Changes in the second messenger cyclic AMP during development may underlie motoric symptoms in attention deficit/hyperactivity disorder (ADHD)
Changes in the second messenger cyclic AMP during development may underlie motoric symptoms in attention deficit/hyperactivity disorder (ADHD)
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DOI：
10.1016/s0166-4328(01)00417-x
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发表时间：
2002-03-10
影响因子：
2.7
通讯作者：
Andersen, SL
中科院分区：
文献类型：
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作者：
Andersen, SL
在儿童期和成年期之间，多巴胺上升系统发生的转变与注意力缺陷多动障碍（ADHD）症状的出现、过程和严重程度平行。在行为上，大鼠在青春期前在开阔场地更活跃，成年雄性的活动水平下降了50%。这种行为高峰与青春期大鼠纹状体（STR）和前额叶皮层（PFC）中D1和D2多巴胺受体的短暂过度产生平行，随后受体密度下降到成年期。虽然很容易推测受体密度在ADHD症状的减弱中起作用，但在延髓核（NA）中不发生受体过度产生，这表明受体密度仅适度增加（10-20%）。考虑到神经元在自发活动中的重要性，研究人员寻找了活动增加的另一种解释。第二信使系统环磷酸腺苷（CAMP）已经经典地与多巴胺受体相关。这些研究的结果表明，CAMP在大鼠海马和STR中的蓄积与观察到的活性水平的上升和下降平行。在青春期，基础CAMP水平是35%以上，相对于成年期的男性adulbens，而一个温和的7%的变化，观察到STR。毛喉素刺激的CAMP是240 - 300%，在青春期的STR和adulbens之前，随着成熟而下降。这些发现表明，青少年多巴胺系统相对于成年人具有更高的“音调”，然而，CAMP对D1或D2刺激的药理学反应性在青春期相对于成年期表现出整体迟钝的反应。这一发现与处于高多巴胺能状态的动物在青春期对压力和药物的敏感性降低一致。这些发现结合CAMP积累升高和CAMP敏感性降低在青春期ADHD及其治疗的假设机制和过程中的临床意义。CAMP活性的成熟性下降可以解释为什么这种疾病消退，同时CAMP在成年期对D1和D2受体刺激的反应性更强。(C)2002 Elsevier Science B. V.保留所有权利。
The transitions that occur in the ascending dopamine systems between childhood and adulthood parallel the emergence, course, and severity of attention-deficit hyperactivity disorder (ADHD) symptoms. Behaviorally, rats are more active in open field during periadolescence, and activity levels decline by 50% in males by adulthood. This peak in behavior parallels a transient overproduction in D1 and D2 dopamine receptors that occurs at puberty in rat striatum (STR) and prefrontal cortex (PFC), followed by a decline in receptor density into adulthood. While tempting to speculate that receptor density plays a role in the waning of ADHD symptoms, receptor overproduction does not occur in the nucleus accumbens (NA), which demonstrates only a modest rise in receptor density (10-20%). Given the importance of the accumbens in locomotor activity, an alternative explanation for increased activity was sought. The second messenger system cyclic adenosine monophosphate (CAMP) has classically been associated with dopamine receptors. The results of these studies demonstrate that CAMP accumulation in the accumbens and the STR parallel the observed rise and fall in activity levels in rats. At puberty, basal CAMP levels are 35% higher relative to adulthood in male accumbens, while a modest 7% change was observed in STR. Forskolin-stimulated CAMP was 240 300% higher in STR and accumbens at puberty before declining with maturation. These findings suggest that, the adolescent dopamine system has a much higher 'tone' relative to adults, However, pharmacological responsiveness of CAMP to D1 or D2 stimulation demonstrates an overall blunted response during puberty relative to adulthood. This finding is consistent with a hyposensitivity to stress and pharmacological agents at puberty in animals that are in a hyperdopaminergic state. These findings of combined elevated CAMP accumulation and reduced CAMP sensitivity during adolescence have clinical implications for hypothesized mechanism and course of ADHD and its treatment. The maturational decline in CAMP activity may explain why this disorder recedes, while, simultaneously CAMP becomes more responsive to D1 and D2 receptor stimulation in adulthood. (C) 2002 Elsevier Science B.V. All rights reserved.