本：伸入式容器、（2）高利益：15％糖液、（3）充足經驗：9天舔飲低瓶。實驗九至十一的藥物測試得到前述動物模式可有效區別多巴胺受體拮抗劑、降低食量藥物與干擾動作藥物有不同影響型態。實驗十二發現單管情境與雙管情境的結果有很高的一致性。結論為（1）較低劑量的多巴胺受體拮抗劑並不減少大白鼠對糖液的總需求、不干擾兩者行為間的區辨選擇與轉換能力，（2）舔飲行為不受多巴胺受體拮抗劑干擾的要件為低成本、高利益與充足經驗三者需同時成立，（3）不符三要件之舔飲行為會因多巴胺受體拮抗劑而降低表現量，因此反駁過去認為完結行為不受此類藥物干擾的想法，（4）本研究建立的雙管舔飲情境可有效區分不同藥物作用，值得做為進一步探討多巴胺與行為之間的關係及其神經機制的動物模式。 / This study investigated the effect of dopamine antagonist on licking sucrose solution behavior under cost-benefit condition, which was designed into a 'high-cost high-benefit with low-cost low-benefit' licking test situation. Experiment 1 confirmed that the difference of licking response between high and low positions indicating the cost difference. Experiment 2 to Experiment 7, manipulating the liquid container, sucrose concentration and the experience of licking low position solution, found that rats only increased low position sucrose intake while decreased high position one in 'high tube 20% with low bottle 15% sucrose solution' condition. Experiment 8 further confirmed three factors of low cost, high benefit and plenty experience were necessary for increasing intake of low position in simultaneous contrast to decreasing the intake of high position. Experiment 9 to Experiment 11 evaluated the drug effects of dopamine antagonists, anorectics and motor relaxants on the present animal model. The results showed the different patterns of reaction for these three types of drugs. Experiment 12 revealed the results of single tube condition were consistent with those of cost-benefit condition. Together, these results demonstrated that dopamine antagonist neither decrease the drive for sucrose nor disrupt the abilities to discriminate and select between two tubes under the present model. Three factors of cost, benefit and experience are important to determine dopamine antagonist effect. Therefore, the resistance of consummatory behavior to dopamine dysfunction may be limited for specific situation. And, the cost-benefit licking model can be useful for further investigation of neurobehavioral mechanism of dopamine system.

過去有關壓力的研究指出，當對實驗動物施予單次禁錮、足部或尾部電擊或是實驗者的抓取動作等壓力源時，其大腦中的前額葉皮質、杏仁核、依核或是紋狀體等處會有隨壓力源產生的多巴胺分泌量增加現象。相對於壓力源對腦中神經化學物質的探討，壓力源對與學習制約有關的行為影響的相關研究證據迄今如缺，因此本研究企圖建立單次壓力源操弄對場地制約偏好行為的動物模式。實驗一A對大白鼠施予單次30分鐘的高台壓力源，發現確實可建立場地制約偏好行為。實驗一B操弄單次高台壓力源觀察其對實驗動物自發性活動量的影響，結果發現其對於實驗受試在大動作持續時問上具有抑制效果。實驗一C操弄單次高台壓力源後的0、30、60及120分鐘時採取實驗受試的前額葉皮質、海馬體、杏仁核、依核及紋狀體等五處組織，檢驗其多巴胺、血清張力素及代謝物的含量。結果發現除海馬體外的四個部位的多巴胺量及其代謝物分別在不同採集時間點有不等的顯著增加現象。血清張力素的變化量在各個部位不及多巴胺。實驗二及實驗三分別經由周邊或中樞前額葉皮質微量注射多巴胺D₁與D₂專屬受體拮抗劑，結果發現其可抑制曲單次高台壓力源操弄所建立的場地制約偏好行為。綜合上述結果，單次高台壓力源的操弄確實可引發大白鼠大腦中的多巴胺量增加藉以形成場地制約偏好行為，而此場地制約偏好行為所依賴的多巴腰量增加位置推論其是依核而非前額葉皮質。另外，多巴胺D1與D2受體對此高台壓力源引發的場地制約偏好行為所扮演的角色相當。 / When experimental animals under single stressor, such as restraint, foot, or tail-shock, or handing, an immediate and robust releasing of dopamine appears in the prefrontal cortex, amygdala, nucleus accumbens, or striatum. In contrast to these neurochemical findings, the behavioral effects under stress are rarely studied and remained uncertain. The purpose of this study was to establish an animal model of single stress-induced conditioned place preference (CPP). Experiment 1A found that the CPP can be induced by a single high-plate stressor. Experiment 1B investigated the effects of this single high plate stressor on rats' locomotion, this stressor was found to inhibit the large movement as measured by duration. Experiment 1C investigated the timing course of this stressor on dopamine, serotonin, and their metabolities in the prefrontal cortex, hippocampus, amygdala, nucleus accumbens, and striatum. The results showed that all the areas, except hippocampus, had distinct patterns of changes on dopamine, serotonin and their metabolities at different times' after stress. Experiment 2 and 3, examined the effects ofdopamine D1 or D2 receptor antagonists, administered respectively via intraperitoneal or local infusion into the prefrontal cortex, on the CPP formed after high-plate stress. The results showed that these drug manipulations can inhibit stress-induced CPP. Taken together, these results indicated the CPP formed after high-plate stressor is developed on the immediate increase ofdopamine releases in the nucleus accumbens and prefrontal cortex. These neurochemical alterations are more profound in the nucleus accumbens than the prefrontal cortex. However, the dopamine D₁ and D₂ receptor in the prefrontal cortex are also important for the formation of CPP after high-plate stressor.

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.

認知功能的提升是當今神經科學領域中的研究重點之一，但其神經機制尚有待釐清。本研究利用一種用於改善阿茲海默症臨床的非競爭型N-甲基-D-天門冬胺酸受體拮抗劑memantine，檢測其對於大白鼠在不同時距相關操作式制約行為及空間工作記憶行為之影響效果。實驗一為針對時間屬性的操作式制約行為實驗，運用大白鼠的區辯性增強低頻反應作業（DRL 10秒行為）與固定時距作業（FI 30秒行為）之行為作業，並操弄連續訓練與間歇訓練的兩種不同模式，測試memantine對前述四組受試的操作式制約行為在表現、消除與自發恢復等三階段之劑量反應。實驗二利用配對性延遲T迷津作業區分出不等基準線(表現好與表現差)之受試，再加以藥理實驗，測試memantine對於前述兩組受試之劑量反應。實驗一結果顯示，受試在兩種不同訓練模式下經十五次習得訓練後，在兩種操作式壓桿行為的壓桿反應相關指標中都有明顯的差異，這證實不同的行為訓練模式會導致學習後的表現有差異之別。memantine藥理實驗結果顯示，此藥對於上述四組受試的操作式行為之三階段的影響效果，會因為不同訓練模式與不同作業而異。實驗二結果顯示，memantine提高空間工作記憶的正確率在表現不好的組別有很顯著的藥效，這證實memantine對於空間式工作記憶行為的影響，也會因學習基準線的不同水平而異。在行為實驗後所進行的蛋白質表現量檢測中，memantine（5 mg/kg）只對五個測試腦區中的背側紋狀體中ERK1磷酸化程度有明顯上升的影響，而其對ERK2及CREB的磷酸化在所有腦組織中皆沒有顯著的影響。綜合以上結果，memantine影響時間與空間屬性的相關行為之藥理效果，會依行為的不同習得歷程(或行為背景經驗)及基準線表現程度而異，而此項行為藥理效果，可能與紋狀體中ERK1的磷酸化有關。 / The neural basis of cognitive enhancement is one of the intriguing topics in neuroscience research; however, the underlying neural mechanisms remain to be elucidated. This study examined the effects of memantine, a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist which is used to treat Alzheimer’s disease in clinic, on operant behaviors and spatial working memory. In Experiment 1, using the differential reinforcement for low-rate-response 10 sec (DRL 10s) and the fixed-interval 30 sec (FI 30s) operant tasks, and with the manipulation of two different training regimens (continuous vs. intermittent) in the acquisition phase, the effects of memantine were evaluated in three stages of behavioral tests including the performance (right after the end of 15-day acquisition), the extinction, and the spontaneous recovery (after the extinction). In Experiment 2, memantine were tested in the subjects with different level of baseline performance (good vs. bad) on the distinctive patterns of operant responding in four different groups which received DRL 10s and FI 30s with different training regimens; indicating that behavioral task and training background are critical to the operant performance of temporal operant behaviors. Such behavioral outcomes led the dissociable effects of memantine appeared in between the four groups as tested in all three different stages. The results of Experiment 2 showed a profound improvement of the correct responses rate on spatial working memory in the low-baseline group as compared to the higher-baseline group. With a pretreatment of memantine (5 mg/kg), brain tissues in five selected areas were collected for western blot assays of ERK 1, ERK 2, and CREB. The results only revealed a significant increase of ERK 1 phosphorylation in the dorsal striatum. Together, the effects of memantine to improve cognition-associated processes in the temporal operant behaviors and the baseline of performance, and the present observation of cognition-enhancing effects of memantine may be resulted by the ERK 1 phosphorylation in the dorsal striatum.