壓力荷爾蒙涉及禁錮壓力引發場地制約偏好之神經機制

Involvement of Stress Hormones in Restraint-Induced Conditioned Place Preference

梅玉瑩(Yu-Ying Mei)

指導教授 ： 李季湜

國立中正大學/社會科學院/心理學系/博士(2014年)

摘要

場地制約偏好 (conditioned place preference) 此一行為典範被廣泛用於檢驗藥物本身的酬賞效果。根據先前研究顯示急性壓力經驗，例如：經過單次三十分鐘禁錮 (restraint) 或高台 (elevated stand) 壓力操弄之後，大鼠會展現出明顯的場地制約偏好。雖然過去已有大量研究在探討壓力對於學習與記憶之調節，但關於壓力可能直接引發正向酬賞效果的研究卻是寥寥可數。個體在壓力經驗下，位於下視丘-腦下垂體-腎上腺皮質的壓力軸 (hypothalamic-pituitary-adrenal axis) 會受到激發而促使下視丘與腎上腺依序分泌促腎上腺皮質素釋放因子 (corticotrophin-releasing factor) 與糖皮質素 (glucocorticoid)。一篇新近研究直接在小鼠的依核核心區 (nucleus accumbens core) 注射促腎上腺皮質素釋放因子發現能引發場地制約偏好。因此在本研究中，我們假設：(1) 糖皮質素與/或促腎上腺皮質素釋放因子本身可能具有正向酬賞效果：(2) 糖皮質素與/或促腎上腺皮質素釋放因子可能透過在依核核心區的作用來調節由禁錮壓力引發場地制約偏好之行為表現。實驗一結果發現，透過皮下注射不同劑量的皮質固醇 (corticosterone, 0, 1, 3, 5, 與 10 mg/kg) 皆無法直接引發場地制約偏好。透過周邊給予不同劑量的糖皮質素拮抗劑美服培酮 (mifepristone, 0, 10, 40, 與 100 mg/kg) 也無法阻斷由禁錮壓力引發之場地制約偏好。相反地，我們在實驗二與實驗三發現，無論在腦室或依核核心區注射選擇性促腎上腺皮質素釋放因子第一類型受器拮抗劑 (antalarmin, 1 與 0.125 μg) 皆可以阻斷上述由禁錮壓力引發之場地制約偏好。其中值得一提的是antalarmin在過去研究中多被認為具有解焦慮、抗憂鬱之效果，然而，本研究在實驗二與實驗三皆發現中、高劑量antalarmin (2.5與 5 μg；0.25 與 0.5 μg) 會使大鼠產生明顯的場地制約嫌惡，而低劑量則無法引發任何場地制約效果。此外，不同於過去在小鼠之研究結果，實驗三發現，直接在大鼠的依核核心區注射不同劑量的促腎上腺皮質素釋放因子 (0, 5, 50 與 500 ng) 皆無法引發場地制約偏好。整體而言，本研究初步排除了糖皮質素的負向回饋機制涉及由禁錮壓力引發場地制約偏好之可能性。更進一步證實，個體在禁錮壓力當下，位於依核核心區促腎上腺皮質素釋放因子第一類型受器的激發是後續引發場地制約偏好之必要條件。然而，本研究在大鼠依核核心區注射促腎上腺皮質素釋放因子並未引發類似於過去在小鼠研究發現的正向酬賞效果，推測此酬賞效果很可能受到大小鼠生理差異或未知因素所影響。最後，不同於以往周邊注射antalarmin具有解焦慮、抗憂鬱之發現，本研究發現中樞注射該藥物會引發明顯的嫌惡效果，未來仍需要更多相關研究來釐清其機制以提供臨床治療研究之參考。

關鍵字

禁錮 ； 糖皮質素 ； 場地制約偏好 ； 美服培酮 ； 促腎上腺皮質素釋放因子 ； 依核核心區 ； 皮質固醇 ； 下視丘-腦下垂體-腎上腺皮質的壓力軸

並列摘要

The conditioned place preference (CPP) paradigm is widely used when examining the reinforcing effects of drugs. A previous study showed that an acute stressor, such as a 30-min restraint or an elevated stand, could induce CPP. Although the modulating effects of stress on the various forms of learning are well known, the finding that a stressor plays a potentially direct role in the reinforcement mechanism is novel. During a stress experience, the glucocorticoid (GC) and corticotropin-releasing factor (CRF) are 2 well-known hormones released from the hypothalamic-pituitary-adrenal (HPA) axis. A recent study indicated that place preference could be induced by administering intraaccumbens CRF in mice. In the present study, we hypothesized that (a) GC and/or CRF might demonstrate beneficial properties; and (b) GC and/or CRF might mediate appetitive behavior through the nucleus accumbens core (NAcC), resulting in restraint-induced CPP. In Experiment 1, the peripheral applications of corticosterone (subcutaneous [sc] administration of CORT at 1, 3, 5 and 10 mg/kg) failed to induce CPP. Furthermore, a GC antagonist mifepristone (sc administration of 10 mg/kg, 40 mg/kg, and 100 mg/kg) also failed to block restraint-induced CPP. By contrast, in Experiments 2 and 3, both intracerebroventricular (icv) and intraaccumbens administrations of a selective corticotropin-releasing factor type-1 receptor (CRFR1) antagonist antalarmin (1 μg and 0.125 μg, respectively) completely blocked restraint-induced CPP. We observed no anxiolytic or antidepressant-like effects of antalarmin in our study. Conversely, midrange and high doses of antalarmin induced place aversion. Inconsistent with previous findings in mice, intraaccumbens CRF (5, 50 and 500 ng) failed to induce CPP in Wistar rats. In summary, we excluded the involvement of the negative feedback of CORT from peripheral sources in the neural mechanism responsible for restraint-induced CPP. However, although CRFR1 in the NAcC might be essential for restraint-induced CPP, we could not obtain a previous finding in mice that an intraaccumbens injection of CRF can induce place preference. We suggest that such inconsistent results are due to physiological differences between the 2 species. Finally, the place-aversion effects of central antalarmin administration observed in our study are apparently inconsistent with well-known clinical applications of antalarmin as anxiolytic drugs and antidepressants. Further study is necessary to address this question.

並列關鍵字

nucleus accumbens core ； mifepristone (RU486) ； glucocorticoid ； corticotropin-releasing factor type-1 receptor ； corticotropin-releasing factor ； corticosterone ； antalarmin ； restraint

參考文獻

Golier, J. A., Caramanica, K., Demaria, R., & Yehuda, R. (2012). A Pilot Study of Mifepristone in Combat-Related PTSD. Depression Research and Treatment, 2012, 393251. doi: 10.1155/2012/393251

Sandi, C., & Pinelo-Nava, M. T. (2007). Stress and memory: behavioral effects and neurobiological mechanisms. Neural Plasticity, 2007, 78970. doi: 10.1155/2007/78970

Shen, Y. L., & Liao, R. M. (2007). The effects of acute stress on conditioned place preference. Chinese Journal of Psychology, 49, 351-363.

Aguilera, G. (2012). Chapter 8 - The Hypothalamic–Pituitary–Adrenal Axis and Neuroendocrine Responses to Stress. In G. Fink, D. W. Pfaff & J. E. Levine (Eds.), Handbook of Neuroendocrinology (pp. 175-196). San Diego: Academic Press.

Arnsten, A. F., Berridge, C., & Segal, D. S. (1985). Stress produces opioid-like effects on investigatory behavior. Pharmacology Biochemistry and Behavior, 22(5), 803-809.