Can a therapeutic dose of amphetamine during pre-adolescence modify the pattern of synaptic organization in the brain?
Can a therapeutic dose of amphetamine during pre-adolescence modify the pattern of synaptic organization in the brain?
复制标题
DOI：
10.1046/j.1460-9568.2003.03067.x
复制
发表时间：
2003-12-01
影响因子：
3.4
通讯作者：
Forssberg, H
中科院分区：
文献类型：
--
作者：
Heijtz, RD;Kolb, B;Forssberg, H
安非他明等兴奋剂几十年来一直是治疗注意力缺陷/多动障碍儿童的首选药物。然而，对其治疗机制或长期暴露的后果知之甚少。在本研究中，我们调查是否重复暴露的低剂量的安非他明（0.5毫克/公斤）的幼年大鼠可以诱导长期的前额叶皮层的形态学改变。此外，为了评估长期暴露于这种药物可能的行为后果，我们检查了这种治疗后对各种多巴胺受体激动剂的运动反应是否发生变化。我们发现，这一剂量的安非他明促进硫酸安非他明在幼年大鼠的血浆浓度的水平对应于用于儿童注意力缺陷/多动症的临床范围。安非他明（0.5 mg/kg; s.c.）在出生后第22-34天每天给药两次，然后在2周后评价动物的脑。这种治疗产生的树突长度和分支的锥体神经元的内侧前额叶皮层的增加，但不是在神经核。这些变化与钙/钙调素依赖性蛋白激酶II的表达增加有关，这是一种在兴奋性突触的突触后密度中高度丰富的信号蛋白。有趣的是，安非他明预处理并没有改变运动反应的各种多巴胺激动剂，包括安非他明。这些数据表明，临床剂量的兴奋剂药物可能是作为一个营养支持在多巴胺能突触，从而增强多巴胺-谷氨酸在前额叶皮层的相互作用。
Stimulant drugs such as amphetamine have, for many decades, been the drugs of choice in the treatment of children with attention-deficit/hyperactivity disorder. However, little is known about their therapeutic mechanisms or about the consequences of their long-term exposure. In the present study we investigated whether repeated exposure of a low dose of amphetamine (0.5 mg/kg) to juvenile rats could induce long-term morphological alterations in the prefrontal cortex. In addition, to assess possible behavioural consequences of prolonged exposure to this drug, we examined whether changes in the motor response to various dopamine agonists occurred after this treatment. We found that this dose of amphetamine promotes plasma concentrations of amphetamine sulphate in juvenile rats to levels corresponding to the clinical range used for children with attention-deficit/hyperactivity disorder. Amphetamine (0.5 mg/kg; s.c.) was administered twice daily during postnatal days 22-34, and then the brains of the animals were evaluated 2 weeks later. This treatment produced an increase in dendritic length and branches of pyramidal neurons of the medial prefrontal cortex, but not in the nucleus accumbens. These changes were associated with an increase in the expression of calcium/calmodulin-dependent protein kinase II, a highly abundant signalling protein in the postsynaptic densities of excitatory synapses. Interestingly, amphetamine pre-treatment did not alter the motor response to various dopamine agonists, including amphetamine. These data suggest that clinical doses of stimulant drugs may be acting as a trophic support at the glutamatergic synapses, thereby enhancing dopamine-glutamate interactions in the prefrontal cortex.