- 學位論文
消旋安非他命引發聽覺驚跳反應之致敏化效用
The Effect of DL-Amphetamine on Inducing Sensitization of the Acoustic Startle Response
摘要
反覆使用精神興奮劑會增強藥物對行為的促進效果，稱為行為致敏化。行為致敏化的產生被認為是引發藥物成癮及藥物導致精神障礙的原因之一，因此透過致敏化相關的研究有助於了解行為異常的機制。本研究利用與實際濫用及醫療處置接近的消旋安非他命作為引發致敏化的藥物，探討其效果。在行為測試上，本研究採用大白鼠的聽覺驚跳反應(acoustic startle response)作為致敏化的指標，並透過自製的驚跳反應系統予以量測。該自製系統通過不同測試檢驗，證實其實用性。本研究應用其探討不同致敏化調節因素的影響，例如藥物注射程序、引發期情境、以及致敏表現期間杏仁核活性。研究結果顯示消旋安非他命如其他異構物同樣可引發行為致敏化，但其效價(potency)較右旋安非他命為低。注射單劑5.0 mg/kg的消旋安非他命，於一個月的戒斷後，可測得對同樣劑量消旋安非他命致敏化，若僅隔兩周測試則無效。然而此單次注射致敏化較不穩定，易受其他因素影響。連續七天重複注射5.0 mg/kg的消旋安非他命可引發立即致敏化，而其效果具有倒U型趨勢，消旋安非他命對驚跳反應的促進效果先隨著注射天數先增加，後續又降低，這現象暗示致敏效果可能同時受藥物引發習慣化作用的影響。經過一個月的戒斷後，重複注射派典下表現出延宕致敏化。透過比較單一與重複注射兩種典範，發現重複注射引發的致敏化效果較單一注射更為穩定。若改變引發期情境，使大白鼠於飼養籠接受消旋安非他命重複注射，仍可於一個月後展現行為致敏化；反之若大白鼠於飼養籠僅接受單次注射，則無法於一個月後展現致敏化。此外在致敏化表現上，以利多卡因抑制杏仁核活性不影響重複注射引發致敏化之表現。綜合以上結果，消旋安非他命如右旋安非他命一般可引發致敏化效果，但會受到各種因素所調節。本研究成果可作為藥物致敏化相關神經機制的研究基礎，同時也可提供實際醫療應用參考，降低消旋安非他命作為處方用藥的負向效果。
並列摘要
Repeated administration of psychostimulants such as amphetamine can lead to a progressive increase in the drug-activating behavior, which is noted as behavioral sensitization. It is considered to be a primary cause for drug addiction and stimulant-related psychosis. Therefore, understanding the mechanism of behavioral sensitization can improve our knowledge about the mechanism of these abnormal behaviors. The present study aimed to examine the behavioral sensitization effect of dl-amphetamine, as this mixed-isomer is widely used in the drug addicts and for the treatment of ADHD. We used it to investigate the phenomenon of behavioral sensitization and the various modulating factors of it, such as the administration protocol and the induction context; as well as the role of amygdala in expression of the sensitization effect. Acoustic startle responses were used to index behavioral sensitization in this study. We developed a complete open-source startle system to conduct the behavioral experiments. This home-made system was verified by empirical data to be reliable and valid for assessing the startle behavior. Results showed that dl-amphetamine could induce a dose-dependent enhancing effect on startle, just as the other forms of isomers, but it was less potent than that of d-amphetamine. A single injection of 5.0 mg/kg of dl-amphetamine could induce behavioral sensitization after one month of withdrawal, but not after two weeks. Yet the effect was not very robust and could be altered by certain modulating factors. Repeated administration of 5.0 mg/kg dl-amphetamine for 7 days induced an immediate form of sensitization with an inverted-U function, with startle augmented at the middle of the injection period but subsided at the end of it. A delayed form of sensitization to the repeated administration paradigm also developed after one month of drug withdrawal. By comparing the sensitization one month after the induction, the sensitization induced by the multiple-injection paradigm was more robust than that by the single-injection paradigm. For example, the effect of the multiple injections was persistent by injecting the drug at the home cage such that the context between induction and challenge was different, while the effect of the single injection was abolished when the injection was given at the home cage. Further, the delayed sensitization induced by the multiple injections was impervious to suppression of the amygdala with lidocaine, while that induced by the single injection vanished by the intra-amygdala cannula implantation and drug infusion procedure. These findings suggest that several factors must be taken into consideration in analyzing dl-amphetamine-induced sensitization, for example, the induction paradigm and the context contingency. Further, a habituation process might be involved in the multiple-injection paradigm that resulted in an immediate form of sensitization during the induction period. These results could contribute to our understanding of the neural mechanisms underlying behavioral sensitization and be applied to clinical practices to minimize the potential negative effects of dl-amphetamine for its therapeutic use.