衝動反應的個別差異之神經基礎：DRL操作式制約行為與藥物酬賞行為的相關

Abstract

不當的衝動反應已被認為與數種精神疾患有關(包含藥癮)，多元面向的衝動反應可區分為衝動選擇及衝動反應。針對衝動反應的個別差異與藥癮之間的關聯，本研究利用區辨性增強低頻反應作業(簡稱DRL作業)之行為表現的個別差異，在兩種安非他命引發的不同藥物酬賞行為［制約性場地偏好(簡稱CPP)與行為致敏化(簡稱BS)］，探討其相關性。行為藥理實驗後藉由西方點墨法，分析中腦多巴胺系統的五個相關腦區之四種蛋白質的含量：第一型多巴胺受體(dopamine D1 receptor)、第二型多巴胺受體(dopamine D2 receptor)、多巴胺轉運蛋白(dopamine transporter；DAT)及腦源性神經營養因子(brain-derived neurotrophic factor；BDNF)。實驗結果發現每一批48隻大鼠(共三批)，經14或17天的DRL行為訓練，其行為反應效率比值排序可以經四分位數，區分出高中低三群不等程度的衝動反應；這三群受試在六項DRL行為反應指標，均有顯著組間差異。實驗1的結果顯示，三組不同衝動程度的受試皆有顯著的CPP，惟DRL行為反應之個別差異與安非他命引發的CPP藥物酬賞效果並無統計相關。實驗1的生化分析顯示安非他命會對四種蛋白質在五個腦區有不同形式的影響效果，但其與DRL行為反應並無任何統計相關。實驗2的結果顯示DRL行為反應之個別差異與安非他命誘發BS的效果有顯著相關，即DRL行為反應效率較好的低衝動組受試，其藥物引發BS行為反應效果較弱；反之亦然。實驗2的生化分析結果顯示，背側紋狀體的D1受器與DRL行為個別差異之表現有正相關，背側紋狀體與海馬迴的DAT與安非他命引發BS藥效結果有正相關。綜合以上實驗結果，DRL行為反應所代表的衝動反應之個別差異，對於安非他命引發之CPP行為並無預測效果，但對於安非他命引發的BS有預測效果；而且這兩項藥物酬賞行為分別與不同腦區的多巴胺相關蛋白有獨特的統計相關，顯示DRL行為的個別差異之多巴胺相關神經基礎，取決於藥物酬賞行為的檢測模式。

Impulsive behavior has been considered to be related to several mental disorders including drug addiction. Individuals with abnormally high level of impulsivity are usually more likely to have drug addiction. This study used a differential reinforcement of low-rate response (DRL) task to investigate impulsive action that could be related to conditioned place preference (CPP) and behavioral sensitization (BS) as induced by amphetamine. Western blotting was used to analyze four proteins, dopamine D1 and D2 receptors, dopamine transporter (DAT) and brain-derived neurotrophic factor (BDNF), expressed in five brain regions relevant to the midbrain dopamine systems after psychopharmacological test. The results show that the subjects (n=47 or 48) in each of three batches trained in a DRL 10-sec task for 14 (or 17), based on the response efficiency, can be sorted by a quartile method into three groups with different levels of impulsivity (i.e., high, intermediate and low). The between-group difference was also confirmed on each of six measures of the present DRL behavior. Data of Experiment 1-1 and Experiment 1-2 together showed significant CPP induced by amphetamine; however, it was not correlated to the individual differences of DRL behavior. Biochemical assay of Experiment 1-2 revealed that amphetamine had different effects on the four proteins in the five brain regions, but these effects were not statistically correlated with behavioral responses of DRL. The results of Experiment 2 showed that the individual differences of DRL behavior were significantly correlated to the effects of amphetamine-induced BS. The low impulsive subjects had a weaker drug-induced BS and vice versa. Biochemical assay of Experiment 2 showed that there was a positive correlation between the amount of D1 receptors expressed in the dorsal striatum and the efficiency of DRL behavior; and in the dorsal striatum and the hippocampus, there was a positive correlation between the DAT and the BS induced by amphetamine. Together, the individual differences of impulse action assessed by DRL behavior can be used to predict the varied magnitudes of BS, but not CPP, induced by amphetamine. And, distinctive neural substrates are involved in psychopharmacological effects of CPP and BS induced by amphetamine.