新生期投予 Dexamethasone 對於成年期母鼠杏仁核功能之影響

The effects of neonatal dexamethasone treatment on amygdala function in adult female rats

鄭瓊音(Chiung-Yin Cheng)

指導教授 ： 呂國棟

國立臺灣師範大學/理學院/生命科學研究所/碩士(2012年)

摘要

臨床研究發現，新生時期接受糖皮質類固醇藥物治療的早產兒，於兒童期及青少年期容易發生神經發育及功能異常；且研究指出，在老鼠新生期投予 dexamethasone (DEX)，會造成腦部杏仁核 (amygdala) 發育不正常有缺陷的現象，以及類憂鬱傾向的行為。台灣衛生署國民健康局統計國內兩萬多名的樣本數中，女性發病的機率為男性的 1.8 倍。女性容易出現憂鬱症的原因，可能與女性的生理週期和體內雌激素 (estrogen) 的濃度變化有關，而過去的研究也發現 DEX 的投予會影響杏仁核等腦區雌激素受體 (estrogen receptor, ER) 的表現量及活化後之反應機制。
本研究於新生鼠出生後第一天到第三天，每天接受一次皮下注射 DEX，並且在出生後每週測量體重一次，以觀察動物的生長情況，結果顯示 DEX 組的動物體重有明顯下降的現象，但在八週齡後此現象改善。進行離體胞外電生理紀錄，探討新生期投予 DEX，對青少年期及成年期雌鼠杏仁核長期增益現象 (long-term potentiation, LTP) 之影響，結果顯示新生期投予DEX之雌鼠於六週齡時，杏仁核長期增益現象會被抑制，此抑制現象於十週齡仍可見。強迫游泳測試 (forced swimming test, FST) 發現六週齡與十週齡 DEX 組雌鼠類憂鬱行為有增加的現象。西方墨漬法探討新生期雌鼠投予 DEX 後雌激素受體的變化，結果顯示六週齡及十週齡 DEX 組雌鼠杏仁核之雌激素α型受體 (estrogen receptor alpha, ERα) 的表現量明顯減少，而杏仁核之雌激素β型受體 (estrogen receptor beta, ERβ) 沒有變化。在本研究第二階段實驗，離體胞外電生理紀錄中，給予腦片表面灌流 20 分鐘的雌二醇 (estradiol, E2) 後，六週齡和十週齡 DEX 組雌鼠杏仁核的長期增益現象有回復的情況；強迫游泳行為測試，在行為前四天給予動物皮下注射 E2，六週齡的 DEX 組雌鼠類憂鬱行為有下降的傾向，但是十週齡的雌鼠則沒有明顯回復。
綜合以上實驗結果，新生期 DEX 的投予，會對雌鼠杏仁核之神經傳導與神經突觸可塑性造成不良影響，以及增加其類憂鬱行為，而且此影響會延續至雌鼠成年期。藉由 E2 的給予，可以降低新生期 DEX 的投予對雌鼠杏仁核功能之影響，以及减少雌鼠青少年期之類憂鬱行為。藉由此研究所得之成果，可提供 DEX 在臨床上用藥的安全考量和治療上的參考。

關鍵字

dexamethasone ； 杏仁核 ； 雌激素 ； 長期增益現象

並列摘要

Clinical studies showed that pharmacotherapy of glucocorticoid steroid drugs in preterm infants have adverse effect on neurological development and dysfunction in childhood and adolescence. Results obtained from animal studies indicated that administration of dexamethasone (DEX) in neonatal rat can cause amygdala development abnormally and defectively. It is long known that the incidence of female in depression is higher than male. The reason that women have depression easily may be due to the fluctuation of estrogen concentration during menstrual cycles. Previous studies have found that the treatment of DEX attenuate the expression and activation of the estrogen receptor (ER) in the pituitary gland and other brain regions.
In this study, we injected DEX to the neonatal rat subcutaneously from the postnatal day-1 to day-3 daily. The body weight was measured weekly. Results showed that neonatal DEX treatment temporary decrease body weight in young rats, but not affected in the later life. We completed the electrophysiological experiments to investigate the possible adverse effect of neonatal DEX treatment on amygdaloid long-term potentiation (LTP) formation in female adolescence and adulthood rats. LTP formation is blocked in basolateral nucleus of amygdala in DEX treatment group, and it’s lasting to adulthood. Neonatal DEX treatment increased depression-like behavior in childhood and adulthood. Western blot results showed that the expression of estrogen receptor alpha (ERα) was attenuated, and the expression level of estrogen receptor beta (ERβ) sustained. Results obtained from extracellular electrophysiological recording showed that the LTP formation on both of the DEX group was rescue by co-administration of estradiol (E2).
Similar rescue effect had also been observed in the forced swimming test, the depression-like behavior was reducing after the E2 injection in four days, but the effect is not appeared in the adulthood. Comprehensively, neonatal DEX treatment changes amygdaloid synaptic plasticity and increasing depression-like behavior in adolescence, these effects persist into adulthood. And it could be partially rescued by E2 treatment.

並列關鍵字

dexamethasone ； amygdala ； estrogen ； long-term potentiation

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