阻斷眼眶前額葉多巴胺D2受器無法消除阿托莫西汀在自發性高血壓大鼠於注意力轉換作業中之行為療效

Blockage of dopamine D2 receptor in orbitofrontal cortex fails to abolish the performance improving effects of atomoxetine on the spontaneusly hypertensive rat in an attentional set-shifting task

黃建源(Jian-Yuan Huang)

指導教授 ： 李季湜

國立中正大學/社會科學院/心理學系/碩士(2013年)

摘要

注意力缺陷過動症(attention-deficit hyperactivity disorder, ADHD) 主要症狀包含注意力不足、過動及衝動控制困難。阿托莫西汀(atomoxetine, ATX) 是目前臨床新一代治療 ADHD 的非中樞神經興奮劑，為選擇性正腎上腺素(norepinephrine, NE)的再回收抑制劑，主要會提高正腎上腺素突觸間的濃度。特別的是，過去研究發現 ATX 在前額葉(prefrontal cortex, PFC)能夠同時提高多巴胺(dopamine)的濃度，類似於第一線藥物 methylphenidate 的作用。然而，目前研究尚無法釐清 ATX 藥物治療的神經機制；ATX 可能直接透過 NE 產生療效，也有可能是間接透過多巴胺系統來作用。本研究嘗試以四至六週大的自發性高血壓大鼠(spontaneously hypertension rat, SHR)作為 ADHD 動物模式，檢驗周邊或中樞給予 ATX 能否改善 SHR 在注意力轉換作業(attentional set-shifting task, ASST)的行為表現，以及在眼眶前額葉注射多巴胺 D2 受器拮抗劑haloperidol 能否阻斷 ATX 的治療效果。實驗一，在測驗當天給予大鼠 ATX (0.3 mg/kg) 30 分鐘之後，讓大鼠進行注意力轉換作業的學習，以確認周邊給予 ATX 的治療效果。其中，在反向學習(reversal learning)階段，大鼠必須學會先抑制之前已習得的反應，並且反轉該行為策略，才能成功獲得酬賞物，屬於較困難的學習階段。實驗二，在測驗當天直接於雙側的眼眶前額葉注射 ATX (0.1 μg/0.5 μl/side)，以確認眼眶前額葉是否為 ATX 改善 SHR 在注意力轉換作業上表現的關鍵腦區。實驗三，在測驗當天腹腔注射 ATX(0.3 mg/kg) 30 分鐘之後，分別於雙側的眼眶前額葉注射多巴胺 D2 受器選擇性拮抗劑 haloperidol (0.5 μg/0,4μl/side)，以檢驗多巴胺 D2 拮抗劑能否阻斷 ATX 的治療效果。結果發現，周邊給予 ATX 能夠有效改善 SHR 在注意力轉換作業中反向學習的表現；而眼眶前額葉是 ATX 作用的關鍵腦區；此外，即使阻斷眼眶前額葉的多巴胺 D2 受器的作用也無法影響 ATX 的治療效果。因此，本研究推測眼眶前額葉是 ATX 改善SHR 在注意力轉換作業上反向學習的表現，並非透過眼眶前額葉的多巴胺 D2 受器作用所致。

關鍵字

思鋭 ； 抑制功能 ； 青少年 ； 注意力缺陷過動症 ； 利他能

並列摘要

Attention-deficit hyperactivity disorder (ADHD) is a clinically heterogeneous disorder. The symptoms include inattention, hyperactivity and impulsivity. Atomoxetine (ATX) is a selective norepinephrine reuptake inhibitor which served as a non-psychostimulant drug for the treatment for ADHD. Previous studies found that ATX increases not only norepinephrine levels but also dopamine levels in prefrontal cortex. The effect of ATX on the dopamine system is similar to methylphenidate, the first-line treatment for ADHD. However, the neural mechanism of ATX treatment of ADHD is still unclear. In experiment 1, we examined the effect of systemic ATX on juvenile SHR and Wistar control in attentional set-shifting task. During reversal learning phase, rats received reinforcements only if they successfully inhibited impulsive responses and learned reversed rules. In experiment 2, we further investigated the effect of central ATX (0.1 μg/0.5 μl/side) in the orbitofrontal cortex (OFC) on juvenile SHR. In order to examine whether the behavior improvement of ATX is indirectly through the dopamine D2 receptors, we applied intra-OFC infusion of haloperidol (0.5 μg/0.4 μl/side) in experiment 3. The results showed that ATX injection through intraperitoneal as well as intra-OFC can remove the reversal learning deficits of SHR. Central infusion of haloperidol in OFC failed to abolish the beneficial effects of ATX. We suggested that the OFC dopamine system might not be involved in the treatment effects of ATX on ADHD.

並列關鍵字

Strattera ； Inhibitory function ； Adolescent ； SHR ； ADHD ； Ritalin

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