Institute of Neuroscience, School of Biomedical Sciences, Medical School, Queens Medical Centre, University of Nottingham, Nottingham NG7 2UH, UK.
Neuropharmacology. 2009 Dec;57(7-8):678-86. doi: 10.1016/j.neuropharm.2009.08.006. Epub 2009 Aug 21.
Attention deficit hyperactivity disorder (ADHD) is a common neuropsychiatric disorder characterised by excessive levels of hyperactivity, inattentiveness and impulsivity. Stimulant drugs which increase dopamine neurotransmission are treatments for ADHD. Hypodopaminergic fronto-striatal function with associated overactivity of the dopamine transporter (DAT) represents one possible neurobiological mechanism underlying ADHD. Few, if any, of the existing animal models of ADHD mimic the underlying neurobiology of the disorder. In this study we have further characterised the behavioural profile of a model of a hyperactive inattentive animal through manipulation of the DAT. The behavioural effects of acute treatment and following withdrawal from sub-chronic treatment with GBR 12909 (30 mg/kg i.p.), a potent and highly selective DAT inhibitor, were examined in juvenile rats. GBR 12909 treatment was used to produce a compensatory up regulation following withdrawal. Acute treatment with GBR 12909 (30 mg/kg i.p.) resulted in a marked increase in locomotor and rearing behaviours on the first and fourth days during a 4 consecutive bi-daily drug treatment regime in postnatal weaned rats. Adolescent rats after 10, 20 and 30 days withdrawal from GBR 12909 pre-treatment maintained mild increases in locomotor activity and failed to discriminate a familiar over a novel object in the novel object discrimination task (using both 1 min and 3 h inter-trial intervals) indicating impaired learning and memory. Prepulse inhibition of acoustic startle was unaltered following withdrawal from GBR 12909 treatment. These data reinforce the potential role of the DAT in the underlying neurobiology of ADHD. They also add further evidence to suggest that postnatal changes in the DAT following withdrawal from treatment with the DAT inhibitor, GBR 12909, may prove to be a useful animal model of ADHD with potential for examining the effectiveness of novel ADHD treatments.
注意缺陷多动障碍（ADHD）是一种常见的神经精神疾病，其特征是过度活跃、注意力不集中和冲动。增加多巴胺神经传递的兴奋剂药物是治疗 ADHD 的方法。多巴胺转运体（DAT）过度活跃的低多巴胺能额纹状体功能代表了 ADHD 潜在的神经生物学机制之一。如果有的话，现有的 ADHD 动物模型中很少有能够模拟该疾病的潜在神经生物学。在这项研究中，我们通过操纵 DAT 进一步描述了一种多动注意力不集中动物模型的行为特征。在幼年大鼠中，检查了急性治疗和亚慢性治疗（30mg/kg ip）后 DAT 抑制剂 GBR 12909 撤药后的行为效应。使用 GBR 12909 治疗以产生撤药后的代偿性上调。急性给予 GBR 12909（30mg/kg ip）可导致新生断奶大鼠连续四天每天两次药物治疗期间的第一天和第四天的运动和站立行为明显增加。从 GBR 12909 预处理中撤药 10、20 和 30 天后的青少年大鼠，在新物体辨别任务（使用 1 分钟和 3 小时的试验间隔）中保持轻微增加的运动活性，并且未能辨别熟悉的物体与新颖的物体，表明学习和记忆受损。从 GBR 12909 治疗撤药后，听觉起始惊跳的前脉冲抑制不变。这些数据强化了 DAT 在 ADHD 潜在神经生物学中的作用。它们还进一步表明，从 DAT 抑制剂 GBR 12909 治疗撤药后 DAT 的出生后变化可能成为 ADHD 的有用动物模型，并有可能检查新型 ADHD 治疗方法的有效性。
