Behavioural and Clinical Neuroscience Institute and Department of Experimental Psychology, University of Cambridge, Downing St, Cambridge, CB2 3EB, UK.
Psychopharmacology (Berl). 2012 Jan;219(2):341-52. doi: 10.1007/s00213-011-2408-z. Epub 2011 Jul 15.
Impulsivity is associated with a number of psychiatric disorders, most notably attention deficit/hyperactivity disorder (ADHD). Drugs that augment catecholamine function (e.g. methylphenidate and the selective noradrenaline reuptake inhibitor atomoxetine) have clinical efficacy in ADHD, but their precise mechanism of action is unclear.
The objective of this study is to investigate the relative contribution of dopamine (DA) and noradrenaline (NA) to the therapeutic effects of clinically effective drugs in ADHD using rats selected for high impulsivity on the five-choice serial reaction time task (5CSRTT).
We examined the effects of direct and indirect DA and NA receptor agonists and selective DA and NA reuptake inhibitors in rats showing high and low levels of impulsivity on the 5CSRTT (designated high impulsive 'HI' and low impulsive 'LI', respectively). Drugs were administered by systemic injection in a randomized, counterbalanced manner.
Low doses of quinpirole (a D2/D3 agonist) and sumanirole (a D2 agonist) selectively reduced impulsivity on the 5CSRTT, whilst higher doses resulted in increased omissions and slower response latencies. The NA reuptake inhibitor, atomoxetine, and the alpha-2 adrenoreceptor agonist, guanfacine, dose dependently decreased premature responding. The dopaminergic reuptake inhibitor GBR-12909 increased impulsivity, whereas the nonselective DA and NA reuptake inhibitor methylphenidate had no significant effect on impulsive responses in HI and LI rats.
These findings indicate that high impulsivity can be ameliorated in rats by drugs that mimic the effects of DA and NA, just as in ADHD, and that activation of D2/3 receptors selectively decreases high impulsivity on the 5CSRTT.
冲动与许多精神疾病有关，尤其是注意力缺陷多动障碍（ADHD）。增强儿茶酚胺功能的药物（例如哌甲酯和选择性去甲肾上腺素再摄取抑制剂托莫西汀）在 ADHD 中具有临床疗效，但它们的确切作用机制尚不清楚。
本研究的目的是使用在 5 选择连续反应时间任务（5CSRTT）中选择高冲动的大鼠，研究多巴胺（DA）和去甲肾上腺素（NA）对 ADHD 中临床有效药物治疗效果的相对贡献。
我们检查了直接和间接的 DA 和 NA 受体激动剂以及选择性的 DA 和 NA 再摄取抑制剂在 5CSRTT 中表现出高和低冲动的大鼠中的作用（分别指定为高冲动“HI”和低冲动“LI”）。药物以随机、平衡的方式通过系统注射给药。
低剂量的喹吡罗（D2/D3 激动剂）和舒马尼洛（D2 激动剂）选择性地降低了 5CSRTT 上的冲动，而较高剂量则导致更多的遗漏和较慢的反应潜伏期。去甲肾上腺素再摄取抑制剂托莫西汀和α-2 肾上腺素能受体激动剂胍法辛剂量依赖性地减少过早反应。多巴胺再摄取抑制剂 GBR-12909增加了冲动，而非选择性 DA 和 NA 再摄取抑制剂哌甲酯对 HI 和 LI 大鼠的冲动反应没有明显影响。
这些发现表明，在大鼠中，通过模拟 DA 和 NA 作用的药物可以改善高冲动，就像在 ADHD 中一样，并且 D2/3 受体的激活选择性地降低了 5CSRTT 上的高冲动。
